2. Clin Chem Lab Med. 2010 Feb 12. [Epub ahead of print]
Association of hyperhomocysteinemia with left ventricular dilatation and mass in
human heart.
Alter P, Rupp H, Rominger MB, Figiel JH, Renz H, Klose KJ, Maisch B.
Internal Medicine - Cardiology, Philipps University, Marburg, Germany.
Abstract Background: Hyperhomocysteinemia is a risk factor for ischemic heart
disease. Several other mechanisms apply also to dilative types of heart failure
of various, non-ischemic etiologies. We hypothesized that hyperhomocysteinemia is
associated with left ventricular (LV) dilatation and hypertrophy in dilative
cardiomyopathy. Methods: Homocysteine was measured in 66 individuals with
suspected cardiomyopathy. Cardiac magnetic resonance imaging was used to assess
LV volume, mass, and wall stress. Results: Hyperhomocysteinemia (>12 mumol/L) was
found in 45 patients (68%). LV mass was greater in these patients compared with
individuals with normal homocysteine (83+/-27 vs. 67+/-19 g/m(2); p<0.02).
Homocysteine was increased in patients with increased brain natriuretic peptide
>/=100 pg/mL (18.3+/-5.9 vs. 14.9+/-5.1 mumol/L; p=0.018). LV mass, LV
end-diastolic and end-systolic volume (LVEDV, LVESV) were significantly increased
in individuals in the upper quartile compared with the lower quartile (90+/-25
vs. 65+/-18 g/m(2), p=0.021; 114+/-50 vs. 71+/-23 mL/m(2), p=0.042; 76+/-51 vs.
36+/-22 mL/m(2), p=0.045). LV dilatation (LVEDV>/=90 mL/m(2)) was more common in
hyperhomocysteinemia (>12 mumol/L, p=0.0166). Normalized LV mass was correlated
with homocysteine (r=0.346, p=0.065). Homocysteine was not significantly
correlated with LVEDV (r=0.229, p=0.065), LV end-diastolic wall stress (r=0.226,
p=0.069) and LV ejection fraction. Conclusions: Hyperhomocysteinemia appears to
be, at least in part, involved in a disproportional LV dilatation, where the
ensuing hypertrophy is not sufficient to compensate for the increased wall
stress. A potential mechanism is the hyper-homocysteinemia associated increase in
oxidative stress that favors muscle fiber slippage. Clin Chem Lab Med 2010;48.
PMID: 20148720 [PubMed - as supplied by publisher]
5. Eur Heart J. 2009 Dec;30(23):2948-9; author reply 2949. Epub 2009 Nov 3.
Occurrence of late gadolinium enhancement in ventricular ballooning or Tako-Tsubo
syndrome: increased wall stress should not be overlooked.
Alter P, Rupp H.
Comment on:
Eur Heart J. 2009 Jul;30(13):1635-42.
PMID: 19889650 [PubMed - in process]
7. Heart. 2009 Aug 31. [Epub ahead of print]
Inverse shift in serum polyunsaturated and monounsaturated fatty acids is
associated with adverse dilatation of the heart.
Rupp H, Rupp TP, Alter P, Maisch B.
Cardiology, Germany.
BACKGROUND: Cardiac dilatation is associated with impaired pump function,
progression of heart failure and electrical instability. Risk of sudden death is
associated with a low blood level of n-3 polyunsaturated fatty acids. OBJECTIVE:
The hypothesis was, therefore, addressed that left ventricular dilatation as
assessed by echocardiography is associated with a reduced serum polyunsaturated
fatty acid level. METHODS: Fatty acids were determined with gas
chromatography/mass spectrometry in serum of 308 patients with dilative heart
failure unrelated to myocardial infarction (Age 48+/-12 years, NYHA class
2.2+/-0.6, ejection fraction 31+/-10%). RESULTS: The extent of left ventricular
dilatation as assessed by left ventricular enddiastolic diameter was associated
with a reduction of both n-3 and n-6 polyunsaturated fatty acids. The n-3
docosahexaenoic acid (1.0+/-0.5% vs. 1.3+/-0.6%, P<0.001) and the n-6 arachidonic
acid (4.6+/-1.8% vs. 5.2+/-1.9%, P<0.01) were reduced in patients with left
ventricular dilatation (enddiastolic diameter, 68-90 mm, upper tertile vs. 48-61
mm, lower tertile). By contrast, monounsaturated fatty acids were increased (the
n-9 oleic acid 26.1+/-4.8% vs. 23.9+/-4.8%, P<0.01). A low docosahexaenoic acid
(0.01-0.9%, lower tertile vs. 1.4-3.1%, upper tertile) was associated with
greater left ventricular dilatation (enddiastolic diameter, 67+/-8 vs. 63+/-7 mm,
P<0.001). The cut-off for the absence of severe dilatation (enddiastolic diameter
>70 mm) was set at >1.24% docosahexaenoic acid. In our sample, the negative
predictive value for severe dilatation was 91% and sensitivity was 84%.
CONCLUSIONS: Docosahexaenoic acid provides a new sensitive biomarker for
monitoring and detecting severe left ventricular dilatation in heart failure
patients.
PMID: 19723686 [PubMed - as supplied by publisher]
8. Adv Ther. 2009 Jul;26(7):675-90. Epub 2009 Jul 27.
Omacor (prescription omega-3-acid ethyl esters 90): From severe rhythm disorders
to hypertriglyceridemia.
Rupp H.
Experimental Cardiology Laboratory, Heart Center, Department of Internal Medicine
and Cardiology, Philipps University of Marburg, 35043 Marburg, Germany.
Rupp@staff.uni-marburg.de
Despite progress made in post-myocardial infarction (MI) revascularization and
background therapy for the failing heart, the prevention of adverse cardiac
remodeling associated with severe rhythm disorders remains an important drug
target. Part of the remodeling can be counteracted by modulating the activity of
ion channels and exchangers by omega-3 acids eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA). In the GISSI-Prevenzione and GISSI-HF trials, omega-3
fatty acids were administered as ethyl esters (Omacor Solvay Pharmaceuticals) and
not as triglycerides present in fish oil. Ethyl esters result in a sustained
intestinal absorption of EPA and DHA and require various purification steps
during production, thereby minimizing the content of environmental toxins. Also
the rather high (38%) DHA content of Omacor should not be ignored since in rats
with low dose intake of omega-3 acids, DHA but not EPA inhibited ischemia-induced
arrhythmias. In patients on multiple tablets, 840 mg EPA+DHA in one capsule is
preferred to increase compliance. It is not justified to refer to Omacor as "n-3
polyunsaturated fatty acid supplementation" or even "fish oil" and, based on
controlled clinical trials, there is no evidence that fish oil could be a
substitute of Omacor. To avoid further confusion, guidelines should be precise
and refer to the medication, eg, as in NICE guideline CG48: "Omega-3-acid ethyl
esters treatment licensed for secondary prevention post-MI." The
anti-arrhythmogenic action of Omacor should be seen in the context of implantable
cardioverter-defibrillator trials (DINAMIT, IRIS) where non-sudden death was
increased and total mortality unaltered. However, Omacor administered in the
GISSI-HF trial reduced the incidence of severe arrhythmic events and mortality.
Also in the GISSI-Prevenzione trial, arrhythmic death and mortality were reduced.
At higher dosages (daily, 3-4 g) Omacor exhibits more pronounced cardiovascular
benefits and, as a licensed indication, improves hypertriglyceridemia and related
lipid parameters.
PMID: 19629408 [PubMed - indexed for MEDLINE]
10. Pacing Clin Electrophysiol. 2009 Mar;32 Suppl 1:S26-31.
Depression of heart rate variability in patients with increased ventricular wall
stress.
Alter P, Rupp H, Rominger MB, Czerny F, Vollrath A, Klose KJ, Maisch B.
Department of Internal Medicine - Cardiology, Philipps University, Marburg,
Gremany. alter@staff.uni-marburg.de
BACKGROUND: Heart failure is characterized by neurohumoral dysfunction that can
be assessed by measurement of heart rate variability (HRV). Depression of HRV is
related to several hemodynamic parameters. We hypothesized that an increased left
ventricular (LV) wall stress is related to a depressed HRV in patients with LV
dilatation or dysfunction. METHODS: Cardiac function and mass were measured in 31
patients with LV dilatation or dysfunction and 21 controls using cardiac magnetic
resonance (CMR) imaging. LV wall stress was calculated using a CMR-based
thick-walled sphere model. Standard deviation of normal-to-normal (NN) intervals
(SDNN) and average NN intervals over 5 minutes (SDANN-i) were calculated.
RESULTS: LV end-diastolic (ED) and end-systolic (ES) wall stress were
significantly increased in patients with SDNN < 75 ms (P < 0.05). SDNN and
SDANN-i were decreased (P = 0.001, P < 0.001) in patients with LVED wall stress
>8 kPa and LVES wall stress >30 kPa (P < 0.05). To examine potential effects of
LVEF, LVED and LVES volume, and wall stress on HRV, a multiple linear regression
analysis was performed, which revealed LVED wall stress as the only independent
parameter influencing SDNN (P = 0.039). LV ejection fraction, LV mass, and
volumes were not significantly related to HRV. CONCLUSIONS: LV wall stress was
independently related with depression of HRV. Therefore, LV wall stress might be
prognostically important and a therapeutic target in heart failure.
PMID: 19250107 [PubMed - indexed for MEDLINE]
11. Lancet. 2009 Jan 31;373(9661):378-9; author reply 380-1.
N-3 polyunsaturated fatty acids and statins in heart failure.
Rupp H, Rupp TP, Alter P, Maisch B.
Comment on:
Lancet. 2008 Oct 4;372(9645):1223-30.
PMID: 19186263 [PubMed - indexed for MEDLINE]
13. Int J Cardiol. 2008 Oct 24. [Epub ahead of print]
A new method to assess ventricular wall stress in patients with heart failure and
its relation to heart rate variability.
Alter P, Rupp H, Rominger MB, Czerny F, Vollrath A, Klose KJ, Maisch B.
Philipps University Internal Medicine - Cardiology.
INTRODUCTION: Heart failure is characterized by an increase in cardiac load, wall
stress and autonomic dysfunction. The neurohumoral imbalance arising from
adrenergic activation and parasympathetic withdrawal is associated with worse
prognosis. We addressed the hypothesis that an increased left ventricular (LV)
wall stress as assessed by cardiac magnetic resonance imaging (CMR) in patients
with heart failure is related to a depression of heart rate variability (HRV).
METHODS: Cardiac function and mass were measured in 37 individuals with suspected
cardiomyopathy using CMR imaging. A thick-walled sphere model was used to
calculate ventricular wall stress. Time domain analysis of HRV was obtained by
long-term Holter ECG. RESULTS: Standard deviation of both normal-to-normal (NN)
intervals (SDNN) and average NN intervals over 5 minutes (SDANN-i) were
negatively correlated with LV enddiastolic wall stress (r = 0.42, P < 0.01). SDNN
and SDANN-i were severely decreased (P < 0.01) in patients with increased
enddiastolic LV wall stress > 12 kPa (vs. normal range: < 4 kPa). CONCLUSION: A
relation between increased cardiac wall stress and depressed heart rate
variability was observed in patients with heart failure. CMR-based measurement of
LV volume and mass is appropriate to calculate LV wall stress which should be
considered not only as a potential prognostic determinant but also as therapeutic
target.
PMID: 18952305 [PubMed - as supplied by publisher]
14. Cardiovasc Hematol Agents Med Chem. 2008 Oct;6(4):253-7.
Clinical profile of eprosartan: a different angiotensin II receptor blocker.
Blankestijn PJ, Rupp H.
Department of Nephrology, University Medical Center, Utrecht, The Netherlands.
p.j.blankestijn@umcutrecht.nl
Rationale. The goal of antihypertensive treatment is to reduce risk of
cardiovascular morbidity and mortality. Apart from blood pressure lowering per
se, also reducing the activities of the renin-angiotensin system and sympathetic
nervous system appears to be important. Angiotensin II receptor blocker drugs
(ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a
relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole)
from all other ARBs (biphenyl tetrazoles). An analysis has been made on available
experimental and clinical data on eprosartan which not only is an effective and
well tolerated antihypertensive agent, but also lowers the activities of the
renin-angiotensin system and sympathetic nervous system. Experimental and
pharmacokinetic studies on eprosartan have shown differences with the other ARBs.
The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant
in the effort to reduce cardiovascular risk, also beyond its blood pressure
lowering capacity.
PMCID: PMC2748700
PMID: 18855637 [PubMed - indexed for MEDLINE]
16. Eur Heart J. 2008 Sep;29(18):2316. Epub 2008 Jul 10.
Assessment and relevance of ventricular wall stress in heart failure.
Alter P, Rupp H, Maisch B.
Comment on:
Eur Heart J. 2008 Mar;29(6):741-7.
PMID: 18621773 [PubMed - indexed for MEDLINE]
17. Mol Cell Biochem. 2008 Jul;314(1-2):179-91. Epub 2008 May 7.
B-type natriuretic peptide and wall stress in dilated human heart.
Alter P, Rupp H, Rominger MB, Vollrath A, Czerny F, Figiel JH, Adams P, Stoll F,
Klose KJ, Maisch B.
Internal Medicine, Cardiology, Philipps University, Baldingerstrasse, Marburg,
Germany. alter@staff.uni-marburg.de
Background Although B-type natriuretic peptide (BNP) is used as complimentary
diagnostic tool in patients with unknown thoracic disorders, many other factors
appear to trigger its release. In particular, it remains unresolved to what
extent cellular stretch or wall stress of the whole heart contributes to enhanced
serum BNP concentration. Wall stress cannot be determined directly, but has to be
calculated from wall volume, cavity volume and intraventricular pressure of the
heart. The hypothesis was, therefore, addressed that wall stress as determined by
cardiac magnetic resonance imaging (CMR) is the major determinant of serum BNP in
patients with a varying degree of left ventricular dilatation or dysfunction
(LVD). Methods A thick-walled sphere model based on volumetric analysis of the LV
using CMR was compared with an echocardiography-based approach to calculate LV
wall stress in 39 patients with LVD and 21 controls. Serum BNP was used as in
vivo marker of a putatively raised wall stress. Nomograms of isostress lines were
established to assess the extent of load reduction that is necessary to restore
normal wall stress and related biochemical events. Results Both enddiastolic and
endsystolic LV wall stress were correlated with the enddiastolic LV volume (r =
0.54, P < 0.001; r = 0.81, P < 0.001). LV enddiastolic wall stress was related to
pulmonary pressure (capillary: r = 0.69, P < 0.001; artery: r = 0.67, P < 0.001).
Although LV growth was correlated with the enddiastolic and endsystolic volume (r
= 0.73, P < 0.001; r = 0.70, P < 0.001), patients with LVD exhibited increased LV
wall stress indicating an inadequately enhanced LV growth. Both enddiastolic (P <
0.05) and endsystolic (P < 0.01) wall stress were increased in patients with
increased BNP. In turn, BNP concentration was elevated in individuals with
increased enddiastolic wall stress (>8 kPa: 587 +/- 648 pg/ml, P < 0.05; >12 kPa:
715 +/- 661 pg/ml, P < 0.001; normal < or =4 kPa: 124 +/- 203 pg/ml). Analysis of
variance revealed LV enddiastolic wall stress as the only independent hemodynamic
parameter influencing BNP (P < 0.01). Using nomograms with "isostress" curves,
the extent of load reduction required for restoring normal LV wall stress was
assessed. Compared with the CMR-based volumetric analysis for wall stress
calculation, the echocardiography based approach underestimated LV wall stress
particularly of dilated hearts. Conclusions In patients with LVD, serum BNP was
increased over the whole range of stress values which were the only hemodynamic
predictors. Cellular stretch appears to be a major trigger for BNP release.
Biochemical mechanisms need to be explored which appear to operate over this wide
range of wall stress values. It is concluded that the diagnostic use of BNP
should primarily be directed to assess ventricular wall stress rather than the
extent of functional ventricular impairment in LVD.
PMID: 18461428 [PubMed - indexed for MEDLINE]
18. Curr Med Res Opin. 2007 Nov;23 Suppl 5:S25-9.
Risk reduction by preventing stroke: need for blockade of angiotensin II and
catecholamines?
Rupp H.
Heart Center, Department of Internal Medicine and Cardiology, Philipps University
of Marburg, Germany. rupp@staff.uni-marburg.de
Angiotensin (AT) II and noradrenaline play major roles in hypertension, stroke
and coronary heart disease, which are themselves interlinked. Harmful effects of
AT II are not blocked solely by angiotensin-converting enzyme inhibitors, as it
is now evident that AT II is generated by other enzymes such as chymase.
Angiotensin II also stimulates noradrenaline release modulated by presynaptic
receptors on sympathetic nerves. Numerous studies have defined the action of the
AT II type 1 receptor blocker (ARB) eprosartan as controlling noradrenergic and
adrenergic effects, resulting from actions on the renin-angiotensin-aldosterone
system and the sympathetic nervous system. Clinical studies have been carried out
to assess the effects of ARBs on morbidity and mortality. The Valsartan
Antihypertensive Long-term Use Evaluation (VALUE) trial compared the effects of
valsartan and the calcium channel blocker (CCB) amlodipine in over 15,000
patients at high risk of a cardiac event. Results showed that blood pressure was
reduced by both treatments and cardiac mortality/morbidity was similar in both
groups. By contrast, the Morbidity and mortality after Stroke, Eprosartan
compared with nitrendipine for Secondary prevention (MOSES) study (n = 1405)
generated results which differed from the VALUE study, in that blood pressure was
reduced by both eprosartan and nitrendipine, but eprosartan reduced all
cardiovascular and cerebrovascular events to a greater extent than nitrendipine.
It is also possible that any delayed clinical benefit of eprosartan could be due
to reverse cardiac remodelling. Eprosartan, by blocking AT II receptors, reducing
noradrenaline release and blocking catecholamine actions, may, therefore, provide
greater protection against vascular events than CCBs or other ARBs.
PMID: 18093411 [PubMed - indexed for MEDLINE]
20. Can J Physiol Pharmacol. 2007 Aug;85(8):790-9.
Relation of B-type natriuretic peptide to left ventricular wall stress as
assessed by cardiac magnetic resonance imaging in patients with dilated
cardiomyopathy.
Alter P, Rupp H, Rominger MB, Vollrath A, Czerny F, Klose KJ, Maisch B.
Philipps University, Internal Medicine - Cardiology, Baldingerstrasse, D-35033
Marburg, Germany. alter@staff.uni-marburg.de
Ventricular loading conditions are crucial determinants of cardiac function and
prognosis in heart failure. B-type natriuretic peptide (BNP) is mainly stored in
the ventricular myocardium and is released in response to an increased
ventricular filling pressure. We examined, therefore, the hypothesis that BNP
serum concentrations are related to ventricular wall stress. Cardiac magnetic
resonance imaging (MRI) was used to assess left ventricular (LV) mass and cardiac
function of 29 patients with dilated cardiomyopathy and 5 controls. Left
ventricular wall stress was calculated by using a thick-walled sphere model, and
BNP was assessed by immunoassay. LV mass (r = 0.73, p < 0.001) and both LV
end-diastolic (r = 0.54, p = 0.001) and end-systolic wall stress (r = 0.66, p <
0.001) were positively correlated with end-diastolic volume. LV end-systolic wall
stress was negatively related to LV ejection fraction (EF), whereas end-diastolic
wall stress was not related to LVEF. BNP concentration correlated positively with
LV end-diastolic wall stress (r = 0.50, p = 0.002). Analysis of variance revealed
LV end-diastolic wall stress as the only independent hemodynamic parameter
influencing BNP (p < 0.001). The present approach using a thick-walled sphere
model permits determination of mechanical wall stress in a clinical routine
setting using standard cardiac MRI protocols. A correlation of BNP concentration
with calculated LV stress was observed in vivo. Measurement of BNP seems to be
sufficient to assess cardiac loading conditions. Other relations of BNP with
various hemodynamic parameters (e.g., EF) appear to be secondary. Since an
increased wall stress is associated with cardiac dilatation, early diagnosis and
treatment could potentially prevent worsening of the outcome.
PMID: 17901889 [PubMed - indexed for MEDLINE]
22. Pflugers Arch. 2008 Jan;455(4):627-36. Epub 2007 Aug 25.
A new methodological approach to assess cardiac work by pressure-volume and
stress-length relations in patients with aortic valve stenosis and dilated
cardiomyopathy.
Alter P, Rupp H, Rominger MB, Klose KJ, Maisch B.
Internal Medicine--Cardiology, Philipps University, Baldingerstrasse, 35033
Marburg, Germany. alter@staff.uni-marburg.de
In experimental animals, cardiac work is derived from pressure-volume area and
analyzed further using stress-length relations. Lack of methods for determining
accurately myocardial mass has until now prevented the use of stress-length
relations in patients. We hypothesized, therefore, that not only pressure-volume
loops but also stress-length diagrams can be derived from cardiac volume and
cardiac mass as assessed by cardiac magnetic resonance imaging (CMR) and
invasively measured pressure. Left ventricular (LV) volume and myocardial mass
were assessed in seven patients with aortic valve stenosis (AS), eight with
dilated cardiomyopathy (DCM), and eight controls using electrocardiogram
(ECG)-gated CMR. LV pressure was measured invasively. Pressure-volume curves were
calculated based on ECG triggering. Stroke work was assessed as area within the
pressure-volume loop. LV wall stress was calculated using a thick-wall sphere
model. Similarly, stress-length loops were calculated to quantify
stress-length-based work. Taking the LV geometry into account, the normalization
with regard to ventricular circumference resulted in "myocardial work." Patients
with AS (valve area 0.73+/-0.18 cm(2)) exhibited an increased LV myocardial mass
when compared with controls (P<0.05). LV wall stress was increased in DCM but not
in AS. Stroke work of AS was unchanged when compared with controls (0.539+/-0.272
vs 0.621+/-0.138 Nm, not significant), whereas DCM exhibited a significant
depression (0.367+/-0.157 Nm, P<0.05). Myocardial work was significantly reduced
in both AS and DCM when compared with controls (129.8+/-69.6, 200.6+/-80.1,
332.2+/-89.6 Nm/m(2), P<0.05), also after normalization (7.40+/-5.07,
6.27+/-3.20, 14.6+/-4.07 Nm/m(2), P<0.001). It is feasible to obtain LV
pressure-volume and stress-length diagrams in patients based on the present novel
methodological approach of using CMR and invasive pressure measurement.
Myocardial work was reduced in patients with DCM and noteworthy also in AS, while
stroke work was reduced in DCM only. Most likely, deterioration of myocardial
work is crucial for the prognosis. It is suggested to include these basic
physiological procedures in the clinical assessment of the pump function of the
heart.
PMID: 17721708 [PubMed - indexed for MEDLINE]
24. Can J Physiol Pharmacol. 2007 Mar-Apr;85(3-4):326-31.
Separation of large mammalian ventricular myosin differing in ATPase activity.
Rupp H, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University of Marburg, Karl-von-Frisch-Strasse 1, 35033 Marburg,
Germany. rupp@staff.uni-marburg.de
To investigate a possible heterogeneity of human ventricular myosin, papillary
muscles of patients with valvular dysfunction were examined using a modified
native gel electrophoresis. Myosin was separated into 2 components termed VA and
VB, whereby the VA to VB proportion appeared to depend on the ventricular load.
The proportion of the faster migrating band VA was correlated (P<0.05) with
end-diastolic pressure and the aortic pressure-cardiac index product. The
regression based on these variables accounted for 67% of the variation in VA
(R2=0.67). The VA proportion was, however, not significantly correlated with
cardiac norepinephrine concentration. The ATPase activity of the 2 components of
myosin was assessed from the Ca3(PO4)2 precipitation by incubating the gel in the
presence of ATP and CaCl2. The ATPase activity of VA was 60% of that of VB. The
VA and VB forms were observed also in the cat (31.4% VA), dog (32.1% VA), pig
(28.5% VA), wild pig (33.7% VA), and roe deer (30.5% VA). VA and VB were not
detected in the rat exhibiting the 3 isoforms V1, V2, and V3, rabbit (100% V3),
and hare (86% V1). The data demonstrate a heterogeneity of large mammalian
ventricular myosin, whereby an increased cardiac load appeared to be associated
with a higher myosin VA proportion that exhibited a reduced ATPase activity.
PMID: 17612641 [PubMed - indexed for MEDLINE]
25. Herz. 2006 Dec;31 Suppl 3:30-49.
Microdetermination of fatty acids by gas chromatography and cardiovascular risk
stratification by the "EPA+DHA level".
Rupp H, Rupp TP, Wagner D, Alter P, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University of Marburg, Germany.
The therapeutic options for interfering with the electrical instability of a
pathologically remodeled or ischaemic heart remain limited. Of increasing
importance become interventions which target the fatty acid composition of blood
and membrane lipids. In particular, the long-chain omega-3 fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide parameters for
stratification of risks associated with severe arrhythmia disorders and sudden
cardiac death. Since EPA and DHA appear to have their anti-arrhythmogenic actions
when present as free fatty acids, the parameters which determine a critical free
fatty acid concentration are of great interest. In the present study, conclusions
on EPA and DHA incorporation in blood lipids are derived from the administration
of Omacor which contains highly purified (84%) EPA and DHA ethyl esters and
reduced the risk of sudden cardiac death by 45% in post-myocardial infarction
patients (GISSI-Prevention study). The "EPA+DHA level" is described as risk
identifying parameter for severe arrhythmia disorders, particularly if they are
associated with myocardial ischaemia. It appears essential not only to build up
body stores for release of EPA and DHA but to provide also a sustained uptake of
EPA and DHA in the form of ethyl esters. In contrast to more rapidly absorbed
triacylglycerols from fish, ethyl esters are taken up slowly within 24 h. For the
administration of 1 g/day Omacor to healthy volunteers, it is shown that in whole
blood EPA is increased from 0.6% to 1.4% within 10 days while DHA is increased
from 2.9% to 4.3%. After withdrawal, the EPA and DHA levels approach baseline
values within 10 days. A gas chromatographic procedure was established which
requires only 10 microl of whole blood for the identification of more than 30
fatty acids. Evidence is summarized strengthening the concept that a low "EPA+DHA
level" presents a risk for severe arrhythmia disorders and sudden cardiac death.
The administration of 840 mg/day of EPA and DHA ethyl esters raises the "EPA+DHA
level" to approximately 6% that is associated with protection from sudden cardiac
death. The pharmacological effects of ethyl esters are compared with the
naturally occurring EPA and DHA triacylglycerols present in fish or fish oils
which are of interest in primary prevention of cardiovascular disorders.
PMID: 17575804 [PubMed - indexed for MEDLINE]
26. Pflugers Arch. 2007 Sep;454(6):937-43. Epub 2007 May 15.
Reduction in beta-myosin heavy chains in stunned myocardium as assessed by
nondenaturing gel electrophoresis.
Garcia SC, Pomblum VJ, Gams E, Rupp H, Schipke JD.
Department of Surgery I, University Hospital Duesseldorf,
Heinrich-Heine-University, Moorenstrasse 5, 40225, Duesseldorf, Germany.
sgarpom@smail.ufsm.br
Myosin plays a key role in the structure and function of cardiac muscle. Three
myosin isoenzymes (V(1), V(2), and V(3)) with different ATPase activities have
been identified in mammalian ventricles based on their heavy chain constituents.
The relative amount of myosin isoenzymes changes under physiological and
pathological conditions. Until now, myosin isoenzymes have frequently been
determined using either tube gel (nondenaturing) polyacrylamide gel
electrophoresis (PAGE), or gradient or uniform sodium dodecyl sulfate
(denaturing) PAGE. Both methods have disadvantages, e.g., a long running time. We
developed, therefore, a uniform, nondenaturing PAGE with slab minigel format for
analyzing the myosin isoenzymes in normoxic and stunned rabbit hearts. In
normoxic hearts of adult rabbits, V(3) predominated over V(1) (46 vs 41%). In
turn, in the stunned hearts, V(1) predominated over V(3) (70 vs 30%), and the
heterodimeric V(2) was not anymore detectable. This alteration appears to result
from a selective loss of myosin heavy chain (MHC)-beta. In parallel, the
biochemical markers troponin I and creatine kinase were increased in the stunned
hearts. We suggest that alterations of myosin isoenzymes in stunned myocardium
can be monitored with native PAGE. The present analysis of myosin isoenzyme
appears thus as a new tool for evaluating defects in MHC dimer formation in
postischemic hearts.
PMID: 17503071 [PubMed - indexed for MEDLINE]
30. Herz. 2006 Nov;31(8):727-35.
Acute heart failure--basic pathomechanism and new drug targets.
Rupp H, Rupp TP, Alter P, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University of Marburg, 35043, Marburg, Germany.
Rupp@staff.uni-marburg.de
In view of the high incidence of heart failure and sudden cardiac death, efforts
in the development of compounds which target-specific mechanisms such as a
reduced expression of SERCA2, the Ca2+ pump of sarcoplasmic reticulum, of
hypertrophied cardiomyocytes of pressure-overloaded or infarcted hearts should be
strengthened. Lead compounds for correcting a dysregulated gene expression are
the carnitine palmitoyltransferase-1 (CPT-1) inhibitors etomoxir and oxfenicine.
Since bypassing the CPT-1 inhibition by a medium-chain fatty acid diet had a
lesser effect on myosin V1 proportion than on lipid droplet number, one has to
infer also other mechanisms such as PPARalpha activation (FOXIB/PPARalpha). In
view of the intricate interrelationship between depressed pump function and
malignant arrhythmias, stimulation of endogenous antiarrhythmogenic mechanisms
linked to an enhanced production of eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) could potentially provide alternatives to the
administration of 1 g EPA and DHA ethyl esters (minimum 84% EPA + DHA) for
secondary prevention of myocardial infarction. The apparently greater efficacy of
omega-3 fatty acids in post-myocardial infarction patients (GISSI-Prevention
study) compared with ICD patients (SOFA study) can be attributed to the greater
ischemia-induced release of membrane-bound EPA and DHA and a better compliance
(one vs. four capsules daily).
PMID: 17149674 [PubMed - indexed for MEDLINE]
32. Clin Res Cardiol. 2006;95 Suppl 6:VI12-6.
[Omega-3 fatty acids in secondary prevention after myocardial infarct]
[Article in German]
Rupp H.
Molekular-kardiologisches Labor, Klinik für Innere Medizin und Kardiologie,
Philipps-Universität Marburg, Karl-von-Frisch-Strasse 1, 35033, Marburg, Germany.
The ESC (European Society of Cardiology) recommends treatment with highly
concentrated omega-3 fatty acids after myocardial infarction. By daily
application of 1 g 84% EPA/DHA-ethyl ester the mortality rate is significantly
reduced as shown in the GISSI-Prevenzione study. The main reason for this
protective effect is the serum concentration of EPA/DHA which can be adjusted by
this dosage. On account of this fact the number of fatal arrhythmias decreases.
Concerning secondary prevention omega-3 fatty acids must be given in this form
continuously, otherwise a clinically effective level of fatty acids cannot be
achieved. Therefore the application of EPA/DHA-ethyl esters should be preferred,
because in this case the serum's level can be kept on a sufficiently high level
as a result of their more prolonged release.
PMID: 17013579 [PubMed - indexed for MEDLINE]
34. Herz. 2006 May;31(3):260-8.
[Myocardial fibrosis: a cardiopathophysiologic Janus head]
[Article in German]
Maisch B, Rupp H.
Direktor der Klinik für Innere Medizin-Kardiologie, Angiologie, Intensivmedizin
und Kardioprävention, Philipps-Universität, Baldingerstrasse, 35043, Marburg,
Germany. bernhard.maisch@med.uni-marburg.de
PMID: 16770563 [PubMed - indexed for MEDLINE]
37. Biochem Biophys Res Commun. 2006 Jan 6;339(1):180-7. Epub 2005 Nov 10.
Activated nuclear transcription factor kappaB in patients with myocarditis and
dilated cardiomyopathy--relation to inflammation and cardiac function.
Alter P, Rupp H, Maisch B.
Philipps University of Marburg, Department of Internal Medicine-Cardiology,
Germany. palter@med.uni-marburg.de
OBJECTIVES AND BACKGROUND: Myocarditis is caused by various agents and autoimmune
processes. It is unknown whether viral genome persistence represents inactive
remnants of previous infections or whether it is attributed to ongoing adverse
processes. The latter also applies to the course of autoimmune myocarditis. One
principal candidate for an adverse remodeling is nuclear factor-kappaB
(NFkappaB). METHODS: A total of 93 patients with suspected
myocarditis/cardiomyopathy was examined. Hemodynamics were assessed by
echocardiography as well as right and left heart catheterization. Endomyocardial
biopsies were taken from the left ventricle. Biopsies were examined by
immunohistochemistry and PCR for viral genomes. Selective immunostaining of
activated NFkappaB was performed. RESULTS: NFkappaB was increased in patients
with myocarditis when compared with controls (11.1+/-7.1% vs. 5.0+/-5.3%,
P<0.005) whereas dilated cardiomyopathy showed no significant increase. Patients
with myocarditis and preserved left ventricular function exhibited increased
activated NFkappaB when compared with reduced function (r2=0.72, P<0.001). In
parallel, inverse correlation of NFkappaB and left ventricular enddiasstolic
volume was found (r2=0.43, P<0.02). Increased activated NFkappaB was found in
adenovirus persistence when compared with controls (P=0.001). Only a trend of
increased NFkappaB activation was seen in cytomegalovirus persistence. Parvovirus
B19 persistence did not affect NFkappaB activation. CONCLUSIONS: Increased
activation of NFkappaB is related to inflammatory processes in myocarditis. Since
activated NFkappaB correlates with left ventricular function, it could be assumed
that NFkappaB activation occurs at early stages of inflammation. Potentially,
NFkappaB could inhibit loss of cardiomyocytes by apoptosis and protect from
cardiac dilation. Since NFkappaB is a crucial key transcription factor of
inflammation, its prognostic and future therapeutic relevance should be
addressed.
PMID: 16297880 [PubMed - indexed for MEDLINE]
39. J Muscle Res Cell Motil. 2004;25(8):608-9.
Drug development based on functional genomics of overloaded cardiomyocytes: a
novel approach for preventing progression of heart failure.
Rupp H.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University of Marburg, Germany.
PMID: 16118846 [PubMed - indexed for MEDLINE]
40. Am Heart J. 2005 Jun;149(6):1082-90.
Indications for angiography subsequent to coronary artery bypass grafting.
Alter P, Vogt S, Herzum M, Irqsusi M, Rupp H, Maisch B, Moosdorf R.
Department of Internal Medicine-Cardiology, Philipps University of Marburg/Lahn,
Marburg, Germany. palter@mailer.uni-marburg.de <palter@mailer.uni-marburg.de>
BACKGROUND: Postoperative myocardial infarction is a rare, but potentially severe
complication after coronary artery bypass grafting (CABG). Early markers for
coronary bypass graft failure or native vessel occlusion are required, because
immediate intervention could prevent major myocardial damage. METHODS: One
thousand patients with coronary artery disease consecutively underwent CABG.
Postoperative coronary angiography was performed in 40 patients with suspected
myocardial ischemia. Creatine kinase (CK), CK-MB, leukocyte count, C-reactive
protein (CRP), lactate dehydrogenase (LDH), and glutamate-oxalacetate
transaminase (GOT) were assessed at 0, 6, 12, 24, 48, and 72 hours after CABG as
well as 12-lead standard electrocardiography (ECG). RESULTS: Postoperative
angiography of 40 patients with suspected myocardial infarction revealed graft
failure or occluded native vessels in 13 (32.5%) individuals. Patients with graft
or vessel occlusion presented elevated (P < .005) leukocyte counts (17,215 +/-
6632 vs 10,773 +/- 3902 G/L) immediately after CABG. CK-MB concentrations
differed ( P < .05) at 6 hours after CABG (54 +/- 48 vs 30 +/- 18 U/L). CK, CRP,
LDH, and GOT did not show any differences between both groups. Frequency of ECG
ST-segment elevation was increased (P < .05) in ischemic patients (69.2% vs
29.6%). CONCLUSIONS: Common signs of myocardial ischemia usually allow to
diagnose unstable angina or myocardial infarction under native conditions. In
contrast, these criteria frequently fail after CABG. Combined diagnostic criteria
of elevated leukocytes (>14,000 G/L, at hour 0) and either ST elevation or CK-MB
concentrations >35 U/L (at hour 6) at least seem to be very useful in detecting
myocardial infarction after bypass grafting. In parallel, CK-MB elevation (>70
U/L, at hour 6) alone seems to predict ischemia. Both criteria should indicate
angiography and potential revascularization. If these conditions were not
fulfilled, the risk of perioperative myocardial infarction appears to be
moderate.
PMID: 15976792 [PubMed - indexed for MEDLINE]
42. Cardiovasc Res. 2005 Jun 1;66(3):423-6. Epub 2005 Apr 19.
Fatty acid oxidation inhibition with PPARalpha activation (FOXIB/PPARalpha) for
normalizing gene expression in heart failure?
Rupp H, Rupp TP, Maisch B.
Comment on:
Cardiovasc Res. 2005 Jun 1;66(3):454-61.
PMID: 15914105 [PubMed - indexed for MEDLINE]
43. Herz. 2004 Sep;29(6):624-36.
Treatment of inflammatory dilated cardiomyopathy and (peri)myocarditis with
immunosuppression and i.v. immunoglobulins.
Maisch B, Hufnagel G, Kölsch S, Funck R, Richter A, Rupp H, Herzum M, Pankuweit
S.
Department of Internal Medicine and Cardiology, Philipps-University Marburg,
Germany. BerMaisch@AOL.COM
OBJECTIVES: Treatment objectives in inflammatory dilated cardiomyopathy (DCMi),
myocarditis (M) and peri(myo)carditis are 1) the elimination of inflammatory
cells from the myocardium and pericardium, 2) the elimination or (second best)
mitigation of B-cell products such as antibodies and immuncomplexes directed
against cardiac epitopes such as sarcolemmal, fibrillary and mitochondrial
epitopes, and 3) the eradication of the causative viral or microbial agent, if
present. ANTIPHLOGISTIC TREATMENT: A "non-specific" anti-inflammatory treatment
in peri(myo)carditis can be carried out with antiphlogistics (NSAIDs preferably
colchicine 1-3 mg/d) independent from the presence of the infective agent. In
larger virus and bacteria negative effusions we recommend intrapericardial
instillation of cristalloid triamcinolon (Volon A) at a dose of 500 mg/m(2),
which should be left in place to have a sustained effect over at least 4 weeks.
This will effectively prevent recurrences particularly when colchicine is added
over a period of at least 3-6 months. Taking into account the 2004 ESC task force
recommendations on the management of pericardial diseases the treatment
recommendation for NSAIDs and colchicine can be classified as level of evidence
A, indication class I, for intrapericardial triamcinolon instillation as level of
evidence B, indication class IIa. IMMUNOSUPPRESSION: In (immuno)histologically
validated autoreactive (virus negative) myocarditis and DCMi double-blind
randomized trials are lacking to demonstrate the superiority of immunosuppression
over conventional heart failure management. The only published randomized and
double-blind immunosuppression treatment trial (American Myocarditis Treatment
Trial) was underpowered and did not distinguish viral from non-viral disease. It
showed neither benefit nor harm of a combination of cyclosporin and prednisone. A
number of retrospective analyses of immunosuppression in myocarditis showed some
benefit of surrogate parameters (ejection fraction, exercise tolerance) but
improvement under conventional heart failure treatment cannot be ruled out
completely as the main cause for amelioration. ESETCID (European Study on the
Epidemiology and Treatment of Cardiac Inflammatory Disease) is a double-blind,
randomized, placebo-controled three-armed trial with prednisolone and
azathioprine for autoreactive (virus negative) DCMi, interferon alpha for
enterovirus positive DCMi, high-dose immunoglobulin for cytomegalovirus and
intermediate dose for adeno- and Parvo B19 DCMi. It has now randomized more than
120 patients to the different treatment arms. Its final result has still to be
awaited.-Patients not willing to randomize in the trial were included in a
registry follow-up, which shows improvement of hemodynamic parameters and
elimination of the inflammation in the majority of patients. This is in
concordance with several non-randomized trials. Since evidence is conflicting
(level of evidence C, indication class IIb; if negative viral etiology is taken
into consideration class IIa) treatment with immunosuppression cannot be
generally recommended but should be further evaluated in doubleblind randomized
clinical trials or at least in controlled trials and registries. This also
applies to treatment with interferon for enteroviral or other viral infections in
the heart. IMMUNOADSORPTION: : The elimination of anticardiac antibodies, which
have been associated with DCMi, is a currently discussed concept, which is
supported by published registry data and a few very small controlled
investigations but not by a randomized double-blind trial with clinical endpoints
of relevance. In some studies immunoglobulins have been substituted, so that an
additional immunomodulatory effect has to be taken into account. The current
proof of concept can be ranked level of evidence C, indication class IIa only. An
even more challenging and still more attractive hypothesis is that cardiac
inflammation caused by specific circulating beta-adrenoceptor antibodies can be
eradicated with the elimination of the beta-receptor antibody thus healing
dilated cardiomyopathy. Application of this approach can be ranked level of
evidence C, indication class IIb at present only. Therefore these two
pathophysiologically attractive concepts have to await further validation by a
double-blind, randomized clinical endpoint trial. IMMUNOGLOBULIN TREATMENT: It
has been shown that immunoglobulins have both an antiviral and an
anti-inflammatory effect. They may suppress proinflammatory cytokines and reduce
oxidative stress. HIGH-DOSE I.V. IMMUNOGLOBULINS (IVIG): In biopsy proven
CMVmyocarditis a controlled trial demonstrated eradication of inflammation and of
the virus (level of evidence B, indication class IIa), which is in accordance
with registry data and case reports. In suspected myocarditis (not biopsy proven,
no viral etiology established or excluded) conflicting data exist with respect to
the improvement of surrogate markers such as the ejection fraction under
high-dose immunoglobulins. More evidence can be weighted in favour of a positive
treatment effect (level of evidence B, indication class IIb). Importantly there
were no detrimental effects of the ivIG reported in these trials. One has to
consider the high costs of this treatment, however. A trial taking into account
the different etiologies (different viruses assessed separately vs.
non-viral/autoreactive vs. placebo) is still lacking. MODERATE-DOSE I.V.
IMMUNOGLOBULINS: Registry data support a positive effect of 20 g i.v. pentaglobin
(IgG and IgM) in adenovirus positive myocarditis for clinical improvement,
eradication of both the inflammation and the virus. In Parvo B19 myocarditis our
own registry data indicate that clinical improvement can be noted, but only
inflammation is successfully eliminated, whereas Parvo B19 persistence remains a
problem in the majority of patients. In Parvo B19 associated DCMi therefore dose
finding studies and randomized trials are needed.
PMID: 15912438 [PubMed - indexed for MEDLINE]
45. Dtsch Med Wochenschr. 2005 Mar 24;130(12):726-30.
[Metabolism and the hypertrophied heart of the elderly]
[Article in German]
Rupp H, Rupp TP, Maisch B.
Molekular-kardiologisches Labor, Klinik für Innere Medizin und Kardiologie,
Philipps-Universität Marburg, Marburg. Rupp@staff.uni-marburg.de
In elderly patients, an inadequately treated high blood pressure often leads to
hypertrophied cardiomyocytes with various defects in gene expression. Due to a
decreased expression of the transcription factor PPARalpha, fatty acid oxidation
is reduced. If it can be compensated by an increased glucose oxidation, it has
been considered as a favorable process. Nonetheless, reduced PPARalpha influences
ensue involving e. g. anti-inflammatory mechanisms. The question arises thus
whether drugs can normalize reduced PPARalpha effects without increasing fatty
acid oxidation. As lead compound of these "fatty acid oxidation inhibitors with
PPARalpha activation", the carnitine palmitoyltransferase-1 inhibitor etomoxir
was characterized. An increased expression and activity of the Ca (2+) pump of
sarcoplasmic reticulum, a faster relaxation and a slowed progression of heart
failure was observed in animal experiments. It should, therefore, be examined
whether the impaired function of pressure overloaded hypertrophied cardiomyocytes
of particularly elderly patients should be a therapeutic target before
progression of heart failure, neuroendocrine activation and symptoms such as
shortness of breath occur.
PMID: 15776359 [PubMed - indexed for MEDLINE]
46. Herz. 2004 Nov;29(7):673-85.
Risk stratification by the "EPA+DHA level" and the "EPA/AA ratio" focus on
anti-inflammatory and antiarrhythmogenic effects of long-chain omega-3 fatty
acids.
Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University of Marburg, Marburg, Germany. Rupp@staff.uni-marburg.de
Erratum in:
Herz. 2004 Dec;29(8):805.
The identification of risks associated with sudden cardiac death requires further
investigations. The question was addressed whether parameters can be established
which not only describe an increased risk for an enhanced electrical instability
of the heart but also of inflammatory events underlying plaque rupture. Emphasis
is placed on dose-dependent effects of the long-chain omega-(omega-)3 fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Since free acids of
EPA and DHA are required for most of their biological effects, it appears
essential not only to build up stores in the body for release of these fatty
acids, but also to provide a sustained uptake of EPA and DHA in the form of ethyl
esters. In contrast to rapidly absorbed triacylglycerols from fish, ethyl esters
are taken up more slowly within 24 h. For the administration of 1 g/day highly
purified EPA+DHA ethyl esters (Omacor) to healthy volunteers, it is shown that
EPA is increased from 0.6% to 1.4% within 10 days, while DHA is increased from
2.9% to 4.3%. After withdrawal, EPA and DHA approach baseline values within 10
days. A gas chromatographic procedure was established which requires only 10
microl of whole blood for the identification of more than 35 fatty acids.
Evidence is summarized strengthening the concept that a low "EPA+DHA level"
presents a risk for sudden cardiac death and that the administration of 840
mg/day of EPA+DHA ethyl esters raises the "EPA+DHA level" to approximately 6%
that is associated with a marked protection from sudden cardiac death. For
reducing pro-inflammatory eicosanoids and cytokines, a higher "EPA+DHA level" is
required which can be achieved with an intake of 2-4 g/day of 84% EPA+DHA ethyl
esters. For assessing influences from pro-inflammatory eicosanoids and cytokines,
the EPA/arachidonic acid ratio ("EPA/AA ratio") was identified as diagnostic
parameter. To assess the dietary EPA+DHA intake, fatty acids were determined in
fish dishes of the cafeteria of the Philipps University Hospital Marburg,
Germany. The EPA+DHA content of the popular Alaska Pollock was 125 +/- 70 mg/100
g. A once daily fish dish can thus not provide the 840 mg/day EPA+DHA
administered in the GISSI Prevention Study in the form of ethyl ester which
markedly reduced the risk of sudden cardiac death in postmyocardial infarction
patients. Nonetheless, at least two preferably oily fish meals per week should be
consumed as preventive measure by persons without coronary artery disease. With
documented coronary heart disease, it was advised to consume approximately 1
g/day of EPA+DHA.
PMID: 15580322 [PubMed - indexed for MEDLINE]
47. Br J Pharmacol. 2004 Nov;143(5):561-72. Epub 2004 Oct 4.
Tedisamil attenuates foetal transformation of myosin in the hypertrophied rat
myocardium.
Turcani M, Thormaehlen D, Rupp H.
Department of Physiology, Faculty of Medicine, Kuwait University, PO Box 24923,
Safat 13110, Kuwait. mturcani@gmx.net
1 Reduction in repolarizing potassium currents has controversial effects on
hypertrophic responses in cardiomyocytes of transgenic models and cultured
cardiomyocytes. It remains thus unknown whether a blockade of potassium channels
with tedisamil
(N,N'dicyclopropylmethylene-9,9-tetramethylene-3,7-diazabicyclo(3.3.1)nonane
dihydrochloride) has any effects on cardiac growth during postnatal development
or pressure overload. 2 To test the hypothesis that a treatment with tedisamil
affects cardiac growth or protein phenotype, sham-operated rats and rats with
ascending aorta constriction were treated with tedisamil (36 mg kg day(-1)) for 7
weeks. Left ventricular mass and geometry, relative expression of myosin
isoforms, hydroxyproline concentration and isovolumic ventricular function were
assessed. 3 Rats with aortic constriction exhibited a marked increase in left
ventricular weight and the diastolic pressure-volume relationship was shifted to
smaller volumes. The hydroxyproline concentration remained unaltered. The
proportion of alpha-myosin heavy chains was, however, reduced (P<0.05).
Hypertrophied left ventricles manifested an enhanced overall performance but
depressed myocardial contractility. 4 Administration of tedisamil was associated
with decreased heart rate (P<0.05). In contrast, cardiac growth in sham-operated
rats and concentric left ventricular hypertrophy of pressure-overloaded animals
was not significantly altered. Hypertrophied hearts from rats treated with
tedisamil expressed more alpha-myosin heavy chains (65+/-4 versus 57+/-4%;
P<0.05). Also, maximal rate of wall stress rise and decline was higher (P<0.05)
in tedisamil-treated pressure-overloaded rats. 5 In the rat model of
pressure-overloaded hypertrophy, tedisamil had no effect on cardiac growth but
partially corrected myocardial dysfunction. Postulated mechanism of this effect
is the phenotype modification of myosin filaments in hypertrophied myocardium.
PMCID: PMC1575437
PMID: 15466442 [PubMed - indexed for MEDLINE]
48. Herz. 2004 Jun;29(4):391-400.
[Physical activity and sports in heart failure due to myocarditis and dilated
cardiomyopathy]
[Article in German]
Alter P, Grimm W, Herzum M, Ritter M, Rupp H, Maisch B.
Department of Internal Medicine-Cardiology, Philipps University of Marburg,
Germany. alter@mailer.uni-marburg.de
BACKGROUND: Sudden cardiac death of suspected healthy young athletes is a rare,
but deeply moving event. Usually, the affected person has been completely free of
symptoms. Commonly, unrecognized inflammatory, hypertrophic or dilated
cardiomyopathies are the most frequent causes. All therapeutic principles of
angiotensin-converting-enzyme (ACE) inhibition, beta-blockade, and diuretics in
heart failure aim to unload the heart. During physical activity increased
sympathetic tonus and loading conditions for the heart point into the opposite
direction. This raises the question to what extent physical activity in patients
with myocarditis, dilated cardiomyopathy or heart failure in general is
tolerable. SYNOPSIS: Several experimental studies revealed disadvantages of
physical exercise during acute myocarditis leading to an increase in mortality.
On the other hand, several small trials in men demonstrate an improvement of
physical fitness and quality of life attributed to controlled supervised exercise
training in patients with heart failure without assessment of mortality. Dilated
cardiomyopathy was diagnosed in one third of these patients. There was no biopsy
confirmation of these conditions. The other two thirds of patients suffered from
ischemic heart diseases. CONCLUSION: Since the borderline between inflammatory
heart disease and noninflammatory or postinflammatory dilated cardiomyopathy is
difficult to determine, abstention from physical training during and shortly
after inflammatory heart disease is recommended, because it is known that viral
persistence or autoimmune processes could last for several months.
PMID: 15241538 [PubMed - indexed for MEDLINE]
49. Am J Hypertens. 2004 Mar;17(3):281; author reply 281-3.
Re: Heusser et al: elevation of sympathetic activity by eprosartan in young male
subjects.
Rupp H.
Comment on:
Am J Hypertens. 2003 Aug;16(8):658-64.
PMID: 15001205 [PubMed - indexed for MEDLINE]
50. Herz. 2003 Dec;28(8):744-53.
Effects of ACE inhibition versus non-ACE inhibitor antihypertensive treatment on
myocardial fibrosis in patients with arterial hypertension. Retrospective
analysis of 120 patients with left ventricular endomyocardial biopsies.
Brilla CG, Rupp H, Maisch B.
Division of Cardiology, Center of Internal Medicine, Philipps University of
Marburg, Germany. brilla@t-online.de
BACKGROUND AND PURPOSE: In experimental arterial hypertension, left ventricular
hypertrophy (LVH) becomes pathologic with impaired myocardial function if
myocardial fibrosis occurs. Myocardial fibrosis is associated with activated
circulating or local renin-angiotensin-aldosterone systems. The primary objective
of this retrospective study was to determine whether patients with arterial
hypertension treated with angiotensin-converting enzyme inhibitors (ACEI) have
less myocardial fibrosis than patients on non-ACEI treatment. MATERIAL AND
METHODS: We examined left ventricular (LV) endomyocardial biopsies of 97
consecutive patients with hypertensive heart disease due to primary hypertension
treated with either any ACEI for at least 6 months (n = 34; HTN + ACEI) or
non-ACEI antihypertensive drugs (n = 63; HTN). Normal hearts designated for heart
transplantation served as controls (n = 23; CTR). Myocyte diameter (MyoD) and
collagen volume fraction (CVF) were measured by morphometry, and pro-matrix
metalloproteinases (proMMPs) 2 and 9 by zymography. In a subset of 35 patients,
LV myocardial stiffness was determined by left heart catheterization with
calculation of stiffness constant k. RESULTS: In HTN + ACEI or HTN, MyoD (21.8
+/- 0.3 micro m and 22.4 +/- 0.3 micro m, respectively) and CVF (5.3 +/- 0.6% and
7.6 +/- 0.7%, respectively) were increased (p < 0.01) compared with CTR (16.0 +/-
0.4 micro m and 0.5 +/- 0.2%, respectively). In HTN + ACEI, CVF was significantly
lower (p < 0.02) and proMMP 2 was higher (0.063 +/- 0.013 OD/mg) compared with
HTN (0.037 +/- 0.006 OD/mg; p < 0.05) while no significant difference of MyoD was
evident. We found no correlation between CVF and MyoD (r = 0.13; p = 0.47), a
positive correlation between k and CVF (r = 0.71; p < 0.00001), and no
correlation between k and MyoD (r = 0.22; p = 0.24). CONCLUSION: In patients with
hypertensive heart disease, myocyte hypertrophy and myocardial fibrosis are
present. Myocardial fibrosis and not myocyte hypertrophy determines myocardial
stiffness. ACEI appear to diminish myocardial fibrosis associated with enhanced
collagen degradation irrespective of LVH regression.
PMID: 14689110 [PubMed - indexed for MEDLINE]
51. Herz. 2003 Dec;28(8):668-73.
Abdominal fat and sympathetic overactivity. From calorie intake to postmenopausal
hypertension.
Rupp H, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University Marburg, Germany. Rupp@staff.uni-marburg.de
BACKGROUND: Epidemiologic studies have found an association between overweight
and increased mortality arising primarily from cardiovascular disorders. A major
determinant is a chronically raised sympathetic nervous system activity which can
arise from calorie intake-dependent and -independent mechanisms.
Calorie-dependent parameters reflecting sympathetic overactivity are an increased
body fat mass and body mass index. VISCERAL FAT: Although influenced by calorie
intake to a certain extent, visceral fat accumulation is a mechanism which is
determined also by estrogen deficiency (postmenopausal hypertension) or enhanced
corticoid influences. It is hypothesized that excess catecholamines trigger
various adverse processes which, if they persist, can lead or aggravate
hypertension and insulin resistance. Visceral but not peripheral fat mass was
correlated with atherogenic metabolites. EXCESS CATECHOLAMINE SYNDROME: The
present focus on visceral fat accumulation strengthens the concept of an "excess
catecholamine syndrome" of which the "metabolic syndrome" appears as one
consequence. It is proposed to further assess the potential of transthoracic
echocardiography as routine imaging method for the prediction of visceral fat
accumulation and its adverse health consequences.
PMID: 14689100 [PubMed - indexed for MEDLINE]
53. Herz. 2002 Nov;27(7):621-36.
The use of partial fatty acid oxidation inhibitors for metabolic therapy of
angina pectoris and heart failure.
Rupp H, Zarain-Herzberg A, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
University of Marburg, Germany. Rupp@mailer.uni-marburg.de
BACKGROUND: Partial fatty acid oxidation inhibitors have raised great interest
since they are expected to counteract a dysregulated gene expression of
hypertrophied cardiocytes. Some of these compounds have been developed for
treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A
shift from fatty acid oxidation to glucose oxidation leads to a reduced
gluconeogenesis and improved economy of cardiac work. An increased glucose
oxidation can be achieved with the following enzyme inhibitors: etomoxir,
oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline
(carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine
palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine
translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid,
trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA
dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS
with trimetazidine and ranolazine showed that this shift in substrate oxidation
has an antianginal action. Etomoxir and MET-88 improved the function of
overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic
reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit
sequences which are expected to respond to transcription factors responsive to
glucose metabolites and/or peroxisome proliferator-responsive element (PPAR)
agonists. Further progress in elucidating novel compounds which upregulate SERCA2
expression is closely linked to the characterization of regulatory sequences of
the SERCA2 promoter.
PMID: 12439634 [PubMed - indexed for MEDLINE]
54. Pflugers Arch. 2002 Oct;445(1):32-9. Epub 2002 Aug 1.
Characterization of sucrose-induced changes in cardiac phenotype.
Rupp H, Wahl R, Maisch B, Hansen M.
Department of Internal Medicine and Cardiology, Karl-von-Frisch-Strasse 1, 35033
Marburg, Germany. Rupp@mailer.uni-marburg.de
The neuroendocrine factors responsible for long-term regulation of cardiac
contractile performance remain ill defined. We examined influences of diet on the
expression of myosin isozymes, sarcoplasmic reticulum (SR) Ca(2+) uptake and
serum parameters. Dietary regimens (ad libitum feeding, intermittent fasting and
32% sucrose feeding) were used to alter the neurohumoral status of rats.
Intermittent fasting decreased serum insulin levels ( P<0.05) and was associated
with decreased SR Ca(2+) uptake and myosin V1 proportion ( P<0.05). Sucrose (32%)
feeding increased myosin V1 of fasted and ad libitum fed rats ( P<0.05) but had
no effect on insulin or SR Ca(2+) uptake. Expression of the alpha-myosin heavy
chain correlated with serum insulin. Treatment of sucrose-fed rats with the
sympatholytic compound moxonidine and the hypoglycaemic compounds BM13.907 and
ciglitazone partially prevented the increase in myosin V1 ( P<0.05) but had no
effect on SR Ca(2+) uptake and insulin. The data show that adrenergic activity
and metabolic signals are important for an increase in myosin V1 in sucrose-fed
rats, which can be associated with an unaltered SR Ca(2+) uptake rate.
PMID: 12397384 [PubMed - indexed for MEDLINE]
55. J Mol Cell Cardiol. 2002 Jul;34(7):847-57.
Modification of myosin gene expression by imidapril in failing heart due to
myocardial infarction.
Wang J, Liu X, Ren B, Rupp H, Takeda N, Dhalla NS.
Institute of Cardiovascular Sciences, St Boniface General Hospital Research
Centre, & Department of Physiology, Faculty of Medicine, University of Manitoba,
Winnipeg, Canada.
Comment in:
J Mol Cell Cardiol. 2002 Sep;34(9):1127-30.
The beneficial effects of imidapril, an angiotensin converting enzyme (ACE)
inhibitor were investigated on changes in myofibrillar ATPase as well as myosin
heavy chain (MHC) content and gene expression due to myocardial infarction (MI).
Three weeks after occluding the left coronary artery, rats were treated with or
without imidapril (1 mg/kg/day), for 4 weeks. The infarcted hearts exhibited
depressed rates of left ventricular (LV) pressure development (57+/-2.4%
reduction) and pressure decay (55.5+/-1.6% reduction). LV myofibrillar Ca(2+)
ATPase activity, unlike that in the right ventricle (RV), was decreased in the
infarcted animals compared with controls (6.8+/-0.4 vs 10.3+/-0.6 micromol
Pi/mg/hr). MHC alpha-isoform contents were decreased by 47 and 41% whereas those
of MHC beta-isoform were increased by 823 and 1200% in the LV and RV due to MI,
respectively. MHC alpha-isoform mRNA levels were decreased by 55 and 35% whereas
those for MHC beta-isoform were increased by 50 and 30% in the infarcted LV and
RV, respectively. Imidapril treatment partially prevented the changes due to MI
in LV function (rate of pressure development, 24+/-2.3% reduction and rate of
pressure decay, 14+/-1.8% reduction), myofibrillar Ca(2+) ATPase activity
(8.2+/-0.7 micromol Pi/mg/hr), MHC protein content (alpha-MHC, 24% reduction and
beta-MHC, 525% increase) and MHC gene expression (alpha-MHC, 18% reduction and
beta-MHC, 15% increase). The results suggest that the beneficial effects of ACE
inhibition on the failing heart are associated with improvements in myofibrillar
ATPase activities as well as prevention of changes in MHC isozyme protein
contents and their gene expression. Copyright 2002 Elsevier Science Ltd. All
rights reserved. (c) 2002 Elsevier Science Ltd. All rights reserved.
PMID: 12099723 [PubMed - indexed for MEDLINE]
56. Mol Cell Biochem. 2002 Mar;232(1-2):57-62.
Differential effects of etomoxir treatment on cardiac Na+-K+ ATPase subunits in
diabetic rats.
Kato K, Lukas A, Chapman DC, Rupp H, Dhalla NS.
Institute of Cardiovascular Sciences, St Boniface General Hospital Research
Centre and Department of Physiology, Faculty of Medicine, University of Manitoba,
Winnipeg, Canada.
Etomoxir, an inhibitor of mitochondrial carnitine palmitoyltransferase-1, is
known to attenuate the changes in myosin isoforms and sarcoplasmic reticular
function that occur in diabetic rat hearts. In the present study, we tested the
hypothesis that etomoxir also prevents the diabetes-induced depression of
sarcolemmal (SL) Na+-K+ATPase activity by differentially affecting its alpha and
beta-subunit levels. Streptozotocin-induced diabetes was associated with a
decreased in alpha2-, alpha3-subunit levels, whereas the alpha1-and
beta1-subunits were unchanged. Treatment of diabetic rats for 4 weeks with
etomoxir (8 mg/kg/day) increased the alpha1-subunit levels, but failed to prevent
the decrease in alpha2- and alpha3-subunit levels. In euglycemic control rats,
etomoxir increased the alpha1-subunit protein level per g heart weight, but did
not alter the alpha2-, alpha3- and beta1-subunit levels. The large decrease in
Na+-K+ ATPase activity per g heart weight in diabetic rats was prevented by
etomoxir, which suggests that the increased alpha1-subunit levels seen with this
drug compensated for the decreased alpha2- and alpha3-subunit levels. The SL
yield was also increased by etomoxir in euglycemic rats in proportion to the
higher alpha1-subunit level, which resulted in an unchanged alpha1-content when
expressed per mg SL protein; however, the alpha2- and beta1-subunit levels were
reduced (p < 0.05). The depressed alpha2- and beta3 subunit levels of diabetic
rats were associated with reduced mRNA abundance. However, no increase in
alpha1-subunit mRNA abundance was seen in the etomoxir treated rats, which
suggests that possibly post-transcriptional mechanisms are occurring in these
hearts.
PMID: 12030380 [PubMed - indexed for MEDLINE]
57. Herz. 2002 Mar;27(2):166-73.
[Functional genomics of pressure-loaded cardiomyocytes: etomoxir in heart
failure?]
[Article in German]
Rupp H, Maisch B.
Klinik für Innere Medizin-Kardiologie, Philipps-Universität Marburg.
Rupp@mailer.uni-marburg.de
BACKGROUND: Drugs for counteracting the neuroendocrine activation in heart
failure can reduce the adverse remodelling of the extracellular matrix of the
heart. Progression of heart failure can, however, often not be prevented and the
question arises whether important pharmacological targets remain unidentified.
Promising are drugs targeted at ventricular diastolic dysfunction which is a
marker of early progression of heart failure. PATHOPHYSIOLOGY: Left ventricular
dysfunction is characteristic of overloaded hypertrophied hearts with molecular
structures that are not adapted to the increased Ca2+ diffusion distances. Thus,
the Ca(2+)-pump (SERCA2) of sarcoplasmic reticulum is inadequately expressed
leading to a reduced force development and relaxation of hypertrophied
cardiomyocytes. ETOMOXIR: Drugs in development (CPT-1 inhibitor/PPARalpha
activator) that increase glucose oxidation can enhance SERCA2 expression. The
lead compound etomoxir had a selective influence on the contraction and
relaxation rate of pressure-overloaded hearts. The functional parameters were
correlated with the proportion of alpha-myosin heavy chains. Since viral or
inflammatory injury of the heart can also induce a fetal phenotype, metabolic
modulators such as etomoxir represent a promising therapeutic approach also for
cardiomyopathies with inadequate SERCA2 expression.
PMID: 12025461 [PubMed - indexed for MEDLINE]
59. Expert Opin Investig Drugs. 2002 Mar;11(3):345-56.
Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a
target.
Zarain-Herzberg A, Rupp H.
Laboratorio de Biología Molecular, Departamento de Bioquímica, Facultad de
Medicina, Universidad Nacional Autónoma de México, Apartado Postal 70-159, México
D.F. 04510. angelz@laguna.fmedic.unam.mx
Inhibitors of carnitine palmitoyl-transferase I (CPT I), the key enzyme for the
transport of long-chain acyl-coenzyme A (acyl-CoA) compounds into mitochondria,
have been developed as agents for treating diabetes mellitus Type 2. Findings
that the CPT I inhibitor, etomoxir, has effects on overloaded heart muscle, which
are associated with an improved function, were unexpected and can be attributed
to selective changes in the dysregulated gene expression of hypertrophied
cardiomyocytes. Also, the first clinical trial with etomoxir in patients with
heart failure showed that etomoxir improved the clinical status and several
parameters of heart function. In view of the action of etomoxir on gene
expression, putative molecular mechanisms involved in an increased expression of
SERCA2, the Ca(2+) pump of sarcoplasmic reticulum (SR) and alpha-myosin heavy
chain (MHC) of failing overloaded heart muscle are described. The first 225 bp of
human, rabbit, rat and mouse SERCA2 promoter sequence have high identity. Various
cis-regularory elements are also given for the promoter of the rat cardiac
alpha-MHC gene. It is hypothesised that etomoxir increases glucose-phosphate
intermediates resulting in activation of signalling pathway(s) mediated by
phosphatases. Regarding the possible direct action of etomoxir on peroxisome
proliferator activated receptor alpha (PPAR-alpha) activation, it could
upregulate the expression of various enzymes that participate in beta-oxidation,
thereby modulating some effects of CPT 1 inhibition. Any development of
alternative drugs requires a better understanding of the signal pathways involved
in the altered gene expression. In particular, signals need to be identified
which are altered in overloaded hearts and can selectively be re-activated by
etomoxir.
PMID: 11866664 [PubMed - indexed for MEDLINE]
60. Am J Cardiol. 2001 Dec 1;88(11):1323-6.
Pericardial access using the PerDUCER and flexible percutaneous pericardioscopy.
Maisch B, Ristić AD, Rupp H, Spodick DH.
Department of Internal Medicine-Cardiology, Philipps University, Marburg,
Germany. BerMaisch@aol.com
PMID: 11728368 [PubMed - indexed for MEDLINE]
62. Br J Pharmacol. 2000 Dec;131(8):1748-56.
Sarcoplasmic reticulum function and carnitine palmitoyltransferase-1 inhibition
during progression of heart failure.
Rupp H, Vetter R.
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology,
Philipps University of Marburg, 35033 Marburg, Germany.
Rupp@mailer.uni-marburg.de
Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic
reticulum (SR) function. The hypothesis was examined that pressure overloaded
hearts fail to increase SR Ca(2+) uptake rate proportionally to the hypertrophy
and that carnitine palmitoyltransferase-1 inhibition by etomoxir ((+/-)-ethyl
2[6(4-chlorophenoxy)hexyl] oxirane-2-carboxylate) can counteract this process.
Severe left ventricular pressure overload was induced in rats by constricting the
ascending aorta for 8, 10, 14 and 28 weeks leading to cardiac hypertrophy (+62 -
+103% of sham-operated rats) and pulmonary congestion. Homogenate
oxalate-facilitated SR Ca(2+) uptake rate g wet wt(-1) was reduced (P<0.05) by
29.9+/-1.8% irrespective of phospholamban phosphorylation (in the presence of
catalytic subunit of protein kinase A) and inhibition of SR Ca(2+) release
channel by ruthenium red. SERCA2 protein level was reduced (P<0.05) by
30.4+/-0.8%. SR Ca(2+) uptake rate was inversely correlated (P<0.05) with left
ventricular weight but was not affected by the occurrence of pulmonary
congestion. Because SR Ca(2+) uptake rate of whole ventricles was not reduced, a
hypertrophy proportional dilution of SR Ca(2+) uptake has to be inferred which
precedes pulmonary congestion. Treatment with etomoxir (15 mg kg body wt(-1)
day(-1) for 10 weeks) did not affect left ventricular weight but decreased
(P:<0.05) the right ventricular hypertrophy related to pulmonary congestion. In
parallel, SR Ca(2+) uptake rate of left ventricle and myosin isozyme V(1) were
increased (P<0.05). Etomoxir represents a candidate approach for prevention of
heart failure by inducing a hypertrophy proportional increase in SR Ca(2+) uptake
rate.
PMCID: PMC1572500
PMID: 11139455 [PubMed - indexed for MEDLINE]
63. Mol Cell Biochem. 2000 Sep;212(1-2):219-25.
Bradykinin (B2) independent effect of captopril on the development of pressure
overload cardiac hypertrophy.
Turcani M, Rupp H.
Institute of Pathophysiology, Medical School, Comenius University, Bratislava,
Slovak Republic.
Besides the reduction of angiotensin II formation, locally increased kinins may
play a role in the cardiovascular action of angiotensin converting enzyme (ACE)
inhibitors. To characterize the contribution of bradykinin to the effects of ACE
inhibition by captopril on the development of pressure overload hypertrophy,
sham-operated rats and rats with ascending aortic constriction were treated with
captopril (80 mg/kg/day) or captopril and B2 kinin receptor antagonist HOE 140
(0.5 mg/kg/day) for 7 weeks. Left ventricular mass and geometry, hydroxyproline
concentration and myosin isozymes (marker of a fetal phenotype) were assessed.
Rats with aortic constriction exhibited a marked increase in left ventricular
weight and diastolic pressure-volume relationship was shifted to smaller volumes.
Signs of congestive heart failure were not apparent. The hydroxyproline
concentration remained unaltered. However, the proportion of isomyosin V3 was
increased (p < 0.05). Administration of captopril reduced (p < 0.05) systolic
blood pressure, body and cardiac weight in all treated rats. The reduction of
left ventricular weight was disproportionally higher in pressure overloaded rats,
thus the relative left ventricular weight decreased by 15% (p < 0.05). Captopril
augmented the isomyosin V1 expression (p < 0.05) in sham operated as well as
pressure overloaded rats. The isomyosin V1 percentage was inversely related to
the relative left ventricular weight. Two different (p < 0.05) correlation lines
were detected for untreated and captopril treated rats. None of captopril
associated effects were removed by simultaneously administered B, kinin receptor
antagonist HOE 140. Thus, stimulation of bradykinin B2 receptor appears not to
mediate the effects of captopril on cardiac growth and contractile proteins
during the development of pressure overload hypertrophy.
PMID: 11108154 [PubMed - indexed for MEDLINE]
64. Mol Cell Biochem. 2000 Sep;212(1-2):135-42.
Control of cardiomyocyte gene expression as drug target.
Rupp H, Benkel M, Maisch B.
Department of Internal Medicine and Cardiology, Philipps University of Marburg,
Germany.
Pressure overload of the heart is associated with a perturbed gene expression of
the cardiomyocyte leading to an impaired pump function. The ensuing
neuro-endocrine activation results in disordered influences of angiotensin II and
catecholamines on gene expression. To assess whether angiotensin II type 1
receptor inhibition can also counteract a raised sympathetic nervous system
activity, spontaneously hypertensive rats fed a hypercaloric diet were treated
with eprosartan (daily 90 mg/kg body wt) and cardiovascular parameters were
monitored with implanted radiotelemetry pressure transducers. Both, blood
pressure and heart rate were increased (p < 0.05) by the hypercaloric diet.
Although eprosartan reduced (p < 0.05) the raised systolic and diastolic blood
pressure, the diet-induced rise in heart rate was blunted only partially. In
addition to drugs interfering with the enhanced catecholamine influence,
compounds should be considered that selectively affect cardiomyocyte gene
expression via 'metabolic' signals.
PMID: 11108145 [PubMed - indexed for MEDLINE]
65. Circulation. 2000 Sep 19;102(12):1388-93.
Lisinopril-mediated regression of myocardial fibrosis in patients with
hypertensive heart disease.
Brilla CG, Funck RC, Rupp H.
Division of Cardiology, Philipps University of Marburg, Marburg, Germany.
Comment in:
Circulation. 2000 Sep 19;102(12):1342-5.
BACKGROUND: In arterial hypertension, left ventricular hypertrophy (LVH) includes
myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and,
finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis
was regressed and LV diastolic function was improved by treatment with the
angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for
patients with hypertensive heart disease was addressed in this prospective,
randomized, double-blind trial. METHODS AND RESULTS: A total of 35 patients with
primary hypertension, LVH, and LV diastolic dysfunction were treated with either
lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6
months, LV catheterization with endomyocardial biopsy, Doppler echocardiography
with measurements of LV peak flow velocities during early filling and atrial
contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring
were performed. Myocardial fibrosis was measured by LV collagen volume fraction
and myocardial hydroxyproline concentration. With lisinopril, collagen volume
fraction decreased from 6.9+/-0.6% to 6. 3+/-0.6% (P:<0.05 versus HCTZ) and
myocardial hydroxyproline concentration from 9.9+/-0.3 to 8.3+/-0.4 microg/mg of
LV dry weight (P:<0.00001 versus HCTZ); this was associated with an increase in
the early filling and atrial contraction LV peak flow velocity ratio from
0.72+/-0.04 to 0.91+/-0.06 (P:<0.05 versus HCTZ) and a decrease in isovolumic
relaxation time from 123+/-9 to 81+/-5 ms (P:<0.00002 versus HCTZ). Normalized
blood pressure did not significantly change in either group. No LVH regression
occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was
reduced from 22. 1+/-0.6 to 20.7+/-0.7 microm (P:<0.01 versus lisinopril).
CONCLUSIONS: In patients with hypertensive heart disease, angiotensin-converting
enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective
of LVH regression, and it is accompanied by improved LV diastolic function.
PMID: 10993857 [PubMed - indexed for MEDLINE]
66. Br J Pharmacol. 2000 Aug;130(7):1671-7.
Heart failure development in rats with ascending aortic constriction and
angiotensin-converting enzyme inhibition.
Turcani M, Rupp H.
Institute of Physiology II, University of Tübingen, Tübingen, Germany.
It remains unknown whether angiotensin-converting enzyme (ACE) inhibition can
prevent heart failure in rats with a fixed high pressure load of the left
ventricle and if this effect could be attributed to normalization of contractile
protein phenotype and cardiac collagen content. Rats with constriction of the
ascending aorta were treated with the ACE inhibitor quinapril (6 mg kg(-1)
day(-1)) (n=95) or placebo (n=96) (starting 6 weeks post surgery. Quinapril
treatment improved survival markedly (P<0.0000001) during the 24 weeks
observation period. There were 69 deaths with placebo and only 25 deaths with
quinapril. At the end of the observation period signs of left ventricular
backward failure were, however, detected in 75 rats with placebo and in 67 rats
treated with quinapril (P=0.229). Cox proportional hazard model with
time-dependent covariates was used to document that the effect of quinapril
treatment had been dependent on time. Quinapril had no significant effect on the
development of morphological signs of left ventricular dysfunction after the
first 54 days of treatment. The increased isomysin V(3) proportion of
hypertrophied non-failing hearts was also not affected by quinapril treatment.
Irrespective of treatment, failing hypertrophied hearts were characterized by an
increase in left ventricular volume (P<0.05), percentage of the 'foetal'
isomyosin V(3) (P<0.05), and hydroxyproline concentration (P<0.05). While the
cause of the improved survival remains unknown, quinapril did apparently not
interfere with the restitution of 'foetal' gene expression of pressure overloaded
cardiomyocytes leading to depressed myocardial performance, ventricular
dysfunction and the consecutive myocardial fibrosis.
PMCID: PMC1572224
PMID: 10928973 [PubMed - indexed for MEDLINE]
68. Am J Cardiol. 1999 Jun 17;83(12A):31H-37H.
Transcriptional modulators targeted at fuel metabolism of hypertrophied heart.
Zarain-Herzberg A, Rupp H.
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma
de México, Mexico City.
The transition of nonfailing to failing cardiac hypertrophy cannot be prevented
by current drug regimens. This investigation examined whether possible drug
targets have remained unexplored because they do not result in acute improvement
of heart function. Of major importance, in this respect, is an inadequate
performance of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2). In the
present approach, binding sequences within the proximal promoter of SERCA2 are
described which may be useful in the development of drugs (i.e., transcriptional
modulators) that interfere selectively with the transcription of genes of the
cardiomyocyte. The proximal promoter region of the SERCA2 genes has a thyroid
response element, 9 potential Sp1-binding sites (5'-GGGCGG-3', 5'-CCGCCC-3' and
5'-GGGAGG-3'), and an E-box motif (5'-CACATG-3'), which may function as glucose
response elements. This region also has 2 putative fatty-acid response elements
(5'-GGGGGA-3'). It is proposed that the beneficial effects of the camitine
palmitoyltransferase-1 inhibitor etomoxir arise from a shift in fuel metabolism
involving glucose response elements and/or peroxisomal proliferator-activated
receptors. Although the relative contribution of these DNA regulatory elements
remains to be defined, it appears that they provide the driving force that
prevents the decrease in transcriptional activity of the SERCA2 gene in the
hypertrophic heart. It is further concluded that etomoxir represents a member of
a novel class of transcriptional modulators that improve function of
hypertrophied hearts with unimpeded blood flow by modulating gene expression of
the cardiomyocyte.
PMID: 10750584 [PubMed - indexed for MEDLINE]
71. J Appl Physiol. 1999 Nov;87(5):1909-13.
Biphasic changes in heart performance with food restriction in rats.
McKnight KA, Rupp H, Dhalla KS, Beamish RE, Dhalla NS.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, and Department of Physiology, Faculty of Medicine, University of
Manitoba, Winnipeg, Canada.
To examine effects of food restriction resembling very-low-calorie dieting on
heart performance, normal rats were fed 25% of ad libitum food intake for 14
days. Although heart weight decreased (P < 0.05) after 5 days, left ventricular
systolic pressure as well as rates of pressure development and fall were
increased (P < 0.05) at 7 days and decreased (P < 0.05) after 14 days. Systolic
and diastolic blood pressures were also increased from 5 to 7 days and decreased
after 14 days. The increased hemodynamic performance of heart was associated with
a raised plasma norepinephrine concentration, which peaked at day 7 of food
restriction; epinephrine concentration was increased (P < 0.05) also at day 7. An
increased catecholamine synthesis was indicated by the raised (P < 0.05) plasma
dopamine beta-hydroxylase activity at 3 days, but this was decreased (P < 0. 05)
at 14 days. The concentration of dopamine in the heart was increased (P < 0.05)
at 2-14 days, of norepinephrine at 7-14 days, and of epinephrine at 10 and 14
days. Food restriction thus appears initially to be associated with an enhanced
catecholamine influence on the heart and is followed by a depressed cardiac
performance.
PMID: 10562636 [PubMed - indexed for MEDLINE]
72. Am J Physiol. 1999 Oct;277(4 Pt 2):H1540-5.
Radiotelemetric characterization of overweight-associated rises in blood pressure
and heart rate.
Rupp H, Maisch B.
Molecular Cardiology Laboratory, Department of Internal Medicine, Philipps
University of Marburg, 35033 Marburg, Germany. Rupp@mailer.uni-marburg.de
We addressed the hypothesis that hypercaloric diets induce hyperkinetic
hypertension irrespective of day-night cycle and locomotor activity that is
associated with altered cardiac myosin isozymes. Normotensive rats with implanted
radiotelemetry pressure transducers were fed increasing amounts of coconut fat
(8, 16, and 24%, each for 2 wk) corresponding to 20-47% of total calories from
fat. Thereafter, increasing amounts of sucrose (16, 32, and 50%) and fructose
(50%) were added to the 24% fat diet corresponding to 13-40% of total calories
from sugar. In contrast to the fat diets, the 32% and 50% sucrose diets as well
as the 50% fructose diets increased (P < 0.05) blood pressure (systolic maximum
+13 mmHg, diastolic maximum +4 mmHg, mean maximum +7 mmHg) and heart rate
(maximum +50 beats/min) irrespective of the day-night cycle and the unaltered
locomotor activity. Furthermore, body weight increased (P < 0.05) during the 32%
and 50% sucrose feedings. The increased blood pressure and heart rate normalized
after rats were fed a regular chow. We concluded that an excessive caloric intake
results in hyperkinetic hypertension that increases the myosin V(1) proportion.
PMID: 10516193 [PubMed - indexed for MEDLINE]
73. Plant J. 1999 Jun;18(5):557-63.
Increased steady state mRNA levels of the STM and KNAT1 homeobox genes in
cytokinin overproducing Arabidopsis thaliana indicate a role for cytokinins in
the shoot apical meristem.
Rupp HM, Frank M, Werner T, Strnad M, Schmülling T.
Universität Tübingen, Centre for Plant Molecular Biology (ZMBP), Allgemeine
Genetik, Germany.
This study investigates the consequences of endogenously enhanced biosynthesis of
the plant hormone cytokinin in Arabidopsis thaliana (L.) Heynh. Transcriptional
enabled temperature-dependent increased cytokinin production in transgenic
plants. Heat-treated plants accumulated higher levels of unbound and bound
zeatin-type cyto-kinins, the latter being preferentially N-conjugated glucosides.
Cytokinin overproduction significantly increased the biomass of seedlings. Ipt
transgenics had higher steady state mRNA levels of the shoot meristem specifying
homeobox genes KNAT1 and STM, similar to the cytokinin-overproducing shoot
meristem mutant amp1 (hpt, cop2, pt) This finding, together with previously
described phenotypic similarities between transgenic cytokinin-overproducing
plants and plants overexpressing the KNAT1 or KN1 genes, suggests that these
factors act on the same pathway. We hypothesize that cytokinins act upstream of
KNAT1 and STM. The influence of cytokinins on homeobox genes provides a link
between the hormone and the developmental genes and indicates a role for
cytokinins in the shoot apical meristem.
PMID: 10417706 [PubMed - indexed for MEDLINE]
74. Ann N Y Acad Sci. 1999 Jun 21;881:430-44.
Excess catecholamine syndrome. Pathophysiology and therapy.
Rupp H.
Molecular Cardiology Laboratory, Philipps University of Marburg, Germany.
In addition to genetic factors, lifestyle has a predominant influence on primary
hypertension and noninsulin-dependent diabetic mellitus (NIDDM). We initiated
studies using radiotelemetry for characterizing molecular events linked with
excess calorie intake and psychologic stress. An increased calorie intake was
associated with raised (p < 0.05) systolic and diastolic blood pressure as well
as heart rate independent of day-night cycle. Sympathetic activity was in excess
when related to the unchanged motility. The hyperkinetic hypertension is expected
to result in adverse remodeling of resistance vessels and to aggravate insulin
resistance. To examine adverse effects of psychological stress, rats were
subjected to intermittent food pellet feeding. Urinary catecholamines and cardiac
norepinephrine stores were increased (p < 0.05). The depressed (p < 0.05) rate of
Ca2+ uptake of sarcoplasmic reticulum is expected to contribute to cellular Ca2+
overload. These lifestyle influences strengthen the notion of an excess
catecholamine syndrome which requires selective reduction of sympathetic outflow
of the brain by I1-receptor agonists.
PMID: 10415947 [PubMed - indexed for MEDLINE]
75. Ann N Y Acad Sci. 1999 Jun 30;874:100-10.
Subcellular remodeling and heart dysfunction in cardiac hypertrophy due to
pressure overload.
Dhalla NS, Golfman L, Liu X, Sasaki H, Elimban V, Rupp H.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnepeg, Manitoba, Canada.
Rats were treated with etomoxir, an inhibitor of palmitoyltransferase-1, to
examine the role of a shift in myocardial metabolism in cardiac hypertrophy.
Pressure overload was induced by abdominal aorta banding for 8 weeks.
Sham-operated animals served as control. Left ventricular dysfunction, as
reflected by decreased LVDP, +dP/dt, -dP/dt, and elevated LVEDP in the pressure
overloaded animals, was improved by treatment with etomoxir. Cardiac hypertrophy
in pressure-overload rats decreased the sarcoplasmic reticular (SR) Ca2+ uptake
and Ca2+ release as well as myofibrillar Ca(2+)-stimulated ATPase and myosin
Ca(2+)-ATPase activities; these changes were attenuated by treatment with
etomoxir. Steady-state mRNA levels for alpha- and beta-myosin heavy chains, SR
Ca(2+)-pump, and protein content of SR Ca(2+)-pump were reduced in hypertrophied
hearts; these alterations were prevented by etomoxir treatment. The results
indicate that modification of changes in myocardial metabolism by etomoxir may
prevent remodeling of myofibrils and SR membrane and thereby improve cardiac
function in hypertrophied heart.
PMID: 10415524 [PubMed - indexed for MEDLINE]
76. Herz. 1999 May;24(3):225-31.
Control of apoptosis of cardiovascular fibroblasts: a novel drug target.
Rupp H, Maisch B.
Department of Internal Medicine and Cardiology, Philipps-University of Marburg,control of the bacterial ipt gene by the Drosophila melanogaster hsp70 promoter
Germany. Rupp@mailer.uni-marburg.de
Adequate control of survival or programmed cell death (apoptosis) of
cardiovascular cells appears as an important drug target. While prevention of
apoptotic death of cardiomyocytes has been assessed in detail, selective
induction of apoptosis of vascular smooth muscle cells or fibroblasts could also
be of relevance. Thus, induction of apoptosis of vascular smooth muscle cells by
p65 NF-kappa B and Bcl-xL antisense oligonucleotides or p53 overexpression could
be useful for limiting vascular lesions associated with restenosis. Although
fibroblasts represent the majority of cardiac cells, few attempts were made to
induce fibroblast apoptosis in disorders associated with excessive collagen
deposition and fibrosis. It is hypothesized that early interference with
fibroblast proliferation after myocardial infarction or inflammatory heart
disease limits fibrosis which further impairs cardiac performance. A candidate
approach could involve growth factor analogues which are known to induce
fibroblast apoptosis when an incomplete growth stimulus persists.
PMID: 10412646 [PubMed - indexed for MEDLINE]
78. Br J Pharmacol. 1999 Jan;126(2):501-7.
Modification of left ventricular hypertrophy by chronic etomixir treatment.
Turcani M, Rupp H.
Institute of Physiology II, University of Tübingen, Germany.
1. Etomoxir (2[6(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), an irreversible
carnitine palmitoyl-transferase 1 inhibitor, reduces the expression of the
myocardial foetal gene programme and the functional deterioration during heart
adaption to a pressure-overload. Etomoxir may, however, also improve the
depressed myocardial function of hypertrophied ventricles after a prolonged
pressure overload. 2. To test this hypothesis, we administered racemic etomoxir
(15 mg kg(-1) day(-1) for 6 weeks) to rats with ascending aortic constriction
beginning 6 weeks after imposing the pressure overload. 3. The right
ventricular/body weight ratio increased (P<0.05) by 20% in etomoxir treated rats
(n = 10) versus untreated rats with ascending aortic constriction (n = 10). Left
ventricular weight was increased (P<0.05) by 8%. Etomoxir blunted the increase in
left ventricular chamber volume. Etomoxir raised the proportion of V1 isomyosin
(35+/-4% versus 24+/-2%; P<0.05) and decreased the percentage of V3 isomyosin
(36+/-4% versus 48+/-3%; P<0.05). 4. Maximum isovolumically developed pressure
was higher in etomoxir treated rats than in untreated pressure overloaded rats
(371+/-22 versus 315+/-23 mmHg; P<0.05). Maximum rates of ventricular pressure
development (14,800+/-1310 versus 12,340+/-1030mmHg s(-1); P<0.05) and decline
(6440+/-750 versus 5040+/-710 mmHg s(-1); P<0.05) were increased as well.
Transformation of pressure values to ventricular wall stress data revealed an
improved myocardial function which could partially account for the enhanced
function of the whole left ventricle. 5. The co-ordinated action of etomoxir on
ventricular mass, geometry and myocardial phenotype enhanced thus the pressure
generating capacity of hypertrophied pressure-overloaded left ventricles and
delayed the deleterious dilative remodelling.
PMCID: PMC1565820
PMID: 10077244 [PubMed - indexed for MEDLINE]
79. J Appl Physiol. 1999 Mar;86(3):812-8.
Alterations of heart function and Na+-K+-ATPase activity by etomoxir in diabetic
rats.
Kato K, Chapman DC, Rupp H, Lukas A, Dhalla NS.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, and Department of Physiology, Faculty of Medicine, University of
Manitoba, Winnipeg, Manitoba, Canada R2H 2A6.
To examine the role of changes in myocardial metabolism in cardiac dysfunction in
diabetes mellitus, rats were injected with streptozotocin (65 mg/kg body wt) to
induce diabetes and were treated 2 wk later with the carnitine
palmitoyltransferase inhibitor (carnitine palmitoyltransferase I) etomoxir (8
mg/kg body wt) for 4 wk. Untreated diabetic rats exhibited a reduction in heart
rate, left ventricular systolic pressure, and positive and negative rate of
pressure development and an increase in end-diastolic pressure. The sarcolemmal
Na+-K+-ATPase activity was depressed and was associated with a decrease in
maximal density of binding sites (Bmax) value for high-affinity sites for
[3H]ouabain, whereas Bmax for low-affinity sites was unaffected. Treatment of
diabetic animals with etomoxir partially reversed the depressed cardiac function
with the exception of heart rate. The high serum triglyceride and free fatty acid
levels were reduced, whereas the levels of glucose, insulin, and
3,3',-5-triiodo-L-thyronine were not affected by etomoxir in diabetic animals.
The activity of Na+-K+-ATPase expressed per gram heart weight, but not per
milligram sarcolemmal protein, was increased by etomoxir in diabetic animals.
Furthermore, Bmax (per g heart wt) for both low-affinity and high-affinity
binding sites in control and diabetic animals was increased by etomoxir
treatment. Etomoxir treatment also increased the depressed left ventricular
weight of diabetic rats and appeared to increase the density of the sarcolemma
and transverse tubular system to normalize Na+-K+-ATPase activity. Therefore, a
shift in myocardial substrate utilization may represent an important signal for
improving the depressed cardiac function and Na+-K+-ATPase activity in diabetic
rat hearts with impaired glucose utilization.
PMID: 10066690 [PubMed - indexed for MEDLINE]
80. Mol Cell Biochem. 1998 Nov;188(1-2):225-33.
Development of pressure overload induced cardiac hypertrophy is unaffected by
long-term treatment with losartan.
Turcani M, Rupp H.
Institute of Pathophysiology, Medical School, Comenius University, Bratislava,
Slovak Republic.
Left ventricular hypertrophy with adequate wall thickness, preserved adult
phenotype and extracellular matrix may be useful in the prevention of heart
failure. Because activation of subtype 1 of angiotensin II (AT1) receptors is
thought to be involved in the hypertrophic response of cardiomyocytes, we tested
the potential of systemic AT1 blockade to modify the development of left
ventricular hypertrophy due to pressure overload. Sham-operated rats and rats
with ascending aorta constriction were treated with losartan (30 mg/kg/day) for 8
weeks. Left ventricular geometry, dynamics of isovolumic contractions,
hydroxyproline concentration as well as myosin isozymes (marker of fetal
phenotype) were assessed. Rats with aortic constriction exhibited a marked
increase in left ventricular weight and the diastolic pressure-volume
relationship was shifted to smaller volumes. An enlarged ventricular
pressure-volume area and increased (p < 0.05) peak values of +dP/dtmax and-
dP/dtmax demonstrated an enhanced overall ventricular performance. Signs of
congestive heart failure were not apparent. In contrast, parameters of myocardial
function (normalized length-stress area, +d delta /dtmax and -d delta /dtmax)
were depressed (p < 0.05), indicating an impaired myocardial contractility. The
hydroxyproline concentration remained unaltered. However, the proportion of
beta-myosin heavy chains (MHC) was increased (p < 0.05). Administration of
losartan decreased (p < 0.05) blood pressure and body weight in sham operated and
pressure overloaded rats. By contrast, neither the concentric left ventricular
hypertrophy or depressed myocardial function nor the increased beta-MHC
expression were significantly altered. Thus, activation of AT1 receptors appears
not to be involved in the initial expression of the fetal phenotype of pressure
overloaded heart which may be responsible for the progressive functional
deterioration of the hypertrophied ventricle.
PMID: 9823028 [PubMed - indexed for MEDLINE]
81. Mol Cell Biochem. 1998 Nov;188(1-2):209-15.
Differential influence of fasting and BM13.907 treatment on growth and phenotype
of pressure overloaded rat heart.
Rupp H, Elimban V, Dhalla NS.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Canada.
To examine metabolic influences on markers of the fetal phenotype of pressure
overloaded rat heart, rats with stenosis of the abdominal aorta were
intermittently fasted for 10-12 weeks. Although intermittent fasting, which
reduces insulin mediated glucose uptake in the heart and moderate pressure
overload of the left ventricle increased the proportion of myosin beta-heavy
chains (beta-MHC) and reduced the Ca(2+)-stimulated ATPase activity of
sarcoplasmic reticulum (SR) to a similar extent, these interventions had no
additive effects when combined. Furthermore, addition of sucrose (0.8%) to the
drinking water prevented the changes in both the beta-MHC proportion and SR
Ca(2+)-stimulated ATPase activity due to pressure overload or fasting. To assess
the effects of a drug which stimulates glucose-carrier translocation, rats with
stenosis of the abdominal aorta were treated with BM13.907 (50 and 100 mg/kg
daily for 10-12 weeks). This treatment amplified the left ventricular hypertrophy
(+43 vs. 21% of untreated rats) and increased the beta-MHC proportion. The SR
Ca(2+)-stimulated ATPase activity of pressure overloaded rats treated with
BM13.907 (100 mg/kg/day) was, however, not reduced compared with sham operated
control rats. Thus, an intervention which is known to stimulate insulin-mediated
glucose-carrier translocation, but not glucose-carrier activation, partially
prevented the characteristic phenotype of pressure overloaded hearts. These data
provide further evidence in favor of metabolic influences linked to glucose
uptake on growth and phenotype of the pressure overloaded heart.
PMID: 9823026 [PubMed - indexed for MEDLINE]
82. Mol Cell Biochem. 1998 Nov;188(1-2):177-85.
Influence of different culture conditions on sarcoplasmic reticular calcium
transport in isolated neonatal rat cardiomyocytes.
Vetter R, Kott M, Schulze W, Rupp H.
Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
This study investigates sarcoplasmic reticulum (SR) calcium-(Ca2+) transport
ATPase (SERCA2a) and phospholamban (PLB) in cultured spontaneously contracting
neonatal rat cardiomyocytes (CM) to ascertain the function of both SR proteins
under various culture conditions. The two major SR proteins were readily
detectable in cultured CM by immunofluorescent microscopy using specific
anti-SERCA2 and anti-PLB antibodies. Double labeling technique revealed that
PLB-positive CM also labeled with anti-SERCA2. Coexpression of SERCA2 and PLB in
CM was supported by measurement of cell homogenate oxalate-supported Ca2+ uptake
which was completely inhibited by thapsigargin and stimulated by protein kinase
A-catalyzed phosphorylation. Under serum-free conditions, incubation of CM with
the SERCA2a expression modulator 3,3', 5-triiodo-L-thyronine (100 nM, 72 h)
resulted in elevated Ca2+ uptake of +33%. Specific Ca2+ uptake activity was not
altered if insulin was omitted from the serum-free culture medium but total SR
Ca2+ transport activity was reduced under this culture condition. The results
indicate that primary culture of spontaneously contracting neonatal rat CM can be
employed as a useful model system for investigating both short- and long-term
mechanisms determining the Ca2+ re-uptake function of the SR under defined
culture conditions.
PMID: 9823023 [PubMed - indexed for MEDLINE]
83. J Mol Cell Cardiol. 1998 Jun;30(6):1237-46.
Angiotensin II and intracellular calcium of adult cardiac fibroblasts.
Brilla CG, Scheer C, Rupp H.
Molecular Cardiology Laboratory, Philipps University of Marburg, Germany.
In various cardiovascular disorders, circulating or myocardial angiotensin II
(Ang II) levels are increased, leading to excess collagen synthesis of cardiac
fibroblasts. To characterize signal transduction mechanisms of Ang II, we
examined changes in intracellular Ca2+ concentration ([Ca2+]i) of fura-2-loaded
cultured adult rat cardiac fibroblasts by fluorescence photometry. [Ca2+]i was
increased by Ang II via AT1 receptors in a dose-dependent manner (EC50 = 2.4 x
10(-8) mol/l) involving two distinct phases, an initial Ca2+ peak and a sustained
elevated plateau phase. The initial Ca2+ peak occurred transiently and
independently of the duration of Ang II application. While the magnitude of the
transient Ca2+ peak did not differ in a nominally Ca(2+)-free (3 mmol/l EGTA)
solution, the Ang II-mediated sustained plateau phase of [Ca2+]i was dependent on
extracellular Ca2+. Thus, the initial transient Ca2+ peak appears to arise from
intracellular Ca2+ stores, whereas the plateau phase involves an external Ca2+
influx. Since collagen synthesis of cardiac fibroblasts is maximally stimulated
by Ang II or by fetal bovine serum (FBS), the effects of Ang II and FBS on
[Ca2+]i were compared. The magnitude of the transient Ca2+ peak induced by 10(-7)
mol/l Ang II was comparable to that of 10% FBS indicating that the rise in
[Ca2+]i might be involved in the signal transduction pathway of Ang II-mediated
collagen synthesis of cardiac fibroblasts.
PMID: 9689597 [PubMed - indexed for MEDLINE]
85. Mol Cell Biochem. 1998 Jan;178(1-2):353-66.
Is a dietary n-3 fatty acid supplement able to influence the cardiac effect of
the psychological stress?
Rousseau D, Moreau D, Raederstorff D, Sergiel JP, Rupp H, Muggli R, Grynberg A.
INRA, Unité de Nutrition Lipidique, Dijon, France.
Epidemiological studies suggest that n-3 polyunsaturated fatty acids (PUFA) are
involved in the prevention of cardiovascular disease. Stress is known to increase
the incidence of CVD and the present study was realised to evaluate some
physiological and biochemical effects of dietary docosahexaenoic acid (DHA) in
male Wistar rats subjected to a psycho social stress. Rats were fed for 8 weeks a
semi-purified diet containing 10% of either sunflower seed oil or the same oil
supplemented with DHA. This food supply represented 50% of their daily
requirement. The remaining 50% were supplied as 45 mg food pellets designed to
induce stress in rats by an intermittent-feeding schedule process. The control
group (n = 12) was fed the equivalent food ration as a single daily feeding. The
physiological cardiovascular parameters were recorded by telemetry through a
transmitter introduced in the abdomen. At the end of the experimentation, the
heart and adrenals were withdrawn and the fatty acid composition and the
catecholamine store were determined. Dietary DHA induced a pronounced alteration
of the fatty acid profile of cardiac phospholipids (PL). The level of all the n-6
PUFAs was reduced while 22:6 n-3 was increased. The stress induced a significant
increase in heart rate which was not observed in DHA-fed group. The time
evolution of the systolic blood pressure was not affected by the stress and was
roughly similar in the stressed rats of either dietary group. Conversely, the
systolic blood pressure decreased in the unstressed rats fed DHA. Similar data
were obtained for the diastolic blood pressure. The beneficial effect of DHA was
also observed on cardiac contractility, since the dP/dt(max) increase was
prevented in the DHA-fed rats. The stress-induced modifications were associated
with an increase in cardiac noradrenaline level which was not observed in DHA-fed
rats. The fatty acid composition of adrenals was significantly related to the
fatty acid intake particularly the neutral lipid fraction (NL) which incorporated
a large amount of DHA. Conversely, n-3 PUFAs were poorly incorporated in adrenal
phospholipids. Moreover the NL/PL ratio was significantly increased in the DHA
fed rats. The amount of adrenal catecholamines did not differ significantly
between the groups. These results show that a supplementation of the diet with
DHA induced cardiovascular alterations which could be detected in conscious
animals within a few weeks. These alterations were elicited by a reduced heart
rate and systolic and diastolic blood pressure.
PMID: 9546620 [PubMed - indexed for MEDLINE]
86. J Hypertens Suppl. 1997 Dec;15(6):S13-9.
Renin-angiotensin system and myocardial collagen matrix: modulation of cardiac
fibroblast function by angiotensin II type 1 receptor antagonism.
Brilla CG, Scheer C, Rupp H.
Division of Cardiology, Philipps University of Marburg, Germany.
BACKGROUND: Left ventricular hypertrophy is an adaptive process to increased
loading of the left ventricle. This condition becomes pathologic with impaired
myocardial function if the various tissue compartments of the myocardium
(myocyte, interstitial and vascular compartments) are inhomogeneously altered,
particularly if myocardial fibrosis occurs. In arterial hypertension, myocardial
fibrosis is known to occur in association with activated circulating or local
renin-angiotensin systems and includes reactive perivascular and interstitial
fibrosis in both the pressure-overloaded hypertrophied left ventricle and the
normotensive non-hypertrophied right ventricle. Therefore, it appears that
hemodynamics are not primarily responsible for the adverse myocardial collagen
matrix remodeling in hypertensive heart disease. Accordingly, we studied the
interaction between cultured adult rat cardiac fibroblasts, which express
messenger (m)RNAs for types I and III collagens, the major fibrillar collagens in
the heart, and angiotensin II (Ang II), the effector hormone of the
renin-angiotensin system. OBJECTIVES: Specifically, we sought to determine
whether Ang II stimulates total collagen synthesis and the expression of type I
collagen mRNA in cultured adult rat cardiac fibroblasts, and to investigate the
effects of Ang II on intracellular Ca2+ levels. MATERIALS AND METHODS: Adult rat
cardiac fibroblasts were cultured in Dulbecco's Modified Eagle's Medium + 10%
fetal calf serum and incubated for 24 h with Ang II with or without specific Ang
II type 1 or type 2 receptor antagonists. Collagen synthesis was measured using a
3H-proline incorporation assay, and type I collagen mRNA was determined using
reverse-transcriptase polymerase chain reaction. Intracellular Ca2+ transients
were measured by fast fluorescence photometry using the fluorescent dye
fura-2-acetoxymethylester. RESULTS: We found a 76% increase in type I collagen
mRNA in cultured cardiac fibroblasts after a 24-h incubation with Ang II, and
this was abolished by simultaneous incubation with the Ang II type 1
(AT1)-receptor antagonist candesartan. Likewise, total collagen synthesis was
stimulated by Ang II in a dose-dependent manner, and this stimulation was also
counteracted by candesartan. Additionally, incubation with Ang II resulted in a
significant dose-dependent increase in intracellular Ca2+ transients which was
also abolished by treatment with candesartan. CONCLUSIONS: Ang II stimulates
collagen synthesis in cultured adult rat cardiac fibroblasts via AT1 receptors,
most likely using Ca2+ as a second messenger. These findings suggest a direct
interaction between Ang II and cardiac fibroblasts in mediating myocardial
fibrosis in arterial hypertension, leading to pathologic left ventricular
hypertrophy with initially impaired diastolic and ultimately reduced systolic
function of the left ventricle. The AT1-receptor antagonist candesartan
cilexetil, which is the prodrug of the active compound candesartan, may prove
valuable in preventing or regressing myocardial fibrosis in hypertensive heart
disease.
PMID: 9493122 [PubMed - indexed for MEDLINE]
87. Am J Physiol. 1998 Feb;274(2 Pt 2):H416-23.
Modification of cardiac beta-adrenoceptor mechanisms by H2O2.
Persad S, Rupp H, Jindal R, Arneja J, Dhalla NS.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Manitoba, Canada.
From the role of oxidative stress in cardiac dysfunction, we investigated the
effect of H2O2, an activated species of oxygen, on beta-adrenoceptors, G
proteins, and adenylyl cyclase activities. Rat heart membranes were incubated
with different concentrations of H2O2 before the biochemical parameters were
measured. Both the affinity and density of beta 1-adrenoceptors were decreased,
whereas the density of the beta 2-adrenoceptors was decreased and the affinity
was increased by 1 mM H2O2. Time- and concentration-dependent biphasic changes in
adenylyl cyclase activities in the absence or presence of isoproterenol were
observed when membranes were incubated with H2O2; however, activation of the
enzyme by isoproterenol was increased or unaltered. The adenylyl cyclase
activities in the absence or presence of forskolin, NaF, and Gpp(NH)p were
depressed by H2O2. Catalase alone or in combination with mannitol was able to
significantly decrease the magnitude of alterations due to H2O2. The cholera
toxin-stimulated adenylyl cyclase activity and ADP ribose labeling of Gs proteins
were decreased by treatment with 1 mM H2O2, whereas Gi protein activities, as
reflected by pertussis toxin-stimulation of adenylyl cyclase and ADP
ribosylation, were unaltered. The Gs and Gi protein immunoreactivities, estimated
by labeling with respective antibodies, indicate a decrease in binding to the
45-kDa band of Gs protein, whereas no change in the binding of antibodies to the
52-kDa band of Gs protein or the 40-kDa subunit of Gi protein was evident when
the membranes were treated with 1 mM H2O2. These results suggest that H2O2 in
high concentrations may attenuate the beta-adrenoceptor-linked signal
transduction in the heart by changing the functions of Gs proteins and the
catalytic subunit of the adenylyl cyclase enzyme.
PMID: 9486243 [PubMed - indexed for MEDLINE]
90. Herz. 1997 Aug;22(4):183-9.
[Transmyocardial laser revascularization--an innovative pathophysiologic concept]
[Article in German]
Brilla CG, Rybinski L, Gehrke D, Rupp H.
Zentrum Innere Medizin, Abteilung Innere Medizin-Kardiologie,
Philipps-Universität Marburg.
In patients with coronary artery disease where standard revascularization
procedures are not appropriate, transmyocardial laser revascularization (TMLR)
represents an innovative technique which is currently validated worldwide.
Initially, it has been assumed that myocardial perfusion of ischemic regions
could be instantly improved by inducing TMLR channels, which, however, might not
be confirmed in ongoing studies. Indeed, the gain in O2 diffusion surface
obtained by 20 patent TMLR channels is only 6 cm2 which accounts for just 0.01%
of the total capillary surface (47000 cm2) of the myocardium. Instead, a chronic
structural remodeling of myocardial regions, adjacent to TMLR channels and
mediated by TMLR-induced expression of vascular endothelial growth factor (VEGF),
may occur leading to neocapillarization of ischemic myocardium irrespective of
the long-term patency of TMLR channels and, thereby, would improve myocardial
perfusion (Figure 1). Six weeks following TMLR in the pig, patent TMLR channels
were not observed. Instead, a marked degree of reparative fibrosis was found at
the site of TMLR-treated myocardial regions (Figure 2). It is, however, not
known, whether ischemic conditions would affect chronic channel patency. TMLR
combined with intramyocardial administration of 0.5 microgram VEGF between the
laser-induced channels resulted in few patent channels (Figure 3). The apparently
low efficacy of VEGF applied as protein could be attributed to degradation of
VEGF by local peptidases. In addition to VEGF, other growth factors and the
interaction of endothelial cells and the extracellular matrix need to be
considered. Of particular relevance appears alpha v beta 3-integrin which is
needed for adhesion of endothelial cells to extracellular matrix components and
is, therefore, required for neocapillarization. Among various other growth
factors associated with neoangiogenesis, TGF-beta 1 and PDGF-BB are involved in
the formation of extracellular matrix anchoring newly formed vessels. Thus, the
expression of VEGF and alpha V beta 3-integrin in myocardial regions surrounding
TMLR channels appears to be of major importance for the development of
neoangiogenesis within the ischemic myocardium. Whether concomitant therapeutical
strategies, i. e., gene transfer leading to over-expression of VEGF, will
optimize the TMLR procedure by improving neoangiogenesis remains to be elucidated
in future experimental studies.
PMID: 9378452 [PubMed - indexed for MEDLINE]
92. Praxis (Bern 1994). 1997 Apr 2;86(14):566-74.
[Spironolactone: renaissance of anti-aldosterone therapy in heart failure?]
[Article in German]
Brilla CG, Schencking M, Scheer C, Rupp H.
Zentrum Innere Medizin, SP Kardiologie, Philipps-Universität Marburg.
Mortality of patients with severe congestive heart failure (CHF) is still high
despite combined treatment with angiotensin-converting enzyme (ACE) inhibitors,
diuretics, and digitalis. Further therapeutic regimens are needed which include
reversal of adverse myocardial remodeling and subsequent ventricular dysfunction.
One third of all patients with CHF have diastolic left ventricular (LV)
dysfunction with preserved systolic function. In these patients myocardial
collagen matrix is the major determinant of myocardial stiffness and therefore
diastolic function. Cardiac fibroblasts, expressing mRNA for types I and III
collagens which are the major fibrillar proteins of the myocardial collagen
network and for matrix metalloproteinase (MMP) 1 which is the key enzyme for
interstitial collagen degradation, are controlled by the
renin-angiotensin-aldosterone (RAAS) system irrespective of hemodynamics and
cardiac myocyte growth. In the rat with primary or secondary hyperaldosteronism,
myocardial fibrosis occurs in the pressure overloaded, hypertrophied left and in
the normotensive, nonhypertrophic right ventricle. In contrast, no fibrosis is
found in either ventricle of rats with infrarenal aortic banding, when the RAAS
is not activated, despite comparable systemic hypertension and LV hypertrophy. In
cultured cardiac fibroblasts, either effector hormone of the RAAS, angiotensin
(Ang) II and aldosterone (Aldo) stimulate collagen synthesis measured by
3H-proline incorporation under serum-free conditions. Aldo is able to stimulate
collagen synthesis normalized per total protein synthesis in a dose-dependent
manner and at concentrations (10(-9) M) which are comparable to stimulated states
in vivo (e.g., CHF). While Aldo does not affect collagen degradation AngII
significantly inhibits, MMP 1 activity that would lead to further accumulation of
collagen in the myocardium. Specific AngII type I or Aldo receptor antagonists
are able to abolish the AngII or Aldo-mediated increase in collagen synthesis,
respectively. In vivo in rats with primary or secondary hyperaldosteronism, the
Aldo antagonist spironolactone has been shown to prevent myocardial fibrosis in
both ventricles irrespective of the development of LV hypertrophy and
hypertension. Thus, in vivo and in vitro evidence could be provided that the
mineralocorticoid. Aldo, plays a pivotal role in promoting myocardial fibrosis
and can be antagonized by its competitive receptor blocker, spironolactone. This
may be of particular clinical relevance in treating patients with CHF where the
RAAS is activated leading to myocardial fibrosis with subsequent deterioration of
myocardial function. Clinical trials are needed to confirm these experimental
data. If the ongoing RALES mortality study will prove that survival and/or
morbidity of patients with CHF are improved by combined ACE
inhibitor/spironolactone treatment a renaissance of anti-aldosterone therapy in
patients with CHF would occur.
PMID: 9198851 [PubMed - indexed for MEDLINE]
93. Am J Physiol. 1997 Mar;272(3 Pt 2):R776-82.
Schedule-induced psychological stress and molecular structures of cardiomyocytes.
Rupp H, Maisch B, Brilla CG.
Institute of Physiology, University of Tübingen, Germany.
Rupp@mailer.uni-marburg.de
To establish a psychological stress model, we characterized in rats the effects
of chronic (5-6 wk) scheduled food pellet feeding (35 mg/80 s for 8 h/day).
Because the scheduled intake of pellets required that rats have access to 80% of
ad libitum intake, the effect of food restriction was also examined by
withholding food intermittently for 24 or 48 h each, followed by 24 h free access
to food. Cardiac norepinephrine concentration was significantly increased (1,076
+/- 169 vs. 693 +/- 107 ng/g, P < 0.05) in rats subjected to pellet feeding
compared with pair-fed rats (same amount of pellets in one portion) or 24- or
48-h intermittently fasted rats; similarly, the epinephrine content of adrenal
glands was increased (P < 0.05). Left ventricular rate of sarcoplasmic reticulum
Ca2+ uptake was decreased (P < 0.05) compared with pair-fed rats, reaching values
observed for 24-h fasted rats, whereas the proportion of alpha-myosin heavy
chains was only slightly reduced. Thus the schedule-induced stress arising from
pellet feeding exhibits features of stress models involving physical pain and
appears to stimulate the adrenergic system with subsequent impairment of Ca2+
cycling that is typical of various heart diseases.
PMID: 9087639 [PubMed - indexed for MEDLINE]
94. J Mol Cell Cardiol. 1997 Feb;29(2):799-811.
Partial inhibition of protein synthesis by Pseudomonas exotoxin A deranges
catecholamine sensitivity of cultured rat heart myocytes.
Müller-Werdan U, Pfeifer A, Hübner G, Seliger C, Reithmann C, Rupp H, Werdan K.
Department of Medicine III, University of Halle-Wittenberg, Klinikum Kröllwitz,
Halle, Germany.
To elucidate cellular mechanisms of myocardial depression in Pseudomonas sepsis
the effects of sublethal concentrations of P. aeruginosa exotoxin A--a main
virulence factor--were studied in cultured neonatal rat cardiomyocytes. It is
known that this toxin exerts its pathogenic effect by inhibition of protein
synthesis via ADP-ribosylation and thereby inactivation of elongation factor 2
(EF-2). Within 48 72 h, half maximal inhibition of protein synthesis occurs at
4-10 ng/ml. The toxin prevents the beta-adrenoceptor(AR)-mediated myosin heavy
chain isozyme shift (V3/V1), while the T3-induced myosin shift is not suppressed.
While beta 1-AR-downregulation by excess of norepinephrine (NE) is not affected,
protein synthesis-dependent receptor upregulation in the recover period after
removal of NE is completely suppressed by P. aeruginosa exotoxin A. Thus, a
non-lethal, partial inhibition of global cellular protein synthesis by P.
aeruginosa exotoxin A: (1) completely prevents beta 1-AR-mediated myosin isozyme
shift and beta-AR upregulation: (2) sustains the cardiomyocytes in a
catecholamine-refractory contractile state in the recovery period after
catecholamine desensitization: (3) suggests cellular mechanisms by which P.
aeruginosa exotoxin A might impair heart function in Pseudomonas sepsis: and (4)
may help reveal the possible influence of endogenous inhibitors of EF-2.
PMID: 9140836 [PubMed - indexed for MEDLINE]
95. Adv Exp Med Biol. 1997;432:35-44.
Regulation and role of myocardial collagen matrix remodeling in hypertensive
heart disease.
Funck RC, Wilke A, Rupp H, Brilla CG.
Molecular Cardiology Laboratory, Philipps-University of Marburg, Germany.
In hypertensive heart disease, reactive myocardial fibrosis represents as an
excessive accumulation of fibrillar collagen within the normal connective tissue
structures of the myocardium. The fact, that the myocardium of both ventricles is
involved, irrespective of ventricular loading conditions, suggests that
circulating factors, and not the hemodynamic load are primary responsible for
this adverse response of the myocardial fibrous tissue. In various experimental
in vivo models, it has been shown that myocardial fibrosis is always associated
with activation of circulating or local renin-angiotensin-aldosterone systems
(RAAS). Cardiac collagen metabolism is regulated by cardiac fibroblasts which
express mRNAs for types I and III collagens, the major fibrillar collagens in the
heart, and for interstitial collagenase or matrix metalloproteinase (MMP) 1 which
is the key enzyme for interstitial collagen degradation. In order to elucidate
the role of the RAAS effector hormones, angiotensin II (AngII) and aldosterone
(ALDO), in the regulation of collagen synthesis or inhibition of MMP 1
production, adult human cardiac fibroblasts were cultured. Collagen synthesis was
determined by 3H-proline incorporation, and MMP 1 activity by degradation of
14C-collagen measured under serum-free conditions in confluent fibroblasts after
24 hour-incubation with either AngII or ALDO over a wide range of concentrations
(10(-11)-10(-6)M). In addition, the effects of the mineralocorticoid,
deoxycorticosterone (DOC), and prostaglandin E2 (PGE2) on cardiac fibroblast
function were determined. Compared with untreated control fibroblasts, collagen
synthesis, normalized per total protein synthesis, showed a significant and
dose-dependent increase after incubation with either mineralocorticoid hormone,
ALDO or DOC, or after incubation with AngII. In contrast, collagen synthesis of
cardiac fibroblasts was significantly decreased by PGE2 treatment. AngII type 1
or mineralocorticoid receptor antagonists, respectively, were able to completely
inhibit the AngII- or mineralocorticoid-mediated increase of collagen synthesis.
Furthermore, AngII significantly decreased MMP 1 activity while ALDO or DOC had
no effect on cardiac fibroblast-mediated collagen degradation. In contrast, PGE2
significantly increased MMP 1 activity. Thus cardiac fibroblast function is
modulated by either effector hormone of the RAAS, AngII and ALDO, via specific
receptors that lead to progressive myocardial fibrosis in disease states where
circulating or local RAAS is activated, i.e., in hypertensive heart disease. In
contrast, PGE2, which would be elevated in myocardial tissue after
angiotensin-converting enzyme inhibition, counteracts the fibrotic effects of the
RAAS on myocardial tissue.
PMID: 9433509 [PubMed - indexed for MEDLINE]
96. Mol Cell Biochem. 1996 Sep 6;162(1):59-64.
Dietary linolenic acid-mediated increase in vascular prostacyclin formation.
Rupp H, Turcani M, Ohkubo T, Maisch B, Brilla CG.
Institute of Physiology II, University of Tübingen, Germany.
To define vascular effects of an enhanced dietary alpha-linolenic acid intake, 28
spontaneously hypertensive rats were fed a 3% sunflowerseed oil (44% linoleic
acid) diet; in 3 groups (7 rats each), the diet was supplemented with 1, 2.5 or
5% linseed oil containing 62% alpha-linolenic acid. alpha-Linolenic acid was
incorporated up to 12% in the aorta of the 5% linseed oil group. The
eicosapentaenoic acid content was not significantly increased. The content of
arachidonic acid and docosatetraenoic acid was moderately reduced in rats fed 5%
linseed oil. The generation of 6-keto-PGF1 alpha (degradation product of
prostacyclin) assessed by HPLC/electrochemical detection was, however, markedly
increased (p < 0.05) in rats fed 2.5 and 5% linseed oil. The minor prostanoids
TXB2, PGE2 and PGF2 alpha were not significantly altered. The high systolic and
diastolic blood pressure of SHR monitored by radio telemetry was more effectively
reduced (p < 0.05) in the light, i.e. sleep, cycle. An increased prostacyclin
formation and lowered vascular arachidonic acid content associated with enhanced
dietary alpha-linolenic acid intake would thus be expected to prove beneficial in
the prevention of vascular disorders.
PMID: 8905626 [PubMed - indexed for MEDLINE]
97. FASEB J. 1996 Sep;10(11):1303-9.
Modification of sarcoplasmic reticulum gene expression in pressure overload
cardiac hypertrophy by etomoxir.
Zarain-Herzberg A, Rupp H, Elimban V, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Manitoba, Canada.
Pressure overload on the heart is known to produce hypertrophy of cardiomyocytes
and distinct changes in protein phenotype, including reduced expression of the
gene for the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA2). In this study we
have shown that the decrease in SERCA2 gene expression (normalized by poly(A)+
mRNA or 18 S rRNA) in rats with 8 wk of aortic constriction was prevented by
treatment with etomoxir, an inhibitor of carnitine palmitoyltransferase 1. The
reduction in steady-state mRNA levels for SR phospholamban (PLP) and Ca2+ release
channel (CRC) in the pressure-overloaded animals was also prevented without any
reduction in the extent of cardiac hypertrophy by treatment with etomoxir.
Although no changes in mRNA levels for GAPDH were evident in rats with pressure
overload, the expression of the alpha-skeletal actin was increased; this change
was prevented by etomoxir. Similar beneficial effects of etomoxir treatment were
also evident when the gene expression for SR SERCA2, PLP, and CRC in the
hypertrophied heart was normalized with respect to mRNA for GAPDH. These results
support the view that drugs such as etomoxir may increase the abundance of the
mRNA for SR proteins in the hypertrophied heart and thus may prevent the
transition of cardiac hypertrophy into heart failure.
PMID: 8836044 [PubMed - indexed for MEDLINE]
98. Herz. 1996 Aug;21(4):258-64.
[Hypertension and alcohol: central and peripheral mechanisms]
[Article in German]
Rupp H, Brilla CG, Maisch B.
Abteilung für Innere Medizin, Schwerpunkt Kardiologie, Molekular-kardiologisches
Labor, Philipps-Universität Marburg.
Despite intense research efforts, the etiology of primary hypertension remains
ill-defined. During our work on molecular influences of lifestyle factors on
hypertension, the question arose to what extent cellular and molecular events
could be involved in alcohol-induced hypertension. There is increasing evidence
that alcohol initiates central as well as peripheral reactions which in a
synergistic manner have a hypertensive action. Thus, alcohol diminishes the baro
(presso) reflex by interacting with receptors in the brain stem, i.e. nucleus
tractus solitarii and rostral ventrolateral medulla. In addition, alcohol induces
an increased sympathetic outflow, most probably linked to secretion of
corticotropin-releasing hormone. The increased sympathetic outflow is expected
not only to induce adrenoceptor-mediated reactions (vasoconstriction, heart rate
increase) but to stimulate oxidation reactions. Deleterious peripheral actions
result from acetaldehyde which binds to macromolecules if the abundance of
cysteine and glutathione is limited. This acetaldehyde induced reduction of low
molecular weight thiol compounds can be interpreted as "oxidative stress" which
has various unfavourable consequences. The hypertensive action of alcohol should
be taken into account when discussing its potential protective influence on
coronary risk.
PMID: 8805006 [PubMed - indexed for MEDLINE]
99. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:251-62.
Drug withdrawal and rebound hypertension: differential action of the central
antihypertensive drugs moxonidine and clonidine.
Rupp H, Maisch B, Brilla CG.
Institute of Physiology, University of Tubingen, Germany.
To examine the antihypertensive action of the centrally acting antiadrenergic
drugs moxonidine and clonidine, systolic and diastolic blood pressure as well as
heart rate were monitored by radio telemetry in spontaneously hypertensive rats
(SHR) with established high blood pressure. Increasing doses were administered
with regular rat chow for 6-8 day periods. Moxonidine reduced (p < 0.05)
diastolic blood pressure at a dose of 8 mg/kg/day and systolic blood pressure at
13 mg/kg/day. Heart rate was reduced during high activity of rats corresponding
to an antitachycardiac action. After withdrawal of 18 mg/kg administered for only
1 day, blood pressure returned to pretreatment values within 8 days. Clonidine
reduced systolic and diastolic blood pressure at 0.3 mg/kg/day. At 0.8 and 1.3
mg/kg/day, systolic blood pressure reduction was less pronounced, although heart
rate was reduced further, reaching values that were below those of untreated
sleeping rats. When 1.3 mg/kg/day clonidine was discontinued, systolic as well as
diastolic blood pressure increased above pretreatment values within 1 day. A
rebound was also observed in heart rate, which increased by 150 beats/ min. A
comparable rebound in blood pressure was observed after withdrawal of 0.3
mg/kg/day. Since a blood pressure rebound occurred also after withdrawal of 0.3
mg/kg/day clonidine in normotensive rats, the rebound phenomenon was independent
of the presence of high blood pressure. No blood pressure rebound was observed
when moxonidine (8 mg/kg/ day) was administered (chow or gavage) in normotensive
rats. These findings in unanesthetized undisturbed rats demonstrate distinct
differences in the mode of action of moxonidine and clonidine, which can be
accounted for by specific interactions of moxonidine with imidazoline
I1-receptors, whereas clonidine would interact not only with I1-receptors but
also with alpha2-adrenoceptors, and most probably also with the vagal activity.
In view of our previous studies demonstrating a rise in blood pressure and heart
rate after a hypercaloric dietary intake, the selective I1-receptor agonist
moxonidine appears particularly appropriate for treating overweight hypertension
associated with an enhanced sympathetic outflow of the brain. Of importance in
this respect is that a moxonidine-induced reduction in sympathetic outflow was
not associated with a gain in body weight but resulted in reduced caloric intake.
PMID: 8827948 [PubMed - indexed for MEDLINE]
100. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:247-50.
Effects of long-term dietary restriction on cardiovascular function and plasma
catecholamines in the rat.
Hilderman T, McKnight K, Dhalla KS, Rupp H, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
To examine the relationship between heart function and plasma catecholamines upon
food restriction, normal adult rats were fed 12 g or 6 g food/day for 14 days and
12 g food/day for 28 days. Food-restricted rats exhibited bradycardia,
hypotension, and decreased rates of cardiac contraction (+dP/dt) as well as
relaxation (-dP/dt) at 14 (12 or 6 g food/day) and 28 (12 g food/day) days.
Plasma norepinephrine and epinephrine levels were significantly elevated in the 6
g food/day group at 14 days, whereas in the 12 g food/day group, plasma
norepinephrine was elevated at 14 days but was significantly decreased at 28
days. Heart norepinephrine and epinephrine concentrations were elevated at both
14 and 28 days of food restriction in the 12 g food/day group as well as at 14
days in the 6 g food/day group. Thus, dietary restriction appears to result in
depressed indices of heart function, while the circulating levels of
catecholamines were elevated at early stages.
PMID: 8827947 [PubMed - indexed for MEDLINE]
101. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:239-46.
Modification of catecholamine-induced changes in heart function by food
restriction in rats.
McKnight KA, Rupp H, Beamish RE, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
In view of the common practice of dieting for weight reduction, the influence of
severe food restriction (about 25% of ad libitum intake) on adrenergic mechanisms
was studied. Cardiac norepinephrine and epinephrine concentrations as well as
plasma norepinephrine levels, were increased upon feeding a restricted diet to
rats for 14 days in comparison with control rats that ingested about 30 g food/
day. Bradycardia as well as characteristic electrocardiographic abnormalities,
including prolongation of the QRS and QT intervals, were observed in
food-restricted rats. Diet-restricted rats did not develop ventricular
arrhythmias in response to epinephrine injections as readily as control rats.
Depression in both + dP/dt and -dP/dt of the heart in situ as well as reductions
in the inotropic responses to epinephrine were evident in diet-restricted rats.
Beta-adrenergic binding studies revealed a significant decrease in receptor
density, but the dissociation constant for binding was also depressed in the
food-restricted rat heart. Downregulation of the beta-adrenergic receptors in the
heart may explain the lack of an epinephrine-induced increase in contractile
force development as well as arrhythmias in food-restricted rats. These data
demonstrate that severe food restriction has marked effects on adrenergic
mechanisms and heart function, and thus some caution should be exercised at early
periods of this therapy for weight reduction.
PMID: 8827946 [PubMed - indexed for MEDLINE]
102. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:231-8.
Mechanisms of alterations in cardiac membrane Ca2+ transport due to excess
catecholamines.
Dhalla KS, Rupp H, Beamish RE, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
The occurrence of excessive catecholamine release is often associated with stress
due to the lifestyle of Western societies. Contrary to the general thinking that
excess catecholamines produce cardiotoxicity mainly via binding to adrenoceptors,
there is increasing evidence that catecholamine-induced deleterious actions may
also occur through oxidative mechanisms. In this overview it is shown that a high
dose of isoproterenol induces a biphasic change in cardiac Ca2+ transport in the
sarcolemma and in sarcoplasmic reticulum. Both sarcolemmal and sarcoplasmic
reticular Ca2+-transport activities are initially increased to maintain Ca2+
homeostasis and then are impaired, which may be associated with the occurrence of
intracellular Ca2+ overload. On the other hand, mitochondrial Ca2+-transport
activities exhibited a delayed increase. Pretreatment with vitamin E partially
prevented the deleterious changes in cardiac membranes as well as the depressed
energetic status of the heart muscle cell. It is concluded that excess
catecholamines affect Ca2+-transport mechanisms primarily via oxidation reactions
involving free radical-mediated damage. Thus drug approaches that reduce
circulating catecholamines and/or prevent their oxidation should prove
beneficial. A combination therapy involving inhibitors of catecholamine release,
blockers of adrenoceptors, and antioxidants may be indicated for stress-induced
heart disease.
PMID: 8827945 [PubMed - indexed for MEDLINE]
103. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:223-30.
Sympathoadrenergic overactivity and lipid metabolism.
Grynberg A, Ziegler D, Rupp H.
INRA, Unité de Nutrition Lipidique, Dijon, France.
Epidemiological studies have identified high heart rates as a risk factor for
coronary heart disease mortality, and heart rate was found to correlate with the
severity of coronary atherosclerosis. Heart rate was positively correlated with
serum concentrations of total cholesterol, triglycerides, and non-HDL
cholesterol. Since heart rate responds sensitively to sympathoadrenergic
activity, it was hypothesized that catecholamines play a crucial role in the
unfavorable lipid alterations. In addition to influences on circulating lipids,
the question arose whether catecholamines have more specific effects on molecular
species of structural lipids. Of particular importance is the question of the
involvement of catecholamines in the recently suggested correlation between
arachidonic acid and stroke mortality. It is therefore attempted to delineate the
possible effects of catecholamines on the fatty acid composition of the
phospholipids of heart muscle and vasculature. This was achieved in rats by
either catecholamine injection or by swimming, a condition known to be associated
with marked sympatho-adrenergic stimulation. In swimming rats, linoleic acid was
decreased by up to 40% in heart phospholipids, whereas stearic acid and
arachidonic acid were increased. Similarly, chronic norepinephrine treatment in
rats resulted in a net decrease in linoleic acid and an increase in arachidonic
acid and docosahexaenoic acid, which was particularly pronounced when rats were
fed an n-3 polyunsaturated fatty acid (PUFA)-rich oil diet. Thus, catecholamines
do affect the PUFA composition of heart membranes, mainly through an increase in
arachidonic acid content. To further define the action of catecholamines on
structural lipids, isolated rat ventricular myocytes in culture were subjected
four times to 30 minutes of isoproterenol (10(-6) M) stimulation over 48 hours.
No changes in membrane lipid parameters were observed, although the beating rate
was increased by 30% during the stimulation. When the cell membranes were
enriched in n-3 PUFAs (in association with a decrease in arachidonic acid), the
positive chronotropic effect elicited by isoproterenol was raised to + 50%,
indicating the modulation of adrenergic function by membrane PUFAs. However,
isoproterenol treatment again had no effect on the phospholipid fatty acid
composition. Thus, the effect of catecholamines on membrane lipids observed in
intact organism appears to be indirect and to involve most probably organs such
as the liver and adipose tissue. Catecholamines are expected to induce a
lipolysis-linked quantitative and qualitative alteration in circulating fatty
acids, which in turn alter the heart membrane composition, similar to the
composition changes elicited by diet lipid alterations. Since there is increasing
evidence that such fatty acid changes affect the activity of membrane proteins,
the possibility emerges that this mechanism may contribute to the
catecholamine-linked cardiovascular mortality.
PMID: 8827944 [PubMed - indexed for MEDLINE]
104. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:213-4.
Nutritional disorders: a target for sympathetic outflow-regulating drugs
(imidazoline I1 receptor agonists)
Rupp H.
PMID: 8827942 [PubMed - indexed for MEDLINE]
106. Basic Res Cardiol. 1996;91 Suppl 2:79-84.
Effect of the renin-angiotensin-aldosterone system on the cardiac interstitium in
heart failure.
Wilke A, Funck R, Rupp H, Brilla CG.
Zentrum für Innere Medizin, Abteilung Kardiologie, Klinikum der
Philipps-Universität, Marburg.
The interaction of the renin-angiotensin-aldosterone system (RAAS) and cardiac
growth is of great interest in chronic heart failure. The pressure or volume
overloaded heart shows a hypertrophic growth of the myocardium, i.e., an
enlargement of cardiac myocytes. In addition, cardiac fibroblast activation is
responsible for the accumulation of fibrillar type I and type III collagens
within the interstitium and adventitia of intramyocardial coronary arteries. This
remodeling of the cardiac interstitium represents a major determinant of
pathological hypertrophy in that it accounts for abnormal myocardial stiffness,
leading to ventricular diastolic and systolic dysfunction and ultimately the
appearance of symptomatic heart failure. The growth of cardiac fibroblasts is not
primarily regulated by the hemodynamic load. In vivo and in vitro studies suggest
that the effector hormones, angiotensin II and aldosterone, of the RAAS are
primarily involved in regulating the structural remodeling of the myocardial
collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and
aldosterone has been shown to stimulate collagen synthesis while angiotensin II
additionally inhibits matrix metalloproteinase I activity, which is the key
enzyme for interstitial collagen degradation in the myocardium. These findings
may serve as rationale for a remedial therapy with angiotensin converting enzyme
inhibition or blockage of the RAAS in congestive heart failure in patients with
hypertensive heart disease, post myocardial infarction or with dilated
cardiomyopathy.
PMID: 8957549 [PubMed - indexed for MEDLINE]
107. Eur Heart J. 1995 Dec;16 Suppl O:107-9.
The renin-angiotensin-aldosterone system and myocardial collagen matrix
remodelling in congestive heart failure.
Brilla CG, Rupp H, Funck R, Maisch B.
Department of Internal Medicine, Philipps University of Marburg, Germany.
In chronic heart failure, various regulatory systems including the Frank-Starling
mechanism, the neuro-hormonal response, cardiac growth and peripheral oxygen
delivery may be operative. Recently, the inter-relationship of the
renin-angiotensin-aldosterone system (RAAS) and cardiac growth has drawn clinical
interest. In the pressure-or volume-overloaded heart, the development of myocyte
growth is primarily dependent on ventricular loading. Non-myocyte cell growth
involving cardiac fibroblasts may also occur but this is not primarily regulated
by the haemodynamic load. Cardiac fibroblast activation is responsible for the
accumulation of fibrillar type I and type III collagens within the interstitium
and adventitia of intramyocardial coronary arteries. In addition to relaxation
abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this
remodelling of the cardiac interstitium represents a major determinant of
pathological hypertrophy in that it accounts for abnormal myocardial stiffness,
leading to ventricular diastolic and systolic dysfunction and ultimately the
progression of symptomatic heart failure. The effector hormones of the RAAS,
angiotensin II (AngII) and aldosterone (Aldo), appear to be primarily involved in
promoting the adverse structural remodelling of the myocardial collagen matrix.
In cultured adult cardiac fibroblasts, AngII and Aldo have been shown to
stimulate collagen synthesis while AngII additionally inhibits matrix
metalloproteinase I activity, which is the key enzyme for degradation of
fibrillar collagen in the cardiac interstitium, leading to excessive collagen
accumulation. These findings may serve as rationale as to why angiotensin
converting enzyme inhibition or blockade of the RAAS represents such remedial
therapy beyond the effect of simply unloading the heart in patients with
congestive heart failure.
PMID: 8682074 [PubMed - indexed for MEDLINE]
108. Am J Cardiol. 1995 Nov 2;76(13):8D-13D.
Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast
collagen turnover.
Brilla CG, Zhou G, Rupp H, Maisch B, Weber KT.
Molecular Cardiology Laboratory, Philipps University of Marburg, Germany.
In hypertensive heart disease, after myocardial infarction or in congestive heart
failure, myocardial fibrosis presenting as a diffuse perivascular and
interstitial accumulation of fibrillar collagens within the normal connective
tissue structures of the myocardium is associated with an activated
renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded
left ventricle and the nonoverloaded right ventricle irrespective of myocyte
necrosis or the development of myocyte hypertrophy. Therefore, it appears that
hemodynamic factors or the load of the ventricle are not primarily responsible
for the adverse fibrous tissue response in the myocardium, and humoral factors
may play a key role in regulating the myocardial collagen matrix. The
neurohumoral response in hypertensive heart disease, after myocardial infarction
with overall deterioration of left ventricular function or congestive heart
failure leads to an activation of either the cardiac or the circulating RAS,
which closely interacts with the bradykinin-prostaglandin system. To ascertain
whether the RAS modulates collagen fibroblasts that express mRNAs for types I and
III collagens (the major fibrillar collagens in the heart) and matrix
metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen
synthesis was measured by [3H]proline incorporation normalized to total protein
synthesis and MMP1 activity was determined by degradation of [14C]collagen in
cultured fibroblasts after 24-hour incubation with various concentrations of
angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In
addition, effects of angiotensin II were evaluated in the presence or absence of
either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2
(10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 7495221 [PubMed - indexed for MEDLINE]
109. Herz. 1995 Oct;20(5):330-9.
[Cardiac structure-function relationship and the renin-angiotensin-aldosterone
system in hypertensive heart disease]
[Article in German]
Funck RC, Wilke A, Rupp H, Maisch B, Brilla CG.
Zentrum Innere Medizin-Schwerpunkt Kardiologie, Philipps-Universität Marburg.
Based on the epidemiologic data of the Framingham heart study, arterial
hypertension and coronary artery disease are the most frequent etiologic factors
for the development of heart failure. In the pressure overloaded heart,
hypertrophic growth of the myocardium includes the enlargement of cardiac
myocytes stimulated by ventricular loading. Non-myocyte cell growth involving
cardiac fibroblasts may also occur but is not primarily regulated by the
hemodynamic load. Cardiac fibroblast activation is responsible for the
accumulation of fibrillar type I and type III collagens within the interstitium
while vascular smooth muscle cell growth accounts for the medial thickening of
resistance vessels. This remodeling of the cardiac interstitium represents a
major determinant of pathological hypertrophy in that it accounts for abnormal
myocardial stiffness and impaired coronary vasodilator reserve, leading to
ventricular diastolic and systolic dysfunction and ultimately to the appearance
of symptomatic heart failure. Several lines of evidence suggest that the
renin-angiotensin-aldosterone system is involved in regulating the structural
remodeling of the nonmyocyte compartment, including the cardioprotective effects
of angiotensin converting enzyme (ACE) inhibition that was found to prevent
myocardial fibrosis in the rat with renovascular hypertension. In rats with
genetic hypertension, established left ventricular hypertrophy, abnormal
diastolic stiffness due to interstitial fibrosis, and reduced coronary
vasodilator reserve associated with medial wall thickening of intramyocardial
resistance vessels, the ACE inhibitor lisinopril was able to restore myocardial
structure and function to normal. These cardioreparative properties of ACE
inhibition may be valuable in reversing left ventricular dysfunction in
hypertensive heart disease.
PMID: 7498880 [PubMed - indexed for MEDLINE]
110. Herz. 1995 Oct;20(5):315-21.
[Experimental types of hypertension--models for essential hypertension in the
human?]
[Article in German]
Rupp H, Brilla CG.
Zentrum für Innere Medizin, Philipps-Universität Marburg.
Since the pathogenesis of essential hypertension is multifactorial, the causal
therapy of primary arterial hypertension remains a great challenge. At a given
genetic predisposition, the manifestation of hypertension depends critically on
lifestyle factors. It is thus essential to study the molecular consequences of
various deleterious lifestyle factors. We demonstrated by radiotelemetric
measurements that an increased caloric intake raises both systolic and diastolic
blood pressure as well as heart rate in spontaneously hypertensive rats (SHR).
This model is comparable to hyperkinetic hypertension in hypertensive persons
which, if it persists, will lead to established hypertension. Overfeeding also
results in the characteristic metabolic derangements (hyperinsulinemia,
hypertriglyceridemia) of insulin resistant hypertensive persons. The enhanced
sympathetic outflow of the brain can be potentiated by lifestyle factors such as
high sodium intake and psychological stress. In contrast to sodium intake,
psychological stress (e.g. schedule-induced stress) is difficult to mimic in
animal experiments. In view of the recent progress in the characterization of
imidazoline receptors in the rostral ventrolateral medulla and the development of
antihypertensive drugs with a high selectivity (moxonidine) for imidazoline
receptors, efforts should be made to elucidate key regulatory mechanisms involved
in brain insulin sensitivity and appetite regulation. Such an approach could help
in pharmacologically reducing the influence of deleterious lifestyle factors at a
given genetic predisposition.
PMID: 7498878 [PubMed - indexed for MEDLINE]
111. Am J Physiol. 1995 Sep;269(3 Pt 2):R630-40.
Dietary medium-chain triglycerides can prevent changes in myosin and SR due to
CPT-1 inhibition by etomoxir.
Rupp H, Schulze W, Vetter R.
Molecular Cardiology, Laboratory, University of Marburg, Germany.
To define determinants of subcellular structures of heart, Wistar-Kyoto rats
(WKY) and spontaneously hypertensive rats (SHR) were treated for 5 wk with 15
mg.kg-1.day-1 etomoxir [reduces mitochondrial carnitine palmitoyltransferase-1
(CPT-1) activity and fatty acid synthesis]. To bypass CPT-1 inhibition,
etomoxir-treated rats were fed a medium-chain fatty acid (MCFA) diet. Etomoxir
induced a proportionate growth of heart, which could partially (WKY, P < 0.05) or
completely (SHR, P < 0.05) be prevented by the MCFA diet. Also the
etomoxir-induced increase in myosin V1 was partially prevented (P < 0.05).
Etomoxir increased (P < 0.05) rate of sarcoplasmic reticulum (SR) Ca2+ uptake of
WKY and SHR ventricular homogenates in the presence or absence of the SR Ca2+
release inhibitor ruthenium red. The MCFA diet resulted in SR Ca2+ uptake rates
that were in between those of etomoxir-treated and untreated rats. The in vitro
32P incorporation into phospholamban and troponin I did not differ significantly
in WKY. Etomoxir induced, however, an increase (P < 0.05) in the phosphorylated
intermediate of the Ca2+ adenosinetriphosphatase in WKY that was prevented by the
MCFA diet. In SHR, etomoxir increased the in vitro phospholamban phosphorylation,
which was reduced compared with WKY. The data show that myosin and SR are
affected by a chronically altered substrate utilization of heart.
PMID: 7573566 [PubMed - indexed for MEDLINE]
114. Eur Heart J. 1995 May;16 Suppl C:15-9.
Differential influences of carnitine palmitoyltransferase-1 inhibition and
hyperthyroidism on cardiac growth and sarcoplasmic reticulum phosphorylation.
Vetter R, Kott M, Rupp H.
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
To characterize interventions resulting in 'physiological' growth of the heart,
Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) had
hyperthyroidism induced (0.05 mg.kg-1.day-1 triiodothyronine for 6 days) or were
treated with a high dose of the carnitine palmitoyltransferase-1 inhibitor,
etomoxir (15 mg.kg-1.day-1 for 5 weeks). Etomoxir increased cardiac growth
evenly, but hyperthyroidism resulted in an over-proportional higher right
ventricular weight. Both interventions increased the proportion of the myosin
isozyme V1. The rate of sarcoplasmic reticulum (SR) Ca2+ uptake was increased to
a greater extent in hyperthyroid rats than in etomoxir-treated rats (P < 0.05).
Left ventricular levels of immunoreactive phospholamban (semiquantitative ELISA)
were moderately decreased (P < 0.05) in hyperthyroid rats but not in
etomoxir-treated rats. The protein kinase A-catalyzed in vitro 32P-incorporation
into the SR Ca2+ pump modulator phospholamban was greatly reduced (P < 0.05) in
hyperthyroid rats, indicating an increased in vivo phosphorylation. Etomoxir did
not affect phospholamban phosphorylation in WKY rats. Thus, both a higher in vivo
phospholamban phosphorylation state and a greater number of active Ca2+ pumps
contributed to an increased rate of SR Ca2+ uptake in hyperthyroidism. The
etomoxir treatment primarily increased the number of active Ca2+ pumps. A scheme
is proposed focusing on long-term vs short-term regulation of the SR Ca2+
pump/phospholamban system in diseased states.
PMID: 7556265 [PubMed - indexed for MEDLINE]
115. Herz. 1995 Apr;20(2):127-34.
Pharmacological modulation of cardiac fibroblast function.
Brilla CG, Maisch B, Rupp H, Funck R, Zhou G, Weber KT.
Molecular Cardiology Lab, Philipps University of Marburg, Germany.
The cardiac interstitium is composed of nonmyocyte cells and a structural protein
network which plays a dominant role in governing the structure, architecture, and
mechanical behavior of the myocardium. The heterogeneity in myocardial structure,
created by the altered behavior of nonmyocyte cells, particularly cardiac
fibroblasts which are responsible for myocardial collagen metabolism and fibrous
tissue accumulation, may largely explain the appearance of diastolic and/or
systolic myocardial failure. Regulatory mechanisms that are related to the
fibrous tissue response in various cardiovascular diseases, e.g., hypertensive
heart disease, dilated cardiomyopathy or post myocardial infarction, are of
primary clinical interest. A better understanding of the hitherto neglected role
of cardiac fibroblasts in mediating an adverse structural remodeling of the
myocardium will lead to specific pharmacologic agents that interfere with the
fibrous tissue response. Several lines of evidence based on in vivo and in vitro
studies suggest that circulating and tissue renin-angiotensin-aldosterone systems
(RAAS) are involved in the structural remodeling of the nonmyocyte compartment,
including the cardioprotective effects of angiotensin converting enzyme (ACE)
inhibition or aldosterone receptor antagonism that was found to prevent
myocardial fibrosis in the rat with renovascular or genetic hypertension. In
cultured adult cardiac fibroblasts, an angiotensin (Ang)II- or
aldosterone-mediated dose-dependent increase in collagen synthesis could be
completely abolished by the use of AngII type 1 or mineralocorticoid receptor
antagonists, respectively. Likewise, the AngII-mediated decrease in the activity
of matrix metalloproteinase 1, the key enzyme for interstitial collagen
degradation, could be antagonized by AngII receptor blockade.(ABSTRACT TRUNCATED
AT 250 WORDS)
PMID: 7774864 [PubMed - indexed for MEDLINE]
116. Med Hypotheses. 1995 Mar;44(3):217-25.
Excess catecholamines and the metabolic syndrome: should central imidazoline
receptors be a therapeutic target?
Rupp H, Jacob R.
Molecular Cardiology Laboratory, University of Marburg, Germany.
A sympathetic overactivity plays a major role in the pathogenesis of
cardiovascular diseases in Westernized affluent societies. Of importance is an
increased caloric intake and psychosocial stress which are associated with a
raised central sympathetic outflow and unfavourable changes in metabolic
parameters. Normalization of central sympathetic outflow could thus be a major
therapeutic target. The newly developed antihypertensive drugs moxonidine and
rilmenidine reduce the excitatory activity of neurons of the rostral
ventrolateral medulla (RVLM) via binding to imidazoline receptors. Using radio
telemetry, it is shown that, in contrast to the first generation centrally acting
drug clonidine, moxonidine did not result in rebound of blood pressure after drug
withdrawal in rats with spontaneous hypertension. In accordance, moxonidine is
characterized by a low affinity for alpha-adrenoceptors and exhibits few
side-effects. It is proposed that normalization of central sympathetic outflow
represents a causal approach for improving crucial features of the metabolic
syndrome.
PMID: 7609678 [PubMed - indexed for MEDLINE]
117. Am J Physiol. 1994 Dec;267(6 Pt 2):H2091-9.
CPT-1 inhibition by etomoxir has a chamber-related action on cardiac sarcoplasmic
reticulum and isomyosins.
Vetter R, Rupp H.
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
To characterize the effect of an altered substrate utilization for cardiac
sarcoplasmic reticulum (SR) Ca2+ transport, normotensive rats were treated for 5
wk with 15 mg.kg-1.day-1 enantiomeric etomoxir, which inhibits mitochondrial
carnitine palmitoyltransferase-1 (CPT-1) and fatty acid synthesis. Ca2+ uptake
rates of left and right ventricular homogenates were differentially (P < 0.05,
two-way analysis of variance) increased by 38 and 13%, respectively. Increased (P
< 0.05) transport rates were also observed in the presence of ryanodine. The
differences were considerably reduced in the protein kinase A-stimulated state.
The levels of phosphorylated phospholamban (PLB) and troponin I as well as
immunoreactive PLB were not affected. By contrast, phosphoenzyme levels (E-P) of
the SR Ca2+ pump were increased in left ventricular (LV) homogenates. Values of
LV E-P and Ca2+ uptake were linearly correlated (P < 0.05) with the myosin V1
proportions in control (31.7 +/- 1.8% V1) and treated (58.3 +/- 2.5% V1) rats.
Thus in the left ventricle the metabolic influences have a coordinated action on
two distinct proteins involved in relaxation or contraction. The chamber-specific
differences in SR function suggest a more pronounced effect of etomoxir in
functional states characterized by a reduced Ca2+ transport rate and myosin V1
proportion.
PMID: 7810710 [PubMed - indexed for MEDLINE]
118. Cardiologia. 1994 Dec;39(12 Suppl 1):389-93.
Myocardial collagen matrix remodeling and congestive heart failure.
Brilla CG, Rupp H.
Division of Cardiology, Philipps-University of Marburg, Germany.
In chronic heart failure, the inter-relationship of the
renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of primary
clinical interest. In the pressure or volume overloaded heart, hypertrophic
growth of the myocardium includes the enlargement of cardiac myocytes--an
adaptation governed by ventricular loading. Nonmyocyte cell growth involving
cardiac fibroblast may also occur but not primarily regulated by the hemodynamic
load. Cardiac fibroblast activation is responsible for the accumulation of
fibrillar type I and type III collagens within the interstitium and adventitia of
intramyocardial coronary arteries. In addition to relaxation abnormalities due to
impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodeling of the cardiac
interstitium represents a major determinant of pathological hypertrophy in that
it accounts for abnormal myocardial stiffness, leading to ventricular diastolic
and systolic dysfunction and ultimately the appearance of symptomatic heart
failure. In vivo and in vitro studies suggest that the effector hormones,
angiotensin II and aldosterone, of the RAAS are primarily involved in regulating
the structural remodeling of the myocardial collagen matrix. In cultured adult
cardiac fibroblasts, angiotensin II and aldosterone have been shown to stimulate
collagen synthesis while angiotensin II additionally inhibits matrix
metalloproteinase 1 activity, which is the key enzyme for interstitial collagen
degradation in the myocardium. These observations may serve as rationale why
angiotensin converting enzyme inhibition or blockade of the RAAS represents such
remedial therapy in congestive heart failure in patients with hypertensive heart
disease, post-myocardial infarction or with dilated cardiomyopathy.
PMID: 7634301 [PubMed - indexed for MEDLINE]
120. Mol Cell Biochem. 1994 Mar 16;132(1):69-80.
Modification of myosin isozymes and SR Ca(2+)-pump ATPase of the diabetic rat
heart by lipid-lowering interventions.
Rupp H, Elimban V, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Canada.
To define metabolic influences on cardiac myosin expression and sarcoplasmic
reticulum (SR) Ca(2+)-stimulated ATPase streptozotocin-diabetic rats were treated
for 9-10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I
(CPT-1) and fatty acid synthesis, or an antilipolytic drug, acipimox. Etomoxir
reduced myosin V3 of diabetic rats but did not normalize it. However, the high
serum triglyceride, free-fatty acid and cholesterol concentrations in diabetic
animals were greatly reduced. After bypassing the CPT-1 inhibition with a
medium-chain fatty acid (miglyol) diet, the V3 contents and serum lipids were
still reduced in the etomoxir-treated diabetic rats; V3 was also reduced in
diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or
triiodothyronine concentrations in diabetic rats were not improved by these
interventions but changes in V3 were correlated with those in triglyceride,
free-fatty acid and cholesterol concentrations, it is likely that myosin may be
influenced by some metabolic factors. To assess the role of adrenergic
influences, diabetic rats (7-8 wk) were treated with an antisympathotonic drug,
moxonidine, a beta-adrenoceptor blocking drug, propranolol, and a bradycardic
drug, tedisamil. Myosin V3 was not reduced significantly in moxonidine-treated or
propranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid
hormones and insulin were not altered, whereas triglycerides were reduced but not
significantly by these antiadrenergic agents. Lowering serum lipids in diabetic
rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR
Ca(2+)-stimulated ATPase activity. On the other hand, in diabetic rats treated
with moxonidine, propranolol or tedisamil, the ATPase activity was not increased
significantly. These results suggest that normalization of blood lipids is
important for improving subcellular organelle function in diabetic hearts with
impaired glucose utilization.
PMID: 8078510 [PubMed - indexed for MEDLINE]
122. J Cardiovasc Pharmacol. 1994;24 Suppl 1:S16-24.
Mechanisms of cardiac cell damage due to catecholamines: significance of drugs
regulating central sympathetic outflow.
Rupp H, Dhalla KS, Dhalla NS.
Institute of Physiology, University of Tübingen, Germany.
A chronically increased rate of catecholamine release has various deleterious
actions. Isoproterenol injections (80 mg/kg body weight) resulted in depressed
Ca2+ transport in the sarcolemma (ATP-dependent Ca2+ uptake, Na(+)-dependent Ca2+
uptake) and sarcoplasmic reticulum (Ca2+ uptake) of rat heart. The formation of
malondialdehyde owing to lipid peroxidation was increased. Pretreatment with
vitamin E (10-25 mg/kg/day) strongly inhibited the membrane damage. The toxic
effects of catecholamines arise most probably from their oxidation, and it is
therefore important either to reduce the central sympathetic outflow or to
prevent the oxidation. An inappropriately high sympathetic outflow is a typical
feature of Western affluent societies, and is linked to psychosocial stress and
hypercaloric nutrition. However, established pharmacologic interventions to
reduce sympathetic outflow have proven not practicable because of marked side
effects. Using radiotelemetry for monitoring cardiovascular parameters of
spontaneously hypertensive rats treated with clonidine or moxonidine, we showed
that clonidine, unlike moxonidine, resulted in rebound hypertension after drug
withdrawal. Because the rebound blood pressure and the typical side effects of
clonidine associated with low patient compliance are mainly mediated by
alpha-adrenoceptors, it can be inferred that the I1-imidazoline agonist
moxonidine does not exhibit the side effects commonly seen with clonidine and
therefore represents a promising approach for reducing an inappropriately high
central sympathetic outflow.
PMID: 7533222 [PubMed - indexed for MEDLINE]
125. Int J Cardiol. 1993 Feb;38(2):119-30.
Characteristics and mechanisms of tachyphylaxis of cardiac contractile response
to insulin.
Sethi R, Rupp H, Naimark BJ, Barwinsky J, Beamish RE, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Manitoba, Canada.
Although insulin is known to cause internalization of its own receptors, the
physiological significance of this phenomenon is not clear. In the isolated rat
heart we observed that the positive inotropic effect of 25 munits/ml insulin was
completely abolished if the heart was preperfused with insulin for 10 min. This
tachyphylactic response to insulin began to appear 3-4 min after starting
preperfusion with insulin and was partially reversible after 30 min of washing.
Preperfusion with insulin did not affect the action of vanadate, which has
insulin-like effect on glucose transport, or the actions of the other positive
inotropic agents, isoproterenol and ouabain. The presence of propranolol in the
perfusion medium, unlike atenolol, phenoxybenzamine, guanethidine, verapamil or
quinidine, modified the inotropic as well as tachyphylactic responses to insulin.
The positive inotropic and tachyphylactic responses to insulin were not altered
in hearts from reserpine-treated animals. Perfusion of heart with glucose-free
solution abolished the tachyphylaxis due to insulin. Likewise, no tachyphylactic
response to insulin was evident when iodoacetate, but not sodium fluoride, was
added in medium containing glucose. These results suggest that ATP formed during
glycolysis may play an important role in insulin-induced tachyphylaxis with
respect to cardiac contractile activity.
PMID: 8454373 [PubMed - indexed for MEDLINE]
127. Mol Cell Biochem. 1992 Oct 21;116(1-2):3-9.
Paradoxical role of lipid metabolism in heart function and dysfunction.
Dhalla NS, Elimban V, Rupp H.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Manitoba, Canada.
The heart utilizes fatty acids as a substrate in preference to glucose for the
production of energy. The rate of fatty acid uptake and oxidation by heart muscle
is controlled by the availability of exogenous fatty acids, the rate of acyl
translocation across the mitochondrial membrane and the rate of acetyl-CoA
oxidation by the citric acid cycle. Carnitine acyl-CoA transferase appears to
have an important function in coupling the fatty acid activation and acyl
transfer to the oxidative phosphorylation. Activated fatty acids are also
utilized for the synthesis of triglycerides and membrane phospholipids in the
myocardium. The inhibition of long chain acyl-carnitine transferase I reduces the
oxidation of fatty acids and promotes the synthesis of lipids in the myocardium.
Accumulation of fatty acids and their metabolites such as long chain acyl-CoA and
long chain acyl-carnitine has been associated with cardiac dysfunction and cell
damage in both ischemic and diabetic hearts. Alterations in the composition of
membrane phospholipids are also considered to change the activities of various
membrane bound enzymes and subsequently heart function under different
pathophysiological conditions. Chronic diabetes was found to be associated with
increased plasma lipids, subcellular defects and cardiac dysfunction. Lowering
the plasma lipids or reducing the oxidation of fatty acids by agents such as
etomoxir, an inhibitor of palmitoylcarnitine transferase I was found to promote
glucose utilization and remodel the subcellular membranous organelles in the
heart.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 1480151 [PubMed - indexed for MEDLINE]
128. Eur Heart J. 1992 Sep;13 Suppl D:56-61.
Metabolically-modulated growth and phenotype of the rat heart.
Rupp H, Jacob R.
Institute of Physiology II, University of Tübingen, Germany.
Heart muscle reacts to work overload and various neuroendocrine stimuli by
inducing myocyte growth. A novel type of hypertrophy can be induced in the rat
heart by etomoxir, which reduces fatty acid oxidation. This hypoglycaemic drug
inhibits the mitochondrial carnitine palmitoyltransferase 1, and thus reduces the
long-chain fatty acid uptake of mitochondria; in a compensatory manner, the
glycolytic flux is enhanced. In rats, etomoxir induced a harmonious growth of the
left and right ventricles of normal and pressure-overloaded hearts. To
characterize the protein phenotype, myosin expression and sarcoplasmic reticulum
(SR) Ca2+ pump activity were determined. In contrast to pressure-overloaded
hearts, etomoxir increased the proportion of myosin V1, Ca(2+)-stimulated SR
ATPase activity and the rate of SR Ca2+ uptake. Since etomoxir did not increase
blood pressure, heart rate or circulating thyroid hormones, it appears that
established mechanisms of other models of cardiac hypertrophy were not involved.
The etomoxir-induced changes thus seem closely linked to the shift in energy
metabolism.
PMID: 1396861 [PubMed - indexed for MEDLINE]
129. Basic Res Cardiol. 1992 Mar-Apr;87(2):99-105.
Insulin resistance, hyperinsulinemia, and cardiovascular disease. The need for
novel dietary prevention strategies.
Rupp H.
Insulin resistance associated with hyperinsulinemia (metabolic syndrome) emerged
in recent years as an important health risk which is present in approximately 25%
of the normal population in western industrialized societies. Insulin resistance
as assessed for the whole body arises from a reduced glucose utilization of
skeletal muscle. If the metabolic syndrome persists over a prolonged period of
time, detrimental influences on the cardiovascular system become apparent
involving diabetes mellitus, hypertension, and arteriosclerosis. Of particular
pathogenic relevance is an unbalanced influence of insulin arising either from a
diminished or enhanced insulin action depending on whether the various tissues of
the body exhibit a reduced or unchanged insulin sensitivity. Since insulin
resistance and hyperinsulinemia appear to be affected by various lifestyle
factors, the unique opportunity exists of reducing cardiovascular mortality by
correcting this syndrome at a time when degenerative changes have not occurred in
the cardiovascular system. Of great importance is the finding that dietary
factors can have a modulatory action on insulin sensitivity. In animal
experiments, an increased intake of (saturated) fat and refined carbohydrates
increased insulin resistance. Since psychosocial distress is expected to be
associated with a sustained activation of the sympathoadrenal axis, it is likely
also to aggravate the metabolic syndrome. A factor with a beneficial action
appears to be physical exercise. In view of the high incidence of cardiovascular
diseases, further research on lifestyle factors with an insulin-sensitizing or
insulin-desensitizing action is required. Of prime importance is the reevaluation
of established dietary recommendations and diets should be designed which take
into account the individual cardiovascular risk factor profile.
PMID: 1590742 [PubMed - indexed for MEDLINE]
130. Am J Physiol. 1992 Mar;262(3 Pt 2):R464-71.
Swimming changes vascular fatty acid composition and prostanoid generation of
rats.
Ohkubo T, Jacob R, Rupp H.
Institute of Physiology II, University of Tübingen, Federal Republic of Germany.
To define the effects of physical activity on vascular fatty acid composition and
prostanoid generation, spontaneously hypertensive and normotensive rats were made
to swim at 34-35 degrees C for 5-7 wk. Fatty acids were determined by gas
chromatography and prostanoids by high-performance liquid chromatography and
electrochemical detection. A characteristic feature of swimming rats was a
markedly reduced linoleic acid content in the iliac artery and the aorta; in
normotensive swimming rats stearic acid and arachidonic acid contents were
increased. These changes could not be attributed to a heat loss during swimming
or to depressed growth characteristics. A chemical sympathectomy using
guanethidine (60 mg/kg body wt daily) did not prevent the alterations in fatty
acid composition. A higher arachidonic acid content was correlated with an
increased generation of 6-ketoprostaglandin F1 alpha in the aorta of untreated
rats and sympathectomized rats. It is concluded that swimming can alter the
vascular fatty acid composition in a manner which results in an increased
potential for prostacyclin production.
PMID: 1558217 [PubMed - indexed for MEDLINE]
131. FASEB J. 1992 Mar;6(6):2349-53.
Modification of subcellular organelles in pressure-overloaded heart by etomoxir,
a carnitine palmitoyltransferase I inhibitor.
Rupp H, Elimban V, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Canada.
To examine the signals regulating cardiac growth and molecular structure of
subcellular organelles, cardiac hypertrophy was induced in rats by constriction
of the abdominal aorta for 12-13 wk or by treatment with a carnitine
palmitoyltransferase I inhibitor, etomoxir (12-15 mg/kg body wt) for 12-13 wk. In
contrast to pressure overload, etomoxir redistributed the myosin isozyme
population from V3 to V1 and increased the sarcoplasmic reticulum (SR)
Ca(2+)-stimulated ATPase activity. When rats with pressure-overloaded hearts were
treated with etomoxir, the cardiac hypertrophy was increased whereas the shift in
myosin isozymes from V1 to V3 was prevented and the depression in SR
Ca(2+)-stimulated ATPase activity was reversed. Plasma thyroid hormone and
insulin concentrations were not altered but triglyceride concentrations were
reduced in etomoxir-treated rats with pressure overload. The data demonstrate a
dissociation between cardiac muscle growth and changes in subcellular organelles
and indicate that a shift in myocardial substrate utilization may represent an
important signal for molecular remodeling of the heart.
PMID: 1531968 [PubMed - indexed for MEDLINE]
132. J Appl Physiol. 1992 Jan;72(1):352-60.
Influence of diet and carnitine palmitoyltransferase I inhibition on myosin and
sarcoplasmic reticulum.
Rupp H, Wahl R, Hansen M.
Institute of Physiology II, University of Tübingen, Federal Republic of Germany.
To examine the role of metabolic signals for ventricular myosin expression and
activity of the sarcoplasmic reticulum Ca2+ pump, Wistar rats were treated for
7-8 wk with 5 or 50 mg/kg etomoxir, which inhibits fatty acid utilization. The
proportion of myosin V1 was increased (P less than 0.05) with 50 mg/kg etomoxir
(75 +/- 5% vs. 62 +/- 6% of control rats), whereas both doses increased the rate
of Ca2+ uptake. A carbohydrate-rich fat-free diet or 8% sucrose drinking
solutions, however, had no effect on myosin and sarcoplasmic reticulum. When rats
were fed diets with an increased content (10 or 20%) of sunflower oil, the
calorie intake and myosin V1 increased (56 +/- 8 or 64 +/- 8% vs. 44 +/- 6% of
control rats). Isocaloric 10% fat diets of varying fatty acid composition
(coconut fat, olive oil, or mackerel oil) also induced a higher calorie intake
and increased V1 (64 +/- 6, 60 +/- 9, or 65 +/- 8% for the respective oils vs. 44
+/- 6% of control rats) but did not significantly increase rate of Ca2+ uptake.
We concluded that calorie-rich diets changed the myosin expression not by
affecting the ratio of fatty acid to glucose utilization but via the increased
calorie intake.
PMID: 1537736 [PubMed - indexed for MEDLINE]
133. Basic Res Cardiol. 1992;87 Suppl 1:95-106.
Structural and functional diversity of human ventricular myosin.
Rupp H, Jacob R.
Institute of Physiology II, University of Tübingen, FRG.
The role of subcellular alterations in the process of heart failure remains
ill-defined. Because contractile performance of failing heart muscle is
depressed, possible alterations in the myosin molecule could be of particular
relevance. There is increasing evidence that myofibrillar ATPase activity is
reduced in congestive heart failure, whereas the findings on myosin ATPase are
still controversial. The molecular causes of the reduced activity are currently
not known. Because alpha-MHC is present only in small amounts in normal
ventricles, a shift in favor of beta-MHC is of minor importance. Also
immunohistochemical data on subspecies of beta-MHC seem not to provide an
explanation. A new type of myosin heterogeneity was found by optimizing native
polyacrylamide gel electrophoresis in the presence of pyrophosphate. Two bands
(VA and VB) were observed in ventricles of patients with valvular disease.
Because the two bands were detected also in normal hearts of large mammals, the
existence of VA/VB cannot be diagnostic of diseased heart. However, the VA/VB
ratio was influenced by the hemodynamic load, whereby the fast migrating band
(VA) increased with the diastolic and systolic load. Because a relationship with
the hemodynamic load was observed only in surgical muscle specimens, it appears
that this heterogeneity is prone to post mortem modification. Further work is
required to identify the molecular nature of this heterogeneity and to examine
the therapeutic potential of a pharmacological modification of the VA/VB ratio.
PMID: 1386732 [PubMed - indexed for MEDLINE]
134. Circ Res. 1991 Apr;68(4):1164-73.
Effect of positive inotropic agents on myosin isozyme population and mechanical
activity of cultured rat heart myocytes.
Rupp H, Berger HJ, Pfeifer A, Werdan K.
Institute of Physiology II, University of Tübingen, FRG.
To examine whether catecholamines have a direct effect on myosin heavy chain
expression of heart myocytes or whether they act via an altered work load,
myocytes from neonatal rat hearts were cultured in thyroid hormone-free media
containing various positive inotropic and chronotropic agents. The velocity and
frequency of contraction of the myocytes were monitored using an optoelectronic
system. After 3-5 days of culture, myosin isozyme populations, cellular cAMP
content, and 2-deoxy-D-glucose uptake of the myocytes were determined. Compared
with myocytes cultured in the absence of inotropic agents (32.6 +/- 3.5% V1), the
proportion of myosin V1 was significantly (p less than 0.05) increased in the
case of 1 microM isoproterenol (48.2 +/- 5.9% V1), 1 microM forskolin (57.1 +/-
11.7% V1), and 1 mM dibutyryl cAMP (79.1 +/- 2.0% V1). Dibutyryl cAMP increased
V1 to a similar level as 30 nM triiodothyronine did (70.2 +/- 13.0% V1). Only a
small increase was observed in myocytes cultured in the presence of 10 microM
phenylephrine (40.4 +/- 8.4% V1), 10 microM ouabain (40.6 +/- 11.9% V1), or 10
microM Bay K 8644 (40.7 +/- 11.7% V1). The agents with a marked effect on myosin
heavy chain expression resulted in a higher cAMP content; isoproterenol and
forskolin also stimulated 2-deoxy-D-glucose uptake. All agents resulted in a
higher velocity of contraction; with the exception of ouabain, frequency of
contraction was also increased. A change in Ca2+ concentration in the medium from
1.3 to 2.4 mM resulted in a small increase in V1 (40.7 +/- 5.2% V1) but had the
same effect on contraction velocity as dibutyryl cAMP did. Furthermore, 10 nM
isoproterenol also increased V1 in myocytes that were arrested with 10 microM
verapamil. The increase in V1 in the case of dibutyryl cAMP, isoproterenol, and
forskolin is thus most probably not a correlate of the increased mechanical
activity but of the high cellular cAMP content.
PMID: 1706966 [PubMed - indexed for MEDLINE]
135. Basic Res Cardiol. 1991;86 Suppl 3:65-81.
The metabolic syndrome and signal transduction of gene expression.
Rupp H.
Physiological Institute II, University of Tübingen, FRG.
Epidemiological studies have clearly shown that the so-called metabolic syndrome
which is linked to insulin resistance and a reduced glucose utilization of muscle
represents an important risk factor for cardiovascular disease. However, only
little is known of the intracellular consequences of insulin resistance. An
important feature of an altered substrate utilization is related to signal
transduction of gene expression. For the example of myosin heavy chain
expression, it is shown that metabolic signals exist which reflect the fuel flux
and substrate utilization of the heart muscle cell. The signals were
characterized in functional states of the heart associated with altered metabolic
influences (fasting, diabetes, sucrose feeding, increased calorie intake,
carnitine palmitoyltransferase inhibition). In the pressure-overloaded heart,
metabolic interventions which are expected to increase glucose utilization
(sucrose feeding, captopril treatment) have a pronounced effect. Although a link
with gene expression remains to be established, it should be noted that the
sarcoplasmic reticulum Ca(2+)-pump activity seems to be affected in a
functionally comparable manner. It is concluded that metabolic signals alter the
protein phenotype of heart muscle and it is expected that a deranged signal
transduction affects, not only the heart, but also vascular muscle.
PMID: 1838254 [PubMed - indexed for MEDLINE]
136. Basic Res Cardiol. 1991;86 Suppl 1:113-30.
Functional consequences of cardiac hypertrophy and dilatation.
Jacob R, Brändle M, Dierberger B, Rupp H.
Physiologisches Institut II, Universität Tübingen, FRG.
Based on animal experiments in rats (spontaneous and renal hypertension,
experimental aortic stenosis, thyroxine and training-induced hypertrophy, and
aorto-caval fistula with and without additional unilateral renal artery
coarctation) as well as clinical data and literature, the functional consequences
of cardiac hypertrophy and structural ventricular dilatation are analyzed and
discussed. A methodological approach, developed on the basis of Frank's diagram
and model calculations, permits quantitatively estimating the significance of
ventricular geometry (wall thickness and inner dimensions) compared to myocardial
alterations (decrease in contractility and distensibility) and hemodynamic load
(preload and systolic pressure). As a rule, hypertrophy causes an increase in
ventricular working capacity, which allows the heart to cope with an increased
hemodynamic load without a decrease in stroke volume and without enhanced
systolic stress requirement. Adverse consequences mainly concern ventricular
compliance, cardiac energetics, and electrophysiological parameters. Particularly
from the example of the aorto-caval fistula, it can be seen that enhanced
systolic wall stress does not necessarily lead to heart failure within a few
months. However, the length of time for which the additional wall stress, with
correspondingly increased energy demand, can be tolerated remains to be
determined. In later stages, a multitude of alterations on the cellular, tissue,
and organ level occurs, affecting myocardial and ventricular mechanics and
energetics, depending on the type, velocity of development, and duration of
overload. A distinction should be made between the adverse alterations, which can
be related to myocardial growth, and those that are not necessarily related to a
certain cell size (receptors, transformation of the contractile proteins) as well
as those changes that do not primarily influence the myocardial cell
(arteriosclerosis, microangiopathy). Structural dilatation alone could lead to
insufficiency only in the case of substantial increase in inner ventricular
radius. Reduced contractility, myocardial distensibility, and increased pressure
load aggravate the negative effects of dilatation in a predictable manner, as
demonstrated on the basis of a representative case of dilative cardiomyopathy.
Using the example of spontaneously hypertensive rats, it is shown that
ventricular mass and shape are differently influenced by various blood-pressure
lowering agents, e.g., atenolol, nifedipine, and dietary interventions. It is
concluded from the analysis of chronic cardiac reactions that adaptive processes
are, in principle, ambiguous in character, revealing negative components even in
the case of regular adaptation. However, it seems unjustified to aim at a
regression of hypertrophy without reducing the underlying hemodynamic overload.
PMID: 1827978 [PubMed - indexed for MEDLINE]
137. Circ Res. 1991 Jan;68(1):27-37.
Mathematical models of myosin heterodimer formation in the rat heart during
thyroid hormone alterations.
Rupp H, Dietz K.
Institute of Physiology II, University of Tübingen, FRG.
To characterize the mechanisms involved in the formation of the myosin heavy
chain (MHC) heterodimer V2 (alpha beta-MHC) and the homodimers V3 (beta beta-MHC)
and V1 (alpha alpha-MHC), 82 5-week-old normotensive rats with homogeneous V1
were made hypothyroid with propylthiouracil (0.8%, drinking water), and the
proportion of V2, V3, and V1 was determined by pyrophosphate gel electrophoresis
in multicellular specimens of the left and right ventricles. After the switch
from alpha-MHC to beta-MHC, the beta-MHC occurred initially in the form of the
heterodimer. After 4 and 6 days, V2 was greater (p less than 0.05) than V3. At
day 8, V2 was smaller than V3, and at day 10, V2 was not statistically different
from V3. From day 12 onward, V2 was smaller than V3. After 21 days, the
propylthiouracil treatment was stopped, and the remaining 34 hypothyroid rats
were injected with a daily dose of thyroxine (average, 0.1 mg/kg body wt),
resulting in a switch from beta-MHC to alpha-MHC. After 1 day, V2 still was
greater than V1; however, already from day 3 onward, V2 was smaller than V1. This
characteristic but unexplained heterodimeric and homodimeric organization of the
thick filament was analyzed by mathematical models involving probability
calculations. Two principally different models were established that assume
either the exchange of MHC dimers or of single MHC in the thick filament. The
parameters of the models were estimated by minimization routines using the
squared discrepancies between the experimental and predicted isoenzyme
populations. Based on goodness of fit and crucial model parameters, we concluded
that the characteristic organization of the thick filament can be accounted for
by an exchange involving predominantly MHC dimers and not single MHC. The fact
that V2 was lower than expected if formation of heterodimers and homodimers were
random was attributed to the preferred homodimerization of 35% of the newly
synthesized MHC.
PMID: 1824618 [PubMed - indexed for MEDLINE]
138. Methods Achiev Exp Pathol. 1991;15:58-83.
Cellular and molecular changes in the heart during stress or exercise.
Hansen M, Rupp H.
Institute of Physiology II, University of Tübingen, FRG.
PMID: 1762552 [PubMed - indexed for MEDLINE]
139. Basic Res Cardiol. 1991;86 Suppl 3:13-23.
Experimental congestive heart failure due to myocardial infarction: sarcolemmal
receptors and cation transporters.
Dhalla NS, Dixon IM, Rupp H, Barwinsky J.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Manitoba, Canada.
Rats, subsequent to loss of a large amount of left ventricular free wall due to
surgically-induced myocardial infarction, form a good model of congestive heart
failure. Since depressed cardiac pump function is the hallmark of heart failure,
it is suspected that decreased influx of Ca2+ into the cardiac cell is
responsible for depressed contractile function. Because Ca2+ movements in the
sarcolemmal membrane are known to involve Ca(2+)-channels, Na(+)-Ca2+ exchange,
Ca(2+)-pump, Na(+)-K+ ATPase, beta-adrenoceptors and alpha-adrenoceptors directly
or indirectly, the status of these mechanisms was examined by employing rats at
different degrees of congestive heart failure. The left coronary artery was
ligated and hearts were examined 4, 8, and 16 weeks later; sham-operated animals
served as controls. The number of Ca2+ channels in the myocardium was depressed
in moderate and severe stages of heart failure. Furthermore, depressions in
sarcolemmal Na(+)-Ca2+ exchange activity and beta-adrenoceptor number were
associated with the development of early stages of heart failure, whereas
sarcolemmal Na(+)-K+ ATPase activity was decreased and the number of
alpha-adrenoceptors was increased at moderate and severe stages. The Ca(2+)-pump
activities were not altered in failing hearts. Thus it appears that changes in
Na(+)-Ca2+ exchange as well as beta-adrenoceptors and Ca2+ channels may
contribute towards decreasing Ca2+ influx at early and moderate stages of
congestive heart failure, respectively. On the other hand, changes in
alpha-adrenoceptors and Na(+)-K+ ATPase may act as compensatory mechanisms for
maintaining Ca2+ influx at moderate and late stages of congestive heart failure.
PMID: 1664205 [PubMed - indexed for MEDLINE]
140. J Appl Physiol. 1990 Mar;68(3):973-8.
Influence of thyroid hormones and catecholamines on myosin of swim-exercised
rats.
Rupp H, Wahl R.
Institute of Physiology II, University of Tübingen, Federal Republic of Germany.
To define the physiological signals involved in the redirection of myosin
expression in the swim-exercised rat, the relative influence of thyroid hormones
and beta-adrenergic blockade was determined. Swimming exercise resulted in an
increased proportion of myosin V1 (60.9 +/- 9.7 vs. 38.0 +/- 4.1% of sedentary
rats fed ad libitum) but did not increase serum concentrations of total and free
thyroxine or triiodothyronine determined either 17-21 h or immediately after
swimming. The proportion of V1 increased, although intermittently food-deprived
rats with the body weight of swimming rats exhibited a reduced proportion of V1
(23.5 +/- 2.7). When swimming rats had only intermittent access to food, they had
reduced concentrations of all thyroid hormones, but the proportion of V1 (51.5
+/- 7.6) was nonetheless increased. Thus the redirection of myosin expression
cannot be attributed to an increased secretion of thyroid hormones. The influence
of the adrenergic system was assessed by treating swimming rats with the
beta-blocking drug atenolol. Because the proportion of V1 was reduced, but
thyroid hormones were not affected, beta-adrenergic blockade seems to influence
myosin expression independently of thyroid hormones.
PMID: 2140349 [PubMed - indexed for MEDLINE]
141. Heart Vessels. 1990;5(2):65-70.
Left ventricular performance in rats with chronic cardiac overload due to
arterio-venous shunt.
Noma K, Brändle M, Rupp H, Jacob R.
Department of Internal Medicine, Jikei University School of Medicine, Tokyo,
Japan.
The effects of experimental arterio-venous shunt (AV shunt) on left ventricular
dynamics and myocardial mechanics were investigated in female Wistar rats,
weighing approx. 240 g. The main goal of the study was to characterize
ventricular and myocardial working capacity and to estimate the significance of
the various processes involved in cardiac adaptation to the altered loading
conditions. Twelve weeks after operation, systemic blood pressure was slightly
elevated in AV shunt rats as compared with age-matched controls, although total
peripheral resistance (as related to a common aortic pressure) was significantly
reduced. Heart rate and cardiac output were considerably increased. Despite
marked left ventricular dilatation with increased end-diastolic and systolic wall
stress, no signs of resting insufficiency were present. Left ventricular weight,
end-diastolic volume and pressure, stroke volume, and ejection fraction were
increased. The area between the curve of isovolumic maxima and the end-diastolic
P-V curve (up to a defined end-diastolic pressure) and the normalized area
between the isovolumic and end-diastolic stress-length curves as well as the
maximum rate of stress development were augmented, even in the specimen with the
highest degree of ventricular dilatation--despite a shift of the myosin isoenzyme
pattern towards VM3. The study reveals that besides the change in ventricular
mass and configuration, augmented preload is involved in cardiac adaptation to
the altered hemodynamic state. Furthermore, there are indications of an
intensified sympathetic stimulation of the heart. Transformation of the
myocardium towards a slower muscle seems to be of minor functional significance
under the conditions of the present experiments.
PMID: 2354989 [PubMed - indexed for MEDLINE]
142. Biochem Biophys Res Commun. 1989 Oct 16;164(1):319-25.
Diabetes-like action of intermittent fasting on sarcoplasmic reticulum Ca2+-pump
ATPase and myosin isoenzymes can be prevented by sucrose.
Rupp H, Elimban V, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Canada.
Experimental diabetes results in a reduction of the sarcoplasmic reticulum (SR)
Ca2+-stimulated ATPase activity and a redirection of myosin isoenzymes from V1 to
V3. Similar, but less pronounced, changes were induced by subjecting rats to
intermittent fasting for 6 weeks. Low amounts of sucrose (0.8%) in the drinking
water prevented the subcellular changes in fasted rats; however, sucrose neither
affected the levels of plasma thyroid hormones nor normalized the reduced body
weight. Plasma glucose was lowered without any changes in plasma insulin in the
fasted rats receiving sucrose; this suggested an enhanced peripheral glucose
utilization. Thus, the signals in the diabetic heart leading to changes in SR and
myosin can be mimicked by intermittent fasting and seem to be linked to a shift
in fuel utilization by the myocytes.
PMID: 2529855 [PubMed - indexed for MEDLINE]
143. Circ Res. 1989 Aug;65(2):370-7.
Differential effect of physical exercise routines on ventricular myosin and
peripheral catecholamine stores in normotensive and spontaneously hypertensive
rats.
Rupp H.
Department of Physiology (II), University of Tübingen, FRG.
The influence of the adrenergic system on the population of ventricular myosin
isoenzymes under physiological conditions was assessed by subjection of
normotensive and spontaneously hypertensive rats (SHR) to different types of
physical exercise that increased the activity of the peripheral adrenergic system
to varying degrees. The routines, which were 5-6 weeks in duration, involved the
mild exercise of enforced swimming (2 x 90 min/day), spontaneous running (daily,
about 15 km/10-12 hr) that resulted in absolute ventricular hypertrophy, and
enforced running of low intensity (daily, 2 x 1.8 km/3 hr) but associated with
marked stressors. Swimming and spontaneous running reduced the high blood
pressure of SHR, whereas enforced running increased it. In both strains, the
myosin isoenzymes were redistributed in the direction of V1 after swimming but
not after running. In SHR, therefore, reduction of pressure load seems
insufficient for induction of a higher proportion of V1. The unique and, until
now, unexplained effect of swimming was attributed to the pronounced activation
of the peripheral adrenergic system as judged from catecholamine stores of
ventricles and adrenal glands. Only swimming increased the norepinephrine content
of ventricles and adrenal glands in normotensive rats. Swimming also had the
strongest influence in SHR. Further evidence for the influence of the adrenergic
system came from the effect of selective cardiac beta-blockade with atenolol (50
mg/kg/day). The diminished adrenergic drive of the heart reduced the proportion
of V1 to a greater extent in the swimming rats than in the sedentary rats. Taken
together, the data demonstrate that substantial changes in adrenergic activity
occur under physiological conditions associated with an altered myosin
heavy-chain expression.
PMID: 2752546 [PubMed - indexed for MEDLINE]
144. Mol Cell Biochem. 1989 May 4;87(1):85-92.
Measurement of adrenolutin as an oxidation product of catecholamines in plasma.
Dhalla KS, Ganguly PK, Rupp H, Beamish RE, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Canada.
Using the reverse phase high-performance liquid chromatography (HPLC) with mobile
phases composed of simple acids, we have developed an assay technique for the
measurement of adrenolutin, one of the oxidation products of catecholamines, in
rat plasma. Ion-pairing chromatography permits the separation and quantitation of
plasma adrenolutin (microM) in a linear manner. Sample preparation involved the
precipitation of plasma proteins with perchloric acid and it is easier to handle
a large number of samples at a time. However, we were unable to demonstrate the
presence of adrenochrome, another oxidation product of catecholamines, in plasma
since adrenochrome was rapidly destroyed in acid as well as in blood and was
quickly changed into adrenolutin. Adrenolutin peak in HPLC was confirmed by 1)
the retention time; 2) co-injection of adrenolutin and; 3) the appearance of
3H-adrenolutin after injection of 3H-norepinephrine. Administration of different
catecholamines as well as adrenochrome and adrenolutin in rats also increased the
level of adrenolutin in plasma. Adrenolutin was found to be present in plasma in
other species including dog, rabbit and pig. High level of adrenolutin, which may
represent total concentration of aminolutin in plasma, suggests the presence of
an efficient mechanism for the oxidation of catecholamines under in vivo
conditions.
PMID: 2770715 [PubMed - indexed for MEDLINE]
145. Acta Physiol Scand. 1989 Feb;135(2):123-32.
Functional and biochemical analyses of isolated rat hearts in renal and reversed
renal hypertension.
Friberg P, Rupp H, Nordlander M.
Department of Physiology, University of Göteborg, Sweden.
The present study evaluates cardiac function, plasma renin activity (PRA) and
left ventricular (LV) myosin isoenzymes in untreated two-kidney, one-clip
Goldblatt hypertensive rats (2KIC) and in 2KIC treated with felodipine and
metoprolol. Normotensive rats (NCR) and another group of 2KIC, in which the renal
artery constriction was removed (UC-2KIC), were also investigated. Cardiac
performance was assessed by means of a working heart perfusion device, allowing
also for measurements of myocardial oxygen consumption. Following
antihypertensive therapy and unclipping, blood pressure became close to
normotensive levels. PRA remained equally elevated in treated and untreated 2KIC,
but became practically normalized after unclipping. Relative LV weight in 2KIC
increased 74% above that in NCR but in treated 2KIC increased by only 20%. In
UC-2KIC LV hypertrophy became reversed, LV weight/body being about the same as in
treated 2KIC. In treated 2KIC, coronary resistance at maximal dilatation was
significantly reduced, implying prevention of hypertensive, structural coronary
vascular changes, and optimal LV function was improved markedly in the lower
range of perfusion pressures compared with untreated 2KIC. When, however, the
hearts were challenged at a high pumping resistance (perfusion pressure), LV
function was similar in untreated and treated 2KIC. Myocardial oxygen consumption
for given levels of stroke work was significantly lower in treated than in
untreated 2KIC. The myosin isoenzyme pattern in the LV of 2KIC was shifted, with
significantly higher amounts of VM-3 than in NCR. This shift was normalized by
antihypertensive therapy or by unclipping. In conclusion, antihypertensive
therapy with felodipine and metoprolol prevents the development of coronary
vascular and left ventricular hypertrophy in 2KIC. This may contribute to enhance
cardiac performance at low aortic pressure. The lack of improvement in optimal
cardiac performance (at high aortic pressure) implies that the hypertensive state
per se, rather than extent of pressure elevation, cardiac hypertrophy, or changes
of LV isoenzymes, determines the reduced cardiac function in renal hypertensive
rats (Friberg & Nordborg 1986).
PMID: 2522266 [PubMed - indexed for MEDLINE]
146. J Hypertens Suppl. 1988 Dec;6(4):S101-3.
Mechanisms behind myocardial depression in rat renal hypertension.
Friberg P, Nordlander M, Rupp H.
Department of Physiology, University of Gothenburg, Sweden.
Cardiac function in rat renal hypertension has been shown repeatedly to be
depressed. The reason for this impairment has not been fully understood, although
cardiac hypertrophy and increased collagen content have been claimed as possible
causes. To further unravel the mechanisms underlying the deterioration of left
ventricular function in rat renal hypertension, we investigated cardiac function,
myocardial morphology, myosin iso-enzymes, plasma renin activity and levels of
myocardial high-energy compounds in hearts from rats exposed to renal and
reversed renal hypertension. Maximal cardiac function was unaltered in hearts
exposed to antihypertensive therapy from the time of renal artery clipping
compared with untreated hypertensive rats. The observed alterations of iso-enzyme
pattern, plasma renin activity levels and myocardial morphology among the groups
showed to be of less importance with respect to cardiac performance. Together
with previous results from our laboratory, the present findings suggest that some
negative inotropic agent of renal or non-renal origin is released during
two-kidney, one clip renal hypertension, which counteracts the enhanced left
ventricular performance induced by cardiac hypertrophy.
PMID: 2977151 [PubMed - indexed for MEDLINE]
147. Biochem Biophys Res Commun. 1988 Oct 31;156(2):917-23.
Sucrose feeding prevents changes in myosin isoenzymes and sarcoplasmic reticulum
Ca2+-pump ATPase in pressure-loaded rat heart.
Rupp H, Elimban V, Dhalla NS.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Canada.
Pressure-overload due to banding of the abdominal aorta in rats for 10 weeks
resulted in cardiac hypertrophy, redistribution of myosin isoenzymes and
reduction in the sarcoplasmic reticulum (SR) Ca2+-stimulated ATPase activity.
Administration of sucrose in the drinking water (0.8%, w/v) to rats prevented
changes in myosin isoenzymes and SR Ca2+-stimulated ATPase in hypertrophied
hearts. This beneficial effect of sucrose feeding with respect to remodeling of
the subcellular organelles in the myocardium was not associated with any
significant changes in plasma glucose or thyroid hormone levels. It is suggested
that the prevention of subcellular changes in the hypertrophied hearts due to
sucrose feeding may be due to a shift in fuel utilization by the myocardium.
PMID: 2973316 [PubMed - indexed for MEDLINE]
148. Eur J Appl Physiol Occup Physiol. 1988;58(1-2):97-9.
Influence of a diet rich in fish oil on blood pressure, body weight and cardiac
hypertrophy in spontaneously hypertensive rats.
von Au D, Brändle M, Rupp H, Jacob R.
Physiologisches Institut II, Universität Tübingen, Federal Republic of Germany.
The effects of a diet rich in fish oil on arterial blood pressure, body weight,
left ventricular weight and heart rate have been investigated in 8 month old
spontaneously hypertensive male rats (SHR) as compared to age-matched
hypertensive controls. A diet containing 10% fish oil decreased blood pressure by
about 40 mmHg within 20 days of starting the experiment, and this effect
persisted over the observation period of 80 days. Permitting the animals free
access to food, the body weight of the diet group increased by 25%. The degree of
hypertrophy as evaluated by relating left ventricular weight to tibial length was
significantly reduced (10%) in the diet fed group. Heart rate was increased by
53%. The study demonstrates that a diet rich in fish oil can lower arterial blood
pressure over several weeks without a recognizable loss in function despite a
considerable increase in body weight. It can be assumed that a more marked
regression of left ventricular hypertrophy is counteracted by a reflex increase
in sympathetic efferentation to the heart.
PMID: 2974415 [PubMed - indexed for MEDLINE]
149. Cardiovasc Res. 1987 Dec;21(12):871-7.
Subacute and long term effect of swimming training on blood pressure in young and
old spontaneously hypertensive rats.
Noma K, Rupp H, Jacob R.
Physiology Institute II, University of Tübingen, Federal Republic of Germany.
The effects of swimming training (three weeks' training with the duration
increasing up to a maximum of 180 min per day, at a water temperature of 36
degrees C) on arterial blood pressure were studied in 4, 11, and 18 month old
spontaneously hypertensive rats. In addition, in the 11 month old rats the change
in blood pressure after individual exercise was determined. The significance of a
training induced loss of body weight in lowering blood pressure was assessed by
pair feeding of sedentary age matched spontaneously hypertensive rats. Blood
pressure was reduced by approximately 50 mmHg within 8-10 days, except in the
oldest rats, which tolerated the physical activity poorly and had, if any, only a
moderate fall in blood pressure. It was possible to distinguish between subacute
transient effects lasting for not more than one day and long term effects. Blood
pressures were 20-25 mmHg lower after individual swimming routines than those
before exercise when measured on the ninth day of the training programme. On
cessation of training, blood pressures approached those of sedentary rats within
two weeks. It seems that the loss of body weight was of minor importance in
lowering blood pressure under these experimental conditions.
PMID: 3455353 [PubMed - indexed for MEDLINE]
150. Basic Res Cardiol. 1987;82 Suppl 2:161-72.
Chronic cardiac reactions. III. Factors involved in the development of structural
dilatation.
Vogt M, Jacob R, Noma K, Onegi B, Rupp H.
Physiologisches Institut II, Universität Tübingen, F.R.G.
The significance of various factors for the development of structural dilatation
in the chronically pressure-loaded and failing heart were evaluated. The
investigations were performed on male rats with renal (Goldblatt II) and
spontaneous (Aoki-Okamoto) hypertension at different stages of haemodynamic
overload. Two groups of SHR were submitted to intermittent feeding (SHR IF); one
group received additionally the beta-blocking agent atenolol (50 mg/kg b.w.; SHR
IF + beta Bl.). Haemodynamic measurements were carried out under open chest
conditions. Myosin isoenzyme pattern, hydroxyproline concentration and
circulating blood volume were determined. Transformation to slower myocardium per
se, induced by IF, did not lead to significant change in ventricular
configuration. After additional blockade of beta-adrenergic receptors there were
indications of unfavourable development of left ventricular configuration.
Inhibition of hypertrophic mass increase due to curtailed adrenergic stimulation
could be an influential factor in the development of dilatation. Further
investigations, however, are required to establish the relationship between the
adrenergic system, on the one hand, and degree of hypertrophy as well as
structural dilatation of the ventricle, on the other hand. The established marked
increase in hydroxyproline concentration of the dilated ventricle of SHR in
congestive failure is consistent with the assumption of a causal link between the
degree of fibrosis and structural dilatation. Observations on rats with
aorto-caval shunt and Goldblatt II rats with eccentric hypertrophy and
corresponding increase in filling potential or circulating blood volume indicate
a correlation between the latter and ventricular size. Thus, we assume that
curtailed protein synthesis, fibrosis and regulatory processes related to water
and electrolyte balance, but not myocardial transformation per se, play a role in
the development of structural dilatation. The relative contribution of each
factor, however, may depend on the experimental model that is used.
PMID: 3663015 [PubMed - indexed for MEDLINE]
151. Basic Res Cardiol. 1987;82 Suppl 2:191-200.
Implications of myocardial transformation for cardiac energetics.
Kissling G, Rupp H, Jacob R.
Physiologisches Institut II, Universität Tübingen, F.R.G.
The influence of isoenzyme pattern of myosin on cardiac energetics was
investigated in a modified in situ heart-lung preparation in the rat. Chronic
pressure load (spontaneous hypertension, aortic stenosis, Goldblatt
hypertension), intermittent feeding, and swim-training elicited redistribution in
the concentration of alpha chains of myosin ranging from 18 to 94%. The influence
of isoenzyme pattern of myosin on cardiac energetics could be quantitatively
assessed by extrapolation of the regression line of oxygen and substrate
consumption related to tension time index. Fast myocardium with 100% alpha chains
had an ATP and oxygen consumption which exceeded that of slow myocardium with 0%
alpha chains by about 60%. This corresponds well to the state of activity of
myofibrillar ATPase of fast myocardium which also exceeds that of slow myocardium
by about 50%. Furthermore it could be shown that acute increase in the ATPase
activity depends on the isoenzyme pattern of myosin. Under the influence of
catecholamines the oxygen consumption related to tension time index increased by
30-40% in fast myocardium, whereby in a myocardium with 40% alpha chains no
increase in oxygen consumption per unit tension time index was observed, when
catecholamines were applied.
PMID: 2959258 [PubMed - indexed for MEDLINE]
152. Basic Res Cardiol. 1987;82 Suppl 2:173-82.
Chronic cardiac reactions. IV. Effect of drugs and altered functional loads on
cardiac energetics as inferred from myofibrillar ATPase and the myosin isoenzyme
population.
Rupp H, Wahl R, Jacob R.
Physiologisches Institut (II), Universität Tübingen, F.R.G.
A major determinant of myocardial energetics is the ATPase activity of
myofibrils. In order to account for chronic changes in myofibrillar ATPase, the
state equation of the intertropomyosin-interaction model of Tawada et al. was
extended by introducing the rates of cross-bridge cycling of myofibrils composed
of V-1 or V-3 and the concentration of the myosin isoenzymes. Cross-bridge
cycling rates of 1.0 or 0.7 were derived for myofibrils composed of V-1 or V-3,
respectively. Ca2+ responsiveness and positive co-operativity were not
significantly affected by the myosin isoenzymes. Redistribution of the myosin
isoenzyme population and thus altered myocardial energetics was observed
following administration of various drugs and as a result of different functional
loads. Besides thyroid hormones, catecholamines had a marked influence on myosin.
Reducing the adrenergic drive by administration of atenolol, guanethidine or
reserpine led to a shift in the direction of V-3. Since serum T3 levels were not
significantly reduced by these interventions, the drugs act most probably at the
organ level. The functional states responsible for the increase in the proportion
of V-3 (pressure load, intermittent feeding, schedule-induced stress) also did
not affect circulating T3 in a manner that could entirely explain the
redistribution. Hypertrophy-induced dilution of sympathetic nerve fibres or
reduced adrenergic responsiveness most likely play a role in the redistribution.
An increase in the proportion of V-1 was observed following swimming exercise but
not, however, after spontaneous or enforced running. In the swim-exercised rats,
T3 was markedly reduced. Thus, the trigger reactions linked most probably to the
high adrenergic drive during swimming have to overcome the lower T3 level. It is
concluded that myocardial energetics can be decisively altered by a variety of
drugs and functional loads, whereby the trigger reactions leading to an altered
gene expression of myosin cannot be accounted for entirely by altered circulating
T3 but most probably involve the adrenergic system.
PMID: 2959257 [PubMed - indexed for MEDLINE]
153. Basic Res Cardiol. 1987;82 Suppl 2:147-59.
Chronic cardiac reactions. II. Mechanical and energetic consequences of
myocardial transformation versus ventricular dilatation in the chronically
pressure-loaded heart.
Vogt M, Jacob R, Kissling G, Rupp H.
Physiologisches Institut II, Universität Tübingen, F.R.G.
Mechanical and energetic consequences of myocardial transformation and of
ventricular configuration on the other were separately analysed. The
considerations were realized on representative samples of normotensive rats and
spontaneously hypertensive rats (SHR) in compensated stages, as well as in SHR in
a state of congestive cardiac failure. Cardiac dynamic measurements were
performed under Urethane anaesthesia and open chest conditions. Myosin isoenzyme
pattern was determined by pyrophosphate gel electrophoresis. Energetic
calculations were based on oxygen consumption data, measured in a specified
heart-lung model. In the compensated stage of SHR the concentric type of left
ventricular hypertrophy with renormalized systolic auxotonic wall stress
predominated. The process of cardiac hypertrophy was associated with a shift in
the myosin isoenzyme pattern towards the "slow" VM-3. Myocardial transformation
did not significantly reduce myocardial performance and pumping ability, but
caused a decrease in oxygen consumption as related to developed stress and LV
weight. Thus, the efficiency of the hypertrophied ventricle of SHR was improved.
However, due to the moderate effect of isoenzyme pattern redistribution for total
energy turnover and the limited adaptive reserve of normotensive controls, the
extent of improvement was small. In SHR with congestive heart failure, myocardial
contractility was severely impaired, when structural dilatation of the left
ventricle had set in. Reduced myocardial contractility could not be explained
solely on the basis of a shift in the myosin isoenzyme pattern. Both impaired
myocardial contractility and structural dilatation contributed to reduced
ventricular performance. Myocardial transformation, along with its energy
economizing effect, failed to compensate for unfavorable energetic consequences
of structural dilatation and therefore the reduced ventricular efficiency is
assumed to be another deleterious factor in the dilated failing heart.
PMID: 2959256 [PubMed - indexed for MEDLINE]
154. J Cardiovasc Pharmacol. 1987;10 Suppl 6:S2-12.
Functional significance of contractile proteins in cardiac hypertrophy and
failure.
Jacob R, Kissling G, Rupp H, Vogt M.
Physiologisches Institut II, Universität Tübingen, F.R.G.
The functional significance of alterations in contractile proteins was
investigated in the chronically overloaded left ventricle of Goldblatt rats and
spontaneously hypertensive rats (SHRs). Congestive cardiac insufficiency
occurring in late stages of pressure overload is associated with impaired
contractility, as well as significant structural dilatation. Only in the event of
extreme dilatation, however, would pumping failure occur in the presence of
intact myocardial contractile capability. The transformation toward a slower
myocardium is associated with a reduced rate of Ca2+ uptake by the sarcoplasmic
reticulum. Transformation influences ventricular and myocardial working capacity
to a much lesser extent than do the velocity parameters of contraction. Although
a fairly homogeneous VM-3 pattern is typical for ventricles when cardiac failure
is experimentally induced, extreme myocardial transformation, as such, does not
cause congestive failure. With cardiac insufficiency, left ventricular volume,
systolic wall stress, and hydroxyproline concentration are overproportionately
increased, as related to VM-3 content, whereas noradrenaline content is
decreased. This is consistent with the assumption that myocardial transformation
is not necessary for the development of these alterations. Myocardial
transformation may be promoted by structural dilatation. Extreme transformation,
however, should, in turn, decrease contractility, contributing to cardiac
failure. A considerable decrease in contractility indirectly causes depletion of
the catecholamine stores. The energy-saving effect of myocardial transformation
toward a slower muscle cannot compensate for the unfavorable effects of a
substantial degree of ventricular dilatation.
PMID: 2485026 [PubMed - indexed for MEDLINE]
155. Eur J Radiol. 1986 Aug;6(3):163-7.
A new classification of proximal humeral fractures.
Seemann WR, Siebler G, Rupp HG.
Neer's classification of humeral fractures was proved on 657 patients. This
classification enables the radiologist to estimate the risk of avascular necrosis
of the head of the humerus. The problematic group is that of four part lesions,
which has a 19% incidence of humeral head necrosis. Since in this group minimal
osteosynthesis produces better functional results than extensive osteosynthesis,
a detailed pre-operative radiological description of the fracture type is
necessary in order to spare the patient from extensive surgery which could have
unsatisfactory results.
PMID: 3769937 [PubMed - indexed for MEDLINE]
156. Basic Res Cardiol. 1986;81 Suppl 1:203-16.
Pathophysiological mechanisms in cardiac insufficiency induced by chronic
pressure overload--an attempt to analyze specific factors in animal experiment.
Jacob R, Vogt M, Rupp H.
Experimental results obtained from studies on Goldblatt rats and spontaneously
hypertensive rats as well as theoretical considerations render possible an
approximate analysis and evaluation of the relative significance of specific
factors at different levels of the heart for the manifestation of cardiac failure
under chronic pressure overload. In our experimental models congestive failure
was never observed independently of structural dilatation. Thus, as a rule
dilatation had already set in before symptoms of heart failure became manifest.
However, at moderate dilatation of the ventricle, e.g., at double the
end-diastolic volume, the geometrical state per se cannot be the cause of
hydropic decompensation whereas extreme dilatation would, in principle, cause
cardiac pumping failure even in the absence of any impairment of myocardial
"contractility". Generally, a more or less marked impairment of myocardial
contractile capability was found, which exceeded the effects due to the altered
isoenzyme pattern of myosin. As a rule, a reduction in myocardial "contractility"
could be ascertained before a marked degree of dilatation was reached. Diffuse
fibrosis impairs the contractile capability of the myocardium and certainly
contributes to the manifestation of heart insufficiency; although, as a rule, it
should not be the main cause. The adaptive transformation of myocardium towards a
slower muscle (isoenzyme pattern of myosin; sarcoplasmatic reticulum) as such
does not lead to resting insufficiency, not even under persisting pressure load.
Further investigations on processes of excitation-mechanical coupling in the
advanced stage of cardiac overload are indicated. The absence of sympathetic
support to the heart, e.g., following blockade of beta-adrenergic receptors can,
in the advanced stage, elicit a transition from the stage of pre-insufficiency to
manifest failure. However, this was only observed when dilatation had already
occurred. A network of factors are responsible for cardiac insufficiency due to
pressure overloading, whereby the respective significance of each component
varies, depending on the experimental model used.
PMID: 3790041 [PubMed - indexed for MEDLINE]
157. Basic Res Cardiol. 1986;81 Suppl 1:147-55.
Correlation between total catecholamine content and redistribution of myosin
isoenzymes in pressure loaded ventricular myocardium of the spontaneously
hypertensive rat.
Rupp H, Jacob R.
In the spontaneously hypertensive rat (SHR) with established hypertension left
ventricular mass closely correlated with the proportion of ventricular myosin
(VM)-3. A 60% VM-3 content was reached corresponding, under the present housing
conditions, to an average age of 40 weeks without any significant change in total
noradrenaline content. However, all 72-week-old SHR showed marked reduction in
total noradrenaline content which corresponded to noradrenaline depletion. At
this stage, the proportion of VM-3 varied greatly; some of the SHR exhibited a
higher proportion of VM-3 than would be expected from their ventricular weight.
The excessive redistribution in the direction of VM-3 might, therefore, be
considered as a reaction secondary to noradrenaline depletion. Total dopamine
content was also reduced in 72-week-old SHR. In younger SHR, a positive
correlation was found for dopamine content and left ventricular weight. It is
concluded that a redistribution of the myosin isoenzymes up to 60% VM-3 in SHR is
not associated with deterioration of ventricular performance to the extent that
an excessive neurohumoral drive ensues. However, in the late stage of
haemodynamic overload, a functional state is reached which is prone to
noradrenaline depletion. A causative factor involved in this process could be the
extreme redistribution of the myosin isoenzyme population, besides other factors
such as fibrosis and dilatation. Which functional determinants or structural
elements are finally decisive for the transition into a myocardium with depleted
noradrenaline stores requires further investigation.
PMID: 3790040 [PubMed - indexed for MEDLINE]
158. Basic Res Cardiol. 1986;81 Suppl 1:103-15.
The influence of myosin isoenzyme pattern on increase in myocardial oxygen
consumption induced by catecholamines.
Kissling G, Rupp H.
Investigations were performed in a modified heart-lung preparation of the rat in
situ to ascertain to what extent the myosin isoenzyme pattern affects the
catecholamine-induced increase in myocardial oxygen consumption. Accordingly, the
myocardial oxygen consumption was measured in young Wistar rats with mostly VM-1
myosin and older spontaneously hypertensive rats with mostly VM-3 myosin, both
under control conditions and after 0.05 mg/kg orciprenaline. In the controls
(73.7 +/- 3.35% VM-1) the oxygen consumption related to TTI increased from 0.098
+/- 0.003 to 0.129 +/- 0.004 microM O2/g X beat under orciprenaline (+32%, p less
than 0.005). In the SHR (27.8 +/- 0.58% VM-1) there was no significant increase
in O2-consumption related to TTI (control conditions 0.093 +/- 0.003;
orciprenaline 0.095 +/- 0.004 microM O2/g X beat; +2%, n.s.). Our investigations
demonstrate that the degree of catecholamine-induced increase in myocardial
O2-consumption depends on the isoenzyme pattern of myosin.
PMID: 3790039 [PubMed - indexed for MEDLINE]
159. Basic Res Cardiol. 1986;81 Suppl 1:157-69.
Significance of physical exercise in hypertension. Influence of water temperature
and beta-blockade on blood pressure, degree of cardiac hypertrophy and cardiac
function in swimming training of spontaneously hypertensive rats.
Vogt M, Ott B, Rupp H, Jacob R.
In previous studies swimming training (ST) of spontaneously hypertensive rats
(SHR) at 36 degrees water temperature (WT) led to a decrease in blood pressure
(BP). A similar effect of ST has not been described in human hypertension. Our
purpose was to investigate the influence of WT on this training effect, the
influence of ST on LV hypertrophy and the involvement of adrenergic stimuli in
the latter. Male SHR (20 weeks old) were divided randomly into 4 groups. 1) SHR
sedentary 2) SHR ST 36 degrees 3) SHR ST 26 degrees 4) SHR ST 36 degrees +
atenolol (50 mg/kg/die). ST was performed 2 X 90 min/day for 31 days and then
reduced to 2 X 60 min/day. After 7 weeks of ST BP was lower in all ST groups
compared with SHR sedentary (p less than 0.001). BP was higher in ST 26 degrees
than in ST 36 degrees (p less than 0.05). No additional effect of atenolol on BP
was observed. The increase in the degree of LV hypertrophy during ST (ST 36
degrees: +15%; ST 26 degrees: +26%) could be prevented by atenolol (ST 36 degrees
+ atenolol: -1.5%). ST 36 degrees led to improved ventricular and myocardial
performance with decreased LV wall stress ("luxury hypertrophy"), while in ST 26
degrees ventricular dilatation occurred with increased systolic wall stress and
elevated LVEDP. It was uncertain whether this should be interpreted as a state of
LV pre-insufficiency in ST 26 degrees in spite of no indications of impaired
myocardial contractile capability. Peripheral vascular resistance (PVR) was
significantly reduced by ST. The reduction was more evident in ST 26 degrees, but
was partially compensated for by an increased cardiac output. The weights of
adrenal glands increased (p less than 0.001), most markedly for ST 26 degrees.
The level of thyroid hormones (T3 and fT3) was increased in ST 26 degrees. In
summary, ST proved to be effective in lowering BP of SHR. WT had great influence
with respect to cardiovascular adaptation and mechanisms involved in ST of SHR.
Cardioadrenergic drive was of great significance for the process of hypertrophy
during ST in SHR.
PMID: 2947562 [PubMed - indexed for MEDLINE]
160. Basic Res Cardiol. 1985 Nov-Dec;80(6):608-16.
Association of ventricular myosin heavy chains in functional states which lead to
isoenzyme populations encompassing the whole range of possible distribution.
Rupp H.
A statistical model is presented which describes quantitatively the distribution
of ventricular myosin (VM) isoenzymes VM-1, VM-2 and VM-3. In order to account
for the actual distribution of the isoenzymes, it was assumed that the
probability for formation of the heterodimer VM-2 (alpha- and beta-heavy chain)
is lower than that of the homodimers VM-1 (2 alpha-heavy chains) or VM-3 (2
beta-heavy chains). The relation VM-2 = 0.85 (VM-1 X VM-3)0.5 describes
quantitatively the proportion of the 3 isoenzymes in a given population. The
model was established for 252 sedentary normotensive Wistar rats and
spontaneously hypertensive rats (SHR) fed ad libitum. It is demonstrated that the
isoenzyme populations of rats subjected to 8 weeks experimental routines
involving intermittent feeding (1 day feeding ad libitum, followed by 1 or 2 days
fasting) or swimming also obey this theoretical distribution. Intermittent
feeding led to an increased proportion of VM-3 in Wistar rats and SHR, whereby
the latter approached the limits of the possible distribution. Intermittent
swimming resulted in an increased proportion of VM-1 which was independent of the
feeding schedule in SHR. In Wistar rats, however, the swimming rats fed
intermittently exhibited a significantly smaller proportion of VM-1. By combining
certain experimental routines, it is thus possible to induce within 8 weeks an
isoenzyme population of a predefined composition, nearly within the whole range
of possible distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 4091777 [PubMed - indexed for MEDLINE]
161. Jpn Heart J. 1985 Nov;26(6):909-22.
Relationship between the myofibrillar ATPase activity of human biopsy material
and hemodynamic parameters.
Takeda N, Rupp H, Fenchel G, Hoffmeister HE, Jacob R.
The myofibrillar ATPase activity and pyrophosphate gel electrophoretic pattern of
native myosin of fresh human left ventricular papillary muscles were examined in
52 cases of mitral valve replacement. The myofibrillar ATPase activity of
hypertrophied myocardium did not differ from that of non-hypertrophied myocardium
(mean +/- SD, 36.2 +/- 8.7 vs 31.8 +/- 8.6 nmolPi/mg/min, ns) and there was no
significant difference in myofibrillar ATPase activity as a function of left
ventricular enddiastolic pressure. Pyrophosphate gel electrophoresis of myosin
revealed the presence of two components. It is questionable whether the component
of higher electrophoretic mobility (approximately 25-35% in concentration) is
identical with rat ventricular myosin VM-1 because an increase in this component
seems to correlate with a decrease of myofibrillar ATPase activity, its
concentration was significantly higher in the hearts with left ventricular
hypertrophy, high enddiastolic pressure, high aortic pressure or low cardiac
index. From these results, it is not necessarily clear whether hemodynamic
overload in valvular heart diseases can alter left ventricular myofibrillar
ATPase activity, but it can be said that the overload influences the
concentration of the two components of native myosin revealed by pyrophosphate
gel electrophoresis.
PMID: 3007796 [PubMed - indexed for MEDLINE]
165. Basic Res Cardiol. 1985 Jul-Aug;80(4):384-91.
Myocardial catecholamine responsiveness of spontaneously hypertensive rats as
influenced by swimming training.
Takeda N, Dominiak P, Türck D, Rupp H, Jacob R.
Alterations of myocardial mechanical catecholamine responsiveness by swimming
training (2 X 90 min/day, 4 weeks) were examined in 13-week-old spontaneously
hypertensive males rats (SHR). The relationships between myocardial mechanical
catecholamine responsiveness and ventricular beta-adrenoceptors as well as myosin
isoenzyme pattern were also examined. Compared with sedentary controls, trained
rats showed a greater responsiveness to isoproterenol (10(-6) mol/l) on isometric
tension (T) and its first derivative (dT/dt) (delta T: 0.45 +/- 0.55 vs. -0.15
+/- 0.11 10(-2) N/mm2, p less than 0.01, delta dT/dt: 17.1 +/- 10.1 vs. 8.3 +/-
3.6 10(-2) N/mm2 X s, p less than 0.05). In sedentary SHR, dT/dtmax increased
significantly, whereas developed tension decreased slightly, coupled with a
decrease of time to peak tension by high dose (10(-6) mol/l) isoproterenol.
Therefore, it can be stated that dT/dt is a better indicator for catecholamine
sensitivity than isometric tension. beta-adrenoceptor density [(
3H]-dihydroalprenolol binding) decreased significantly in trained rats (68.7 +/-
7.62 vs. 102.4 +/- 4.37 fmol/mg protein, p less than 0.01) with no significant
difference in KD values (4.61 +/- 2.26 vs. 6.11 +/- 1.94 nM, ns). In addition,
myosin isoenzyme pattern revealed by pyrophosphate gel electrophoresis shifted
towards VM-1 after swimming training. The increased catecholamine sensitivity of
fast contracting myocardium is, in principle, compatible with the assumption of
cAMP-dependent regulation of myofibrillar ATPase activity (21) or cross bridge
kinetics (9), although other postreceptor processes should also be taken into
consideration for the increased catecholamine sensitivity.
PMID: 2996481 [PubMed - indexed for MEDLINE]
169. Basic Res Cardiol. 1985 Jan-Feb;80(1):88-99.
The influence of endurance training on mechanical catecholamine responsiveness,
beta-adrenoceptor density and myosin isoenzyme pattern of rat ventricular
myocardium.
Takeda N, Dominiak P, Türck D, Rupp H, Jacob R.
An investigation was carried out on the effects of 4 weeks' swimming training (2
X 90 min/day) on myocardial isometric tension development and rate of tension
rise, and also on the changes induced therein by in vitro application of
isoproterenol. This was done in 9 isolated papillary muscles of 9-week-old male
Wistar rats and the results were compared with the data of age-matched sedentary
controls. Ventricular beta-adrenoceptors [( 3H]-dihydroalprenolol binding) and
the isoenzyme pattern of myosin (pyrophosphate gel electrophoresis) were examined
in the same individuals. Isometric tension (T) and its first derivative (dT/dt)
measured at the optimum of the length-tension diagram were moderately increased
by long-term swimming training. Isoproterenol (10(-5) mol/l) induced a greater
absolute and relative increase of both mechanical parameters in specimens of
trained animals than in age-matched controls (delta T: 3.6 +/- 1.6 vs. 1.9 +/-
0.6 X 10(-2) N/mm2, p less than 0.05. delta dT/dt: 43.4 +/- 14.0 vs. 30.4 +/- 9.5
X 10(-2) N/mm2 X s, p less than 0.05). KD decreased significantly (4.23 +/- 1.0
vs. 2.44 +/- 0.3 nM, p less than 0.02), indicating an increase in receptor
affinity, whereas receptor density revealed a tendency to decrease (98.8 +/- 22.6
vs. 67.1 +/- 18.0 fmol/mg protein, p less than 0.1). In addition, there was a
shift in the isoenzyme pattern of myosin towards VM-1 after swimming training.
Thus, under the conditions of the present experiments, the mechanical response to
isoproterenol does not correlate to beta-adrenoceptor density. It is probable
that, apart from the altered sensitivity of the receptors, other membrane or
post-membrane processes, are responsible for the increased mechanical
responsiveness to catecholamines. Although a relationship between myosin
isoenzyme pattern and mechanical responsiveness to catecholamines is apparent
taking into account our results and the findings on hypertensive rats as reported
in the literature, it cannot be accounted for simply by altered beta-adrenoceptor
density.
PMID: 2985041 [PubMed - indexed for MEDLINE]
170. Eur Heart J. 1984 Dec;5 Suppl F:13-26.
Cardiac alterations at the myofibrillar level: is a redistribution of the myosin
isoenzyme pattern decisive for cardiac failure in haemodynamic overload?
Jacob R, Kissling G, Ebrecht G, Jörg E, Rupp H, Takeda N.
Cardiac muscle physiology, cardiac dynamics and energetics of normotensive and
hypertensive rats [Goldblatt II, spontaneously hypertensive rats (SHR)] are
analyzed in the light of the question of whether a shift in the isoenzyme pattern
of myosin in favour of the isoenzyme VM-3--i.e., transformation towards a slower
muscle--is the essential factor for manifestation of cardiac insufficiency under
chronic haemodynamic overload. Earlier investigations on chemically skinned
myocardial preparations with homogeneous VM-3 and VM-1 patterns revealed that the
decrease in unloaded shortening velocity attributable to extreme redistribution
of the isoenzyme pattern can amount to approx. 40% whereas isometric tension
development at the myofibrillar level is not significantly reduced. Findings from
old normotensive and spontaneously hypertensive rates show that even substantial
prevalence of VM-3 permits adequate ventricular pumping function. The decrease in
the systolic parameters observed in later stages of chronic pressure overload may
be attributed primarily to regressive alterations (fibrosis, structural
dilatation). Under chronic haemodynamic overload, experimentally imposed
isoenzyme redistribution towards a faster myocardium (small thyroxine doses) as
well as transformation towards a slower muscle (thyrostatic treatment) affects
the time parameters of contraction and oxygen consumption more than left
ventricular work capacity. Signs of congestive heart failure are absent. It is
concluded that mere transformation of myocardium towards a more slowly
functioning muscle should not be considered the cause of cardiac failure in the
rat model although this adaptive process may have detrimental consequences under
certain conditions.
PMID: 6241888 [PubMed - indexed for MEDLINE]
171. Can J Physiol Pharmacol. 1984 Sep;62(9):1209-18.
Modulation of myosin isoenzyme populations and activities of monoamine oxidase
and phenylethanolamine-N-methyltransferase in pressure loaded and normal rat
heart by swimming exercise and stress arising from electrostimulation in pairs.
Rupp H, Felbier HR, Bukhari AR, Jacob R.
The question of whether the effects of physical exercise on the heart of 15-weeks
normotensive and hypertensive rats can be modulated by additional stressors was
studied. Intermittent swimming (33-35 degrees C water, maximum 2 X 1.5 h/day, 2-6
weeks) was employed as a model of exercise. Electrostimulation of rats in pairs
(maximum 2 X 1.5 h/day, 6 weeks) served as a model leading predominantly to
stress. When the above procedures were combined, electrostimulation in pairs was
performed in one session and was followed up by swimming. The myosin isoenzyme
population was used as a marker of changes in contractile performance of
myofibrils. Activities of the catecholamine-degrading enzyme monoamine oxidase
(MAO) and the adrenaline-synthesizing enzyme
phenylethanolamine-N-methyltransferase (PNMT) served to monitor chronic
alterations of catecholamine turnover in myocardium. Redistribution in favour of
VM-1 (ventricular myosin isoenzyme 1) occurred as early as 2 weeks after the
onset of intermittent swimming and was observed under several experimental
conditions. The redirection of genetic expression of the isoenzymes was not
linked to the presence of an increased ratio of right to left ventricular weight,
most probably arising from intermittent hypoxia during drownproofing. The myosin
isoenzyme population of swimming spontaneously hypertensive rats (SHR) resembled
that of sedentary Wistar rats. The enzyme activities of MAO and PNMT were both
significantly reduced following 6 weeks intermittent swimming in Wistar rats and
SHR. This can most probably be attributed to the exercise component of swimming
which, on average, led to reduced catecholamine turnover in heart.
Electrostimulation of rats in pairs for 6 weeks, which resulted in aggressivity
and aggressions, did not alter the myosin isoenzyme population in Wistar rats; in
SHR, it further augmented the proportion of VM-3 (ventricular myosin isoenzyme
3), which had already increased in the sedentary state. Furthermore,
electrostimulation increased PNMT activity, but did not affect MAO activity.
Electrostimulation in pairs, followed by swimming, altered the myosin isoenzyme
population in the same way as did swimming alone. However, the activities of PNMT
and MAO seemed to be governed by the routine involving stress and not by the
exercise routine. This demonstrates that stressors supplementing exercise can
decisively modify or even prevent reactions of the organism in response to
exercise.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 6498634 [PubMed - indexed for MEDLINE]
174. Adv Myocardiol. 1983;4:55-77.
Adaptive and pathological alterations in experimental cardiac hypertrophy.
Jacob R, Kissling G, Ebrecht G, Holubarsch C, Medugorac I, Rupp H.
PMID: 6222443 [PubMed - indexed for MEDLINE]
175. Z Kardiol. 1982 Sep;71(9):553-65.
[The significance of the isoenzyme pattern of myosin for myocardial mechanics and
energetics. Relevance to the definition of cardiac contractility]
[Article in German]
Jacob R, Rupp H, Ebrecht G, Holubarsch C, Kissling G.
PMID: 6216677 [PubMed - indexed for MEDLINE]
176. Can J Physiol Pharmacol. 1982 Aug;60(8):1098-103.
Response of blood pressure and cardiac myosin polymorphism to swimming training
in the spontaneously hypertensive rat.
Rupp H, Jacob R.
Cardiac muscle can adapt to different functional demands, as evidenced by
polymorphism of myosin. Pressure load in spontaneously hypertensive rats induced
a shift of the myosin isoenzymes towards myosin V3 (18% V1, 27% V2, 55% V3)
relative to normotensive Wistar rats (49% V1, 29% V2, 22% V3). A swimming routine
with Wistar rats resulted in a shift towards myosin V1 (72% V1, 18% V2, 10% V3).
The training effect is not restricted to normotensive rats, since spontaneously
hypertensive rats subjected to the same swimming routine exhibited a myosin
isoenzyme pattern (38% V1, 31% V2, 31% V3) approaching that of the sedentary
Wistar rats. Swimming training can, therefore, prevent the myosin isoenzyme
redistribution towards myosin V3 found in sedentary spontaneously hypertensive
rats. Furthermore, systolic blood pressure was significantly reduced (130 +/- 8
mmHg (1 mmHg = 133.322 Pa) ) in the swim-trained compared with the sedentary
spontaneously hypertensive rats (157 +/- 12 mmHg). The training-induced changes
in myosin polymorphism and systolic blood pressure are, at least partially,
attributed to substantially normalized sympathetic activity. The functional
relevance of swimming training in the spontaneously hypertensive rat is seen in
the increased potential of coping with situations requiring fast contraction
which may occur during sudden physical exertion or emotional stress.
PMID: 7127222 [PubMed - indexed for MEDLINE]
177. Basic Res Cardiol. 1982 May-Jun;77(3):255-69.
Alterations in cardiac oxygen consumption under chronic pressure overload.
Significance of the isoenzyme pattern of myosin.
Kissling G, Rupp H, Malloy L, Jacob R.
Hypertension and resulting left ventricular hypertrophy was induced in young male
Wistar rats (60 to 70 days old) by narrowing of one renal artery (Goldblatt II).
8 and 24 weeks after operation, myocardial oxygen consumption was measured on a
modified in situ heart-lung preparation with nearly isovolumetric left
ventricular contractions. Measured myocardial oxygen consumption was related to
left ventricular wall stress. The myosin isoenzyme pattern of each heart was
determined with pyrophosphate gel electrophoresis. Oxygen consumption related to
wall stress averaged over the entire heart cycle amounted to 15 mumoles O2/g X
min 8 weeks after operation, and 24.4 mumoles O2/g X min in age-matched controls
(delta 38%, p less than 0.0005). When wall stress was averaged over systole,
oxygen consumption of the hypertrophied hearts amounted to 0.112 mumoles O2/g x
beat, and 0.149 mumoles O2/g x beat in the controls (delta 25%, p less than
0.05). The proportion of VM-3 (the cardiac myosin isoenzyme of lowest ATPase
activity) increased from 26.3% in the controls to 30.1% in the Goldblatt hearts
(delta 14%, n.s.). 24 weeks after operation, oxygen consumption related to wall
stress averaged over the entire heart cycle amounted to 16.1 mumoles O2/g x min,
in age-matched controls 20.5 mumoles O2/g x min (delta 21%, p less than 0.05).
When wall stress was averaged over systole, oxygen consumption of the Goldblatt
hearts amounted to 0.080 mumoles O2/g x beat, and in the controls 0.107 mumoles
O2/g x beat (delta 25%, p less than 0.0005). The proportion of VM-3 increased
from 33.5% in the controls to 43.2% in the hypertrophied hearts (delta 29%, p
less than 0.05). The present findings indicate that the reduced oxygen
consumption of the pressure-loaded heart should be attributed to a redistribution
of myosin isoenzymes. The transformation of myocardium into a slower, but more
efficiently working muscle due to an increase in VM-3 can be interpreted as an
adaptational process.
PMID: 6214250 [PubMed - indexed for MEDLINE]
178. Basic Res Cardiol. 1982 Mar-Apr;77(2):220-34.
Alterations of mechanical parameters in chemically skinned preparations of rat
myocardium as a function of isoenzyme pattern of myosin.
Ebrecht G, Rupp H, Jacob R.
Myofibrillar ATPase activity, maximum unloaded shortening velocity, and isometric
tension development were evaluated in left ventricular preparations of 5-week-old
rats with a high endogeneous level of thyroid hormones and hypothyroid rats after
4-week treatment with propylthiouracil (PTU). The range of possible alterations
of the above functional parameters was defined in relation to myosin isoenzyme
distribution. The mechanical behaviour of the ventricular preparations was
investigated in native myocardium as well as in the glycerinated state. The
essential results of the present study is that alterations of myofibrillar ATPase
activity and mechanical Vmax, evaluated in glycerinated preparations, are limited
to a well-defined range of similar magnitude for both functional parameters:
32-40% of maximum values (obtained from rat myocardium with homogeneous myosin
V1). Isometric tension was only insignificantly decreased in glycerinated
preparations of the PTU-treated group. The alteration in the apparent maximum
shortening velocity of native myocardium (V0) was of the same magnitude as
changes in Vmax of chemically skinned preparations. Physical training revealed a
shift in the direction of V1-type myosin with increased ATPase activity and
shortening velocity; aging and pressure overload showed an opposite effect. The
documented mechanical alterations do not contradict an adaptational
interpretation of the myosin isoenzyme redistribution in pressure-induced
hypertrophy.
PMID: 6212048 [PubMed - indexed for MEDLINE]
180. Basic Res Cardiol. 1982 Jan-Feb;77(1):34-46.
Polymorphic myosin as the common determinant of myofibrillar ATPase in different
haemodynamic and thyroid states.
Rupp H.
PMID: 6462131 [PubMed - indexed for MEDLINE]
181. Adv Myocardiol. 1982;3:455-66.
Calcium-dependent activation of cardiac myofibrils. The mechanisms that modulate
myofibrillar ATPase and tension and their significance for heart function.
Rupp H.
Myocardial function can be modulated at the level of the sarcolemma, the
intracellular Ca2+ stores, and the myofilaments. A way of following myofibrillar
modulation of mechanochemical activity is by studying the Ca2+-dependent
activation of myofibrils. In this study, the role of Mg2+ in the Ca2+ activation
of myofibrillar ATPase was evaluated. The concentrations of both free Ca2+ and
free Mg2+ were varied at a given concentration of MgATP (3.16 mM), ionic strength
(0.12), and pH 7.0. The experimental ATPase-vs.-Ca2+ data were fit to the
model-independent Hill equation and to Tawada's model of intertropomyosin
cooperation. In the micromolar range, Mg2+ did not affect the Ca2+ sensitivity,
whereas it was reduced at high Mg2+ (5 mM), corresponding to a shift of the
activation curve to higher Ca2+ concentrations. Positive cooperativity (n = 2.4)
and ATPase activity at saturating Ca2+ concentrations were affected only at low
Mg2+. At 0.032 mM Mg2+, the positive cooperation was partially lost (n = 1.3),
and maximum ATPase was reduced by 23%. The consequences of a change in the
activation curves for the mechanogram are shown. The influence of other
modulatory mechanisms on the activation properties was also analyzed on the basis
of the Hill equation and the intertropomyosin cooperation model. Acute changes in
contractility can arise from changes in the intracellular pH, in sarcomere
length, and from phosphorylation of troponin I. Long-term modifications of
cardiac performance involve genetic expression of different myosin isoenzymes.
The relevance of these different modulatory mechanisms for myocardial function is
shown.
PMID: 6302787 [PubMed - indexed for MEDLINE]
182. Basic Res Cardiol. 1981 Jan-Feb;76(1):79-88.
The adaptive changes in the isoenzyme pattern of myosin from hypertrophied rat
myocardium as a result of pressure overload and physical training.
Rupp H.
The distribution of cardiac myosin isoenzymes is altered as a result of pressure
overload and physical training. Using polyacrylamide gel electrophoresis in
sodium pyrophosphate, it was found that myosin from left ventricles of adult rats
exists in three polymorphic forms, V1, V2 and V3. Cardiac hypertrophy due to
renal hypertension (Goldblatt II) led to a shift of the isoenzymes towards V3,
whereas swimming training resulted in an opposite redistribution. The isoenzyme
V1 predominated, only traces of V2 and V3 were detectable. The changes in the
isoenzyme distribution were reflected in an altered ATPase activity of
myofibrils. In a representative sample of the Goldblatt rats, the activity was
reduced by 11%, and the swimming training led to an increase by 10%. Changes in
myofibrillar ATPase can, therefore, be traced to alterations in the isoenzyme
pattern of myosin. The polymorphism of myosin has a two-faced aspect as regards
cardiac performance. For example, a shift towards V3 is expected to increase the
economy for tension development during isovolumetric contraction at the expense
of a reduced maximum speed of ventricular contraction.
PMID: 6453582 [PubMed - indexed for MEDLINE]
183. Basic Res Cardiol. 1980 Mar-Apr;75(2):295-317.
Modulation of tension generation at the myofibrillar level -- an analysis of the
effect of magnesium adenosine triphosphate, magnesium, pH, sarcomere length and
state of phosphorylation.
Rupp H.
PMID: 6967310 [PubMed - indexed for MEDLINE]
184. Basic Res Cardiol. 1980 Jan-Feb;75(1):157-62.
Cooperative effects of calcium on myofibrillar ATPase of normal and hypertrophied
heart.
Rupp H.
The ATPase of myofibrils from normal and hypertrophied rat heart was studied in
relation to the Ca2+-dependence of the reaction. The experimental data were
fitted to theoretical curves based on the Hill equation. A positive cooperativity
(n = 1.6) was found for the activation curve of the ATPase from normal heart. For
hypertrophied heart no significant change in either the cooperativity or the
Ca2+-sensitivity of troponin was detected. This indicates that the
troponin-tropomyosin system is not altered during pressure-overload hypertrophy.
However, it should be noted that no precautions were taken to control the state
of phosphorylation of contractile proteins during the preparation of myofibrils.
PMID: 6446285 [PubMed - indexed for MEDLINE]
185. Biochim Biophys Acta. 1979 Dec 6;548(3):552-64.
The electron spin relaxation of the electron acceptors of photosystem I reaction
centre studied by microwave power saturation.
Rupp H, de la Torre A, Hall DO.
Photosystem I particles from spinach were reduced by illumination at 77 K. Under
these conditions the one-electrom transfer from P-700 resulted in a reduction of
only one acceptor molecule of the reaction centre. The EPR signals at g=2.05,
1.94 and 1.86 were attributed to reduced centre A and the smaller signals at
g=2.07, 1.92 and 1.89 to reduced centre B. Reduction of both centres by
dithionite in the dark lead to signals at g=2.05, 1.99, 1.96, 1.94, 1.92 and
1.89. Thus, the features at g=2.07 and 1.86 disappeared and new signals at g=1.99
and 1.96 were observed. From the spectral changes it followed that the
iron-sulphur centres A and B interact magnetically. Temperature dependent EPR
spectra demonstrated a faster electron spin relaxation of centre A than of centre
B. These conclusions were corroborated using microwave power saturation of the
respective EPR signals. The saturation data of the fully reduced centres A and B
could not be fitted using the saturation equation for a one-electron spin system.
The magnetic interaction between the (4Fe-4S) CENTRes of the electron acceptors A
and B resulted in saturation properties which are simular to those of the
2(4Fe-4S) ferredoxin from Clostridium pasteurianum. For centre X a high
proportion of homogeneous broadening of the EPR lines was inferred from the
inhomogeneity parameter (b=1.83). It was, therefore, concluded that centre X is
most probably an anion radical of chlorophyll. From the low temperature necessary
for observing the EPR signal of centre X followed that the drastic relaxation
enhancement has to be attributed to a magnetic interaction of the anion radical
with iron.
PMID: 228715 [PubMed - indexed for MEDLINE]
186. Biochim Biophys Acta. 1979 Oct 10;548(1):16-29.
Characterization of iron-sulphur centres of plant mitochondria by microwave power
saturation.
Rupp H, Moore AL.
The electron spin relaxation of iron-sulphur centres and ubisemiquinones of plant
mitochondria was studied by microwave power saturation of the respective EPR
signals. In the microwave power saturation technique, the experimental saturation
data were fitted by a least-squares procedure to a saturation function which is
characterized by the power for half-saturation (P1/2) and the inhomogeneity
parameter (b). Since the theoretical saturation curves were based on a
one-electron spin system, it became possible to differentiate between EPR signals
of iron-sulphur centres which have similar g values but different P1/2 values. If
the difference in the P1/2 values of the overlapped components was small, no
significant deviation from these theoretical saturation curves was observed, as
shown for the overlapped signals of centre S-3 and the Ruzicka centre of mung
bean mitochondria. By contrast, the microwave power saturation data for the g =
1.93 signal (17--26 K) of Arum maculatum submitochondrial particles reduced by
succinate could not be fitted using one-electron saturation curves. Reduction by
NADH resulted in a stronger deviation. Since the iron-sulphur centres of Complex
I were present only in an unusually low concentration in A. maculatum
mitochondria, it was proposed that an iron-sulphur centre of the external NADH
dehydrogenase contributes to the spectrum of centre S-1. For mung bean
mitochondria, the g = 1.93 signal below 20 K could be attributed mainly to centre
N-2. The microwave power saturation technique was also suitable for detecting
magnetic interactions between paramagnetic centres. From the saturation data of
the complex spectrum attributable to centre S-3 and an interacting ubisemiquinone
pair in mung bean mitochondria (oxidized state) followed that centre S-3 has a
faster electron spin relaxation than the ubisemiquinone molecules. It is
noteworthy that the differences in the relaxation rates were maintained despite
the interaction between centre S-3 and the ubisemiquinones. Furthermore, a
relaxation enhancement was observed for centre S-1 of A. maculatum
submitochondrial particles upon reduction of centre S-2 by dithionite. This
indicated a magnetic interaction between centres S-1 and S-2.
PMID: 226132 [PubMed - indexed for MEDLINE]
187. Biochim Biophys Acta. 1979 Jun 19;578(2):462-75.
Oxidation-reduction reactions of copper-thiolate centres in Cu-thionein.
Rupp H, Cammack R, Hartmann HJ, Weser U.
Cu-thionein from yeast was investigated by EPR spectroscopy to probe the
oxidation state of copper, and the effects on it of oxidizing and reducing
agents. At pH 0.2 the copper was released, but no EPR signal from Cu(II) was
observed, unless air was present. Optical experiments did not detect any
disulphide groups which might have been formed during anaerobic release of
copper. The mercurial, p-hydroxymercuribenzoate caused the release of
EPR-detectable copper only under aerobic conditions, and EDTA caused release of
Cu(II) on heating. No reduction of the copper-thiolate units in Cu-thionein by
ascorbate was detected. Potentiometric titrations with hexachloroiridate(IV) or
hexacyanoferrate(III) produced several different Cu(II) EPR signals at various
stages of oxidation. The former oxidizing agent required a lower
oxidation-reduction potential (+350 mV) to oxidize the copper, than the latter
(+410 mV) and neither titration was fully reversible. The EPR signal from Cu(II)
oxidized by hexachloroiridate(IV) resembled that produced by
p-hydroxy-mercuribenzoate in air, suggesting that the copper was released from
its thiolate ligands. It is concluded that the EPR non-detectable copper in the
native protein is Cu(I). Oxidation-reduction of the copper-thiolate clusters of
Cu-thionein is proposed to be decisive for controlling storage and transport of
cellular copper.
PMID: 226164 [PubMed - indexed for MEDLINE]
188. Experientia Suppl. 1979;34:221-30.
Copper-thionein and other metal-sulphur-proteins.
Weser U, Rupp H.
PMID: 299367 [PubMed - indexed for MEDLINE]
189. Experientia Suppl. 1979;34:231-40.
Structural aspects and reduction oxidation reactions of metallothionein.
Rupp H, Weser U.
PMID: 233615 [PubMed - indexed for MEDLINE]
190. Biochim Biophys Acta. 1978 Dec 20;537(2):255-60.
Electron spin relaxation of iron-sulphur proteins studied by microwave power
saturation.
Rupp H, Rao KK, Hall DO, Cammack R.
The electron-spin relaxation of iron-sulphur centres in a range of simple
proteins (ferredoxin, high-potential iron-sulphur protein and rubredoxin) was
investigated by means of the temperature dependence and microwave power
saturation of the EPR signal. The proteins containing [2Fe-2S] centres all showed
temperature optima higher than those for [4Fe-4S] centres, but the difference
between the slowest-relaxing [4Fe-4S] protein (Chromatium high-potential
iron-sulphur protein) and the fastest-relaxing [2Fe-2S] protein (Halobacterium
halobium ferredoxin) was small. A greater distinction was seen in the power
saturation behaviour at low temperature (10--20 K). The behaviour of the signal
intensity as a function of microwave power was analyzed in terms of the power for
half saturation P 1/2 and the degree of homogeneous/inhomogeneous broadening. The
effect of distorting the protein structure by salts, organic solvents and urea
was to decrease the electron-spin relaxation rate as shown by a decreased value
of P 1/2. The addition of Ni2+ as a paramagnetic perturbing agent caused an
increase in the electron-spin relaxation rate of all the proteins, with the
exception of adrenal ferredoxin, as shown by an increased P 1/2 and, in a few
cases, broadening of the linewidth. Ferricyanide, a commonly used oxidizing
agent, has similar effects. These results are discussed in relation to the use of
paramagnetic probes to determine whether iron-sulphur centres are near to a
membrane surface. Spin-spin interactions between two paramagnetic centres in a
protein molecule such as a 2[4Fe-4S] ferredoxin, lead to more rapid electron-spin
relaxation. This method was used to detect a spin-spin interaction between
molybdenum V and centre Fe-SI in xanthine oxidase.
PMID: 215217 [PubMed - indexed for MEDLINE]
191. Biochim Biophys Acta. 1978 Mar 28;533(1):209-26.
Circular dichroism of metallothioneins. A structural approach.
Rupp H, Weser U.
A comprehensive study on circular dichroism of metallothioneins containing Zn, Cd
and Cu was carried out. The contributions of the metals, the sulphur and the
polypeptide chain to the observed Cotton effects was shown. From the pH
dependency of the extrinsic Cotton effects which are due to the metal-thiolate
chromophore the stability of the metal clusters was found to decrease in the
order Cu greater than Cd greater than Zn. The pH values corresponding to the
dissociation of half of the bound metal ions are 0.44 for Cu-thionein, 3.05 for
Cd-thionein and 4.6 for Zn-thionein. The extrinsic Cotton effects of Cd,
Zn-thioneins of varying Cd to Zn ratio could be simulated using the difference
circular dichroic spectra of Cd-thionein (bands at 227, 242.5 and 262 nm),
Zn-thionein (bands at 225 and 244 nm) and the circular dichroic spectrum of
cysteine-thionein (band at 200 nm, shoulder at 225 nm). Since during the
dissociation of the metals the circular dichroic spectra exhibited changes only
in amplitude and not in shape we can conclude that the dissociation of the metal
ions involves the complete sequential degradation of metal clusters. In the
near-ultraviolet region the metal-free proteins show only Cotton effects
attributable to a disulphide chromophore. Thus Cotton bands are observed for
cystine-thionein at 282.5 and 260 nm. From the intrinsic circular dichroism of
Cd- and Zn-thionein (negative Cotton effect at 200 nm, shoulder at 225 nm) it
follows that the protein conformation consists of less than 5% helical or pleated
sheet structure and therefore has to be classified as unordered structure or
"fixed" random coil
PMID: 25087 [PubMed - indexed for MEDLINE]
192. Biochim Biophys Acta. 1976 Sep 28;446(1):151-65.
Copper(I) and copper(II) in complexes of biochemical significance studied by
X-ray photoelectron spectroscopy.
Rupp H, Weser U.
X-ray photoelectron spectroscopic measurements of copper complexes of biochemical
significance were carried out to permit the conclusion whether or not copper is
present in the Cu(I) or Cu(II) state. Only one single homogeneous signal in the
X-ray photoelectron spectra of the Cu(I) 2p1/2 and 2p3/2 levels was seen
regardless whatever Cu(I) complex was used. By contrast one more or less split
satellite in addition to the main 2p copper signal appeared when Cu(II) complexes
were studied. The extent of satellite splitting was dependent on the nature of
the ligands coordinated with Cu(II). Thus, a strong splitting was observed in the
spectra of Cu-(trifluoroacetylacetonate)2 and Cu-(biuret)2Cl2 were Cu(II) is
exclusively bound to oxygen having a formal double bond. No such splitting was
seen in Cu(II) chelates where the metal was bound to single bonded oxygen and/or
nitrogen. It excited great interest to see that in the antiferromagnetically
coupled Cu(II) complexes Cu2-(succinate)2-4H2O, Cu-(HCCO)2, CuO and in the
completely diamagnetic Cu2-(u,3-diphenyltriazene)4 complex Cu(II) could be
detected. The reaction of Cu(I) and Cu(II) with the thiol sulphur of either
cysteine, penicillamine or alpha-mercaptopropionylglycine yielded Cu(I)
complexes. During the X-ray exposure of the different samples photoreduction of
Cu(II) was not observed. For example, the satellite structure of the copper 2p
levels using Cu(II)-cystine remained unchanged during the measurement.
PMID: 974109 [PubMed - indexed for MEDLINE]
193. Biochem Biophys Res Commun. 1976 Sep 7;72(1):223-9.
Reactions of D-penicillamine with copper in Wilson's disease.
Rupp H, Weser U.
PMID: 985469 [PubMed - indexed for MEDLINE]
194. Bioinorg Chem. 1976;6(1):45-59.
X-ray photoelectron spectroscopy of copper(II), copper(I), and mixed valence
systems.
Rupp H, Weser U.
X-ray photoelectron spectroscopy using copper(II), copper(I) and the mixed
valence Cu(II)/Cu(I) compounds was employed as a means of studying electron
transfer reactions in copper proteins. The X-ray photoelectron spectra of
copper(II) compounds display characteristic satellites of both variable size and
resolution. Some of these satellites could be assigned to specific ligand
interactions. Unlike electron paramagnetic resonance spectroscopy, the X-ray
photoelectron spectroscopic measurements of copper(I) compounds allowed the
unequivocal assignment of this oxidation state. No satellites at all could be
detected in the Cu(I) spectra. Furthermore, established mixed valence
Cu(II)/Cu(I) complexes including Cu2SO3-CuSO3-2H2O and Cu4Cl5 (ethylenediamine)2
proved essentially a mixture of distinct portions of Cu(I) and Cu(II). This
indicates that both oxidation states of copper survive in such complexes. In
contrast, all Cu X-ray photoelectron signals of the more tentatively described
mixed valence complexes Na2Cu3S3 and the mineral covellite, CuI4CuII2(S2)2S2,
could be attributed exclusively to Cu(I). In view of the known binding of copper
with sulfur in many copper proteins, it was of utmost importance to study the
copper-sulfur interactions. We have demonstrated the absence of Cu(II) in CuS.
This indicates strong metal-induced polarization of sulfur resulting in electron
transfer to copper to yield Cu(I).
PMID: 953045 [PubMed - indexed for MEDLINE]
195. Hoppe Seylers Z Physiol Chem. 1975 Jun;356(6):755-65.
Molecular biology of copper. A circular dichroism study on copper complexes of
thionein and penicillamine.
Rupp H, Voelter W, Weser U.
Chicken liver Cd, Zn-thionein (metallothionein) was isolated from Cd-pretreated
chickens weighing 1 500 g. The native Cd, Zn-thionein contained 9 g-atoms of
metals per 12 000 g of protein. Upon the addition of Cu(CH3CN)4ClO4, all Cd2 and
Zn2 were successfully replaced. 15 g-atoms of Cu from the acetonitrile
perchlorate complex were bound to the protein. Due to the absence of aromatic
amino acid residues, thionein has unique ultraviolet and circular dichroism
properties. The shoulder of the ultraviolet spectrum at 250 nm (A250 X A280(-1) =
23.9) was shifted to 275 nm (A250 X A280(-1) = 1.6). No significant absorption
was detected in the visible region. Th conformational changes of the protein
moiety were much more visible in the circular dichroism spectra. The titration
with Cu(CH3CH)2 caused the appearence of three new Cotton effects: 257.5 nm (+),
350 nm (+) and 301 nm (-). The negative Cotton effect at 239 nm of the original
metallothionein was completely levelled off. The binding strength of copper with
thionein is extraordinarily high: it survives proton treatment up to pH 1.9.
Displacement of the Cd2 by Cu employing Cd-thionein which was formed at pH 2.2
resulted in the same circular dichroism properties as observed for Cu-thionein.
D-Penicillamine proved a suitable model for the metal-free thionein, since redox
reactions and polymerization of the sterically hindered thiol residue are known
to be slow. The correlation of the circular dichroism properties of either copper
complex using thionein or D-penicillamine was surprisingly high. Circular
dichroism measurements of Cu(I)-D-penicillamine revealed Cotton effects at 255 nm
(+), 280 nm (+) and 355 nm (-). Upon examining the red-violet mixed
Cu(-i)-cu(II)-D-penicillamine complex, Cotton bands in the visible region at 425
nm (-) and 495 nm (+) were seen. In many blue copper enzymes, the copper is
assumed to be in the neighborhood of both cysteine and aromatic amino acid
residues, which are known to play an important role in the electron transfer.
This is not the case in the Cu-thionein, which would explain many different
properties of this copper protein. It is very attractive to conclude that the
sterically hindered SH-group of D-penicillamine reacts with excess copper in a
specific way, similar to the Cu-thionein. This phenomenon could explain the
considerable success of D-penicillamine in the treatment of Wilson's disease.
PMID: 241690 [PubMed - indexed for MEDLINE]
196. Bioinorg Chem. 1975;5(1):21-32.
X-ray photoelectron spectroscopy of some selenium containing amino acids.
Rupp H, Weser U.
X-ray photoelectron spectra of some inorganic selenium compounds, Se-methionine,
Se-cystine, Se-urea and selenodicysteine were recorded and compared with the XPS
data obtained from the respective sulphur containing compounds. The oxidation
state of selenium could be monitored by the observed chemical shifts of the
Se(3p1/2),Se(3p3/2) and Se(3d3/2,5/2) levels. Though having a formal oxidation
state near zero, the binding energy of the core electrons of Se in Se-methionine,
Se-cystine and selenodicysteine was shifted by 0.4, 0.7 and 0.4 eV, respectively.
This phenomenon was attributed to the rather distinct polarization of Se. The
reversible oxidation of Se-cystine using H2O2 and NaBH4 could be successfully
demonstrated by this XPS-technique.
PMID: 1182207 [PubMed - indexed for MEDLINE]
198. Eur J Biochem. 1974 Dec 16;50(1):91-9.
Nuclear-magnetic-resonance with 13C and 31P and circular-dichroism studies of a
ternary complex of spermine, Cu2+ and AMP.
Weser U, Strobel GJ, Rupp H, Voelter W.
PMID: 4548872 [PubMed - indexed for MEDLINE]
199. FEBS Lett. 1974 Aug 30;44(3):293-7.
Conversion of metallothionein into Cu-thionein, the possible low molecular weight
form of neonatal hepatic mitochondrocuprein.
Rupp H, Weser U.
PMID: 4472041 [PubMed - indexed for MEDLINE]
200. FEBS Lett. 1974 Mar 15;40(1):176-9.
270 MHz proton magnetic resonance spectra of metallothionein.
Rupp H, Voelter W, Weser U.
PMID: 4369453 [PubMed - indexed for MEDLINE]
201. Eur J Biochem. 1973 Nov 1;39(1):127-40.
Characterization of Cd, Zn-thionein (metallothionein) isolated from rat and
chicken liver.
Weser U, Rupp H, Donay F, Linnemann F, Voelter W, Voetsch W, Jung G.
PMID: 4770787 [PubMed - indexed for MEDLINE]
203. FEBS Lett. 1973 May 15;32(1):171-4.
Cadmium-induced synthesis of hepatic metallothionein in chicken and rats.
Weser U, Donay F, Rupp H.
PMID: 4715680 [PubMed - indexed for MEDLINE]