This proposal seeks to test the hypothesis that the myocardial sarcoplasmic reticulum undergoes profound changes during the transition from stable compensatory hypertrophy to decompensation, dilatation, and failure. Furthermore, these changes, which affect the release process(es) as well as kinetics of unidirectional calcium uptake, are caused by intrinsic changes in the sarcoplasmic reticulum as well as regulatory systems involving calmodulin, cAMP, and other second messengers. This hypothesis will be tested using a strain of hypertensive, obese, male rats with non-insulin-dependent diabetes mellitus, the SHHF/Mcc-cp. These animals all develop a fatal dilated cardiomyopathy between 10 and 12 months of age. Contractile performance, with special emphasis on mechanical alternans and the interval-strength relationship, will be investigated in Langendorff perfused SHHF hearts at various stages during the transition to failure. Simultaneous 31P-NMR spectra will be obtained to assess energy status and intracellular pH. Ventricular myocytes will be isolated from SHHF hearts at varying stages during the transition to failure and characterized in terms of electrically-stimulated Ca-dependent fura-2 ratio transients, hormone responsiveness, membrane receptors, and cAMP and IP 3 production. Calmodulin and proteins of the sarcoplasmic reticulum including calsequestrin, phospholamban, the ryanodine-binding release channel protein, and Ca-dependent ATPase will also be quantified in intact myocytes. Lysed myocytes will be used to probe 45Ca 2+ uptake and release by the physically intact, in situ, sarcoplasmic reticulum. Results will be compared to those from age-matched control WKY/N and estrone pre-treated obese SHHF male rats. The latter develop end-stage failure several months later than untreated obese males.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048835-02
Application #
3368004
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Dumitrescu, Cristian; Narayan, Prakash; Efimov, Igor R et al. (2002) Mechanical alternans and restitution in failing SHHF rat left ventricles. Am J Physiol Heart Circ Physiol 282:H1320-6
Houle, M S; Altschuld, R A; Billman, G E (2001) Enhanced in vivo and in vitro contractile responses to beta(2)-adrenergic receptor stimulation in dogs susceptible to lethal arrhythmias. J Appl Physiol 91:1627-37
Sharkey, L C; Holycross, B J; McCune, S A et al. (2001) Obese female SHHF/Mcc-fa(cp) rats resist antihypertensive effects of renin-angiotensin system inhibition. Clin Exp Hypertens 23:227-39
Altschuld, R A; Billman, G E (2000) beta(2)-Adrenoceptors and ventricular fibrillation. Pharmacol Ther 88:14-Jan

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