Abstract

This proposal will investigate excitation-contraction (EC) coupling in the hypertrophied and failing hearts of SHHF/Mcc-facp (SHF) rats. The SHF rat is spontaneously hypertensive and typically dies of heart failure between one and two years of age.
Specific aim #1 will test the hypothesis that the major components linking excitation to Ca2+ release from the sarcoplasmic reticulum (SR) are present in normal amounts in the failing SHF rat heart.
Specific aim #2 will examine b-adrenergic modulation of EC coupling.
Specific aim #3 will test the hypothesis that the functional coupling between the L-type Ca2+ release channels of the sarcolemma and the Ca2+ release channels, or ryanodine receptors, of the SR declines during the cellular remodeling that occurs as SHF hearts hypertrophy and eventually fail. Myocardial function will be characterized in vivo using echocardiography and in vitro with Langendorff perfused ventricles and single isolated left ventricular myocytes. In vitro studies will examine the effects of varied stimulation patterns and the effects of b1- and b2-adrenergic agonists. The relationship between L-type Ca2+ current and SR Ca2+ release events (Ca2+ sparks) will be examined using line scanning laser confocal microscopy of cells loaded with the fluorescent dye, fluo-3. The in vivo and in vitro functional data will be correlated with protein content and phosphorylation status of phospholamban and the ryanodine receptors in hearts from lean male SHF rats with heart failure, and from age-matched SHF rats with compensatory hypertrophy and normal Sprague-Dawley rats.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048835-09
Application #
6183491
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1992-08-01
Project End
2002-06-30
Budget Start
2000-07-10
Budget End
2002-06-30
Support Year
9
Fiscal Year
2000
Total Cost
$271,810
Indirect Cost

  Institution

Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Black, D J; Halling, D Brent; Mandich, David V et al. (2005) Calmodulin interactions with IQ peptides from voltage-dependent calcium channels. Am J Physiol Cell Physiol 288:C669-76
Janssen, Paul M L; Stull, Linda B; Leppo, Michelle K et al. (2003) Selective contractile dysfunction of left, not right, ventricular myocardium in the SHHF rat. Am J Physiol Heart Circ Physiol 284:H772-8
Tang, Wei; Halling, D Brent; Black, D J et al. (2003) Apocalmodulin and Ca2+ calmodulin-binding sites on the CaV1.2 channel. Biophys J 85:1538-47
Kogler, Harald; Fraser, Heather; McCune, Sylvia et al. (2003) Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium. Cardiovasc Res 59:582-92
Dumitrescu, Cristian; Narayan, Prakash; Cheng, Yuanna et al. (2002) Phase I and phase II of short-term mechanical restitution in perfused rat left ventricles. Am J Physiol Heart Circ Physiol 282:H1311-9
Radin, M Judith; Holycross, Bethany J; Sharkey, Leslie C et al. (2002) Gender modulates activation of renin-angiotensin and endothelin systems in hypertension and heart failure. J Appl Physiol 92:935-40
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
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
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
Altschuld, R A; Billman, G E (2000) beta(2)-Adrenoceptors and ventricular fibrillation. Pharmacol Ther 88:14-Jan

Showing the most recent 10 out of 32 publications