It is now well established that the Ca++ ion plays a central role in the process of excitation-contraction coupling in the heart. The general purpose of this study is to evaluate the abnormalities in excitation-contraction coupling that occur in cardiac hypertrophy and failure in experimental animals and man, and to determine the effects of potential therapeutic interventions on hypertophied heart muscle. A large amount of information has accumulated to suggest that intracellular Ca++ handling is abnormal in cardiac hypertrophy, with or without the onset of failure. By use of aequorin, a bioluminescent calcium indicator that emits light when it combines with Ca++, it is possible to directly record intracellular Ca++ transients during contraction and relaxation of cardia muscle fibers. Aequorin will be used to determine how changes in intracellular Ca++ handling are related to the mechanical and electrical abnormalities that occur with hypertrophy and hypoxia of mammalian working myocardium. The subcellular actions of inotropic agents on intracellular Ca++ transients in hypertrophied cardiac muscle will be studied, including the triggerable activity that occurs with toxic doses of these agents. Papillary muscles and isolated myocytes from control and hypertrophied ferrets and hamsters will be loaded with aequorin; light (i.e., intracellular Ca++,) tension and electrical activity will be recorded. Human working myocardium removed at the time of cardiac surgery from patients with hypertrophy will also be studied. The aequorin signals from intact muscle will be correlated with Ca++ handling by isolated sarcoplasmic recticulum vesicles. By directly recording intracellular Ca++ transients in intact and actively contracting cardiac fibers that are hypoxic or hypertrophied, it will be possible for the first time to test the functional significance of the subcellular abnormalities in intracellular Ca++ handling that have been reported by other investigators, particularly with regard to the function of the sarcoplasmic reticulum. In addition, these studies will provide new information of clinical importance regarding the therapeuitc and toxic effects of inotropic drugs on hypertrophied cardiac muscles, and, in the long-term, should help to define the role of Ca++ in the pathogenesis of the hypertrophic response. Moreover, these studies will lay the groundwork for the use of intracellular calcium indicators as diagnostic and prognostic tools in clinical medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001611-02
Application #
3073919
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1985-09-01
Project End
1990-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Brooks, W W; Conrad, C H; Morgan, J P (1995) Reperfusion induced arrhythmias following ischaemia in intact rat heart: role of intracellular calcium. Cardiovasc Res 29:536-42
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Bing, O H; Hague, N L; Perreault, C L et al. (1994) Thyroid hormone effects on intracellular calcium and inotropic responses of rat ventricular myocardium. Am J Physiol 267:H1112-21
Kihara, Y; Sasayama, S; Inoko, M et al. (1994) Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mammalian working myocardium. Evidence from aequorin-loaded ferret ventricular muscles. J Clin Invest 93:1275-84
Brooks, W W; Bing, O H; Litwin, S E et al. (1994) Effects of treppe and calcium on intracellular calcium and function in the failing heart from the spontaneously hypertensive rat. Hypertension 24:347-56
Perreault, C L; Hague, N L; Morgan, K G et al. (1993) Negative inotropic and relaxant effects of cocaine on myopathic human ventricular myocardium and epicardial coronary arteries in vitro. Cardiovasc Res 27:262-8
Perreault, C L; Gonzalez-Serratos, H; Litwin, S E et al. (1993) Alterations in contractility and intracellular Ca2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure. Circ Res 73:405-12
Wang, J; Flemal, K; Morgan, J P (1993) Endothelin-1 enhances cross-bridge function of ferret myocardium: role of second messengers. Am J Physiol 265:H2168-74
Bing, O H; Kihara, Y; Brooks, W W et al. (1993) Fluorocarbon simulation of myocardial ischaemia and reperfusion: studies of relationships between force and intracellular calcium. Cardiovasc Res 27:1863-8
Meuse, A J; Perreault, C L; Morgan, J P (1992) Pathophysiology of cardiac hypertrophy and failure of human working myocardium: abnormalities in calcium handling. Basic Res Cardiol 87 Suppl 1:223-33

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