The goal of this proposal is to investigate the mechanism underlying the development of abnormal cardiac rhythms in single cells isolated from the hearts of guinea pigs with cardiac hypertrophy induced by pressure overload. This model produces animals that develop cardiac hypertrophy both with and without heart failure. Based on our previous experimental work our working hypothesis is that alterations or altered interactions between the following electrical components may be involved in generating arrhythmias in hypertrophied hearts. (1) The voltage and time-dependence of spontaneous and induced oscillations of current, (2) Changes in the net conductance of the membrane during repolarization and during diastole, (3) The contribution of changes in the magnitude of kinetics of calcium currents. An important related goal is to investigate the effects of cardioactive agents (digitalis, catecholamines, low K+, quinidine, and verapamil on these factors) since the sensitivity of pathologic tissue to potentially toxic electrical effects of these agents has not been studied systematically. The goals of the proposal will be achieved by using the voltage clamp technique with two microelectrodes to study the oscillatory currents, calcium currents, and both isochronal and steady-state current-voltage relationships in single myocytes isolated from hearts of guinea pigs with cardiac hypertrophy with and without heart failure. Our studies should allow us to describe the critical interactions between these potentially arrhythmogenic currents and changes in membrane conductances that generate or fail to generate abnormal rhythmic activity in a realistic pathologic model of cardiac hypertrophy and failure. The results of the proposal also should provide a better understanding of the role of cardioactive agents in the either promoting or inhibiting abnormal rhythmic activity in the diseased heart. We believe the results of our proposed studies may lead to improved ways to treat or prevent the lethal arrhythmias associated with cardiac hypertrophy and failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032688-06
Application #
3344099
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1984-08-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Nordin, C (1997) Computer model of electrophysiological instability in very small heterogeneous ventricular syncytia. Am J Physiol 272:H1838-56
Nordin, C (1996) Response of Ca(2+)-loaded, depolarized guinea pig myocytes to critically timed premature stimulations. Am J Physiol 270:H447-65
Nordin, C; Ming, Z (1995) Computer model of current-induced early afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol 268:H2440-59
Ming, Z; Nordin, C (1995) Terfenadine blocks time-dependent Ca2+, Na+, and K+ channels in guinea pig ventricular myocytes. J Cardiovasc Pharmacol 26:761-9
Ming, Z; Nordin, C; Aronson, R S (1994) Role of L-type calcium channel window current in generating current-induced early afterdepolarizations. J Cardiovasc Electrophysiol 5:323-34
Ming, Z; Aronson, R; Nordin, C (1994) Mechanism of current-induced early afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol 267:H1419-28
Ming, Z; Nordin, C; Siri, F et al. (1994) Reduced calcium current density in single myocytes isolated from hypertrophied failing guinea pig hearts. J Mol Cell Cardiol 26:1133-43
Nordin, C (1993) Computer model of membrane current and intracellular Ca2+ flux in the isolated guinea pig ventricular myocyte. Am J Physiol 265:H2117-36
Goldberger, J J; Aronson, R S (1992) Effects of verapamil on ventricular tachycardia induced by ouabain in guinea pigs. Pacing Clin Electrophysiol 15:162-70
Malhotra, A; Siri, F M; Aronson, R (1992) Cardiac contractile proteins in hypertrophied and failing guinea pig heart. Cardiovasc Res 26:153-61

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