Effective treatment of arrhythmias ultimately depends on understanding the cellular mechanisms underlying cardiac rhythm disorders. Our studies on myocytes isolated from rat hearts by collagenase digestion showed that cells invariably develop spontaneous voltage and current oscillations that resemble some forms of clinical rhythm disorders and thus may be a useful model. This research proposal is intended to evaluate the following hypotheses: (1) Spontaneous current and voltage oscillations in isolated myocytes are due to opening and closing of a channel of low ion specificity; (2) Opening and closing of this channel depends on the level of myoplasmic calcium; (3) Spontaneous voltage oscillations, like those observed in isolated cells, develop in intact ventricular muscle under conditions that lead to partial electrical uncoupling and can transform into slow response action potentials; (4) Antiarrhythmic drugs may act by blocking the calcium-dependent membrane channels, by inhibiting fluctuations in myoplasmic calcium that regulates the opening and closing of these channels, or by altering cell-to-cell electrical coupling resistance. Voltage clamp and internal injection techniques will be used to establish the characteristics of the current oscillations, to identify the ions that carry the oscillatory current, and to study the effects of antiarrhythmic drugs on the current oscillations. Voltage clamp strategies will rely on varying the concentrations of external ions to determine their effect on the reversal potential of the oscillatory current. The effects of internal injection of EGTA, Ca2+, and cyclic AMP on the oscillatory current also will be studied by voltage clamp. To establish a relationship between cell-to-cell electrical coupling and the appearance of spontaneous voltage oscillations, we will study the effects, in intact myocardial strips, of interventions that appear to lead to partial electrical uncoupling. This will be done by measuring passive membrane properties of intact preparations under conditions of digitalis intoxication and hypoxia. We will extend our studies to another species, the cat, and to pathologic tissue from hypertrophied rat hearts and human biopsy specimens. By obtaining a profile of the electrical actions of antiarrhythmic drugs, we anticipate we will be able to identify specific mechanisms of actions of such drugs. The results of our proposal should amplify our current understanding of the cellular mechanisms underlaying oscillatory electrical activity in the heart and the relation of these oscillations to some aspects of ventricular rhythm disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032688-03
Application #
3344097
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1984-08-01
Project End
1988-03-31
Budget Start
1986-08-01
Budget End
1988-03-31
Support Year
3
Fiscal Year
1986
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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