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.
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