Early arrhythmias during myocardial ischemnia are believed to result from depolarization of ischemic cells and resultant flow of """"""""injury"""""""" current across the infarct border. Recent research suggests that depolarization of ischmic myocardium may, in turn, be caused by intracellular calcium overload, which is know to increase the sodium permeability of cardiac cell membranes. Since many drugs that diminish ischemic """"""""injury"""""""" currents and arrhythmias also correct calcium overload, the above mechanism may represent an important mode of action for these drugs. This hypothesis will be tested by recording DC epicardial """"""""injury"""""""" potentials during serial ischemia episodes in dogs, and by assessment of intracellular calcium overload through computer-aided histochemical studies of myocardial biopsy specimens. The effects of drugs on ischemic depolarization (T-Q depression in the epicardial electrograms) will be compared with their effects on extracellular postassium activity, measured by valinomycin electrodes, and hemodynamic parameters, including cardiac work, myocardial oxygen consumption, and (in some cases) regional blood flow. In some experiments, drug-induced reduction of myocardial oxygen consumption will be deliberately counteracted by increasing afterload with a variable constrictor clamp. Improvement of ischemic depolarization may be better correlated with drug effects on calcium metabolism than with changes in myocarial oxygen supply or demand. Moreover, the drug effects migh be independent of cellular potassium loss. Three types of experimental interventions will be studied (i) Drugs that are known to suppress ischemic depolarization or arrhythmias, including calcium channel blockers, beta adrenergic blockers, and alpha adrenergic blockers; (ii) Drugs that are known to produce calcium overload, including calcium gluconate, catecholamines, and toxic doses of digitalis; (iii) Experimental maneuvers that affect cardiac work, including variation in heart rate and afterload. For many of the above interventions, changes in the time course of ischemic depolarization will be correlated with simultaneous effects on calcium overload, as determined by digital quantification of electron dense precipitates in myocardial biopsy specimens treated with potassium pyroantimonate. Preliminary studies show that brief periods of ischemia (90 sec.) produce a marked increased in the density of these granules. This effect is unassociated with ultrastructural damage, and can be prevented by pretreatment with diltiazem in doses that reduce ischemic """"""""injury"""""""" potentials and arrhythmias. Similar improvement of calcium overload may occur with other classes of drugs, and may be the factor most consistently correlated with beneficial electrophysiological effects.
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