Intracellular microelectrode recording techniques were used to elucidate the mechanism of the antiarrhythmic action of disopyramide in an isolated rabbit ventricular muscle perfused by hypoxic Tyrode's solution. Hypoxia induced no significant changes of the resting membrane potential or action potential amplitude but decreased the maximum upstroke velocity of the action potential (dV/dt max) and shortened the action potential duration and the effective refractory period. Disopyramide in a dose of 5 microgram/ml induced a significant decrease of resting membrane potential and action potential amplitude of hypoxic muscle while it did not alter these parameters in oxygenated muscle. Disopyramide depressed dV/dt max in hypoxic muscle as well as in oxygenated muscle. However, there was much greater depression in hypoxic cells. After disopyramide, action potential duration at the 90% level of repolarization and the effective refractory period were prolonged in both hypoxic and oxygenated ventricular muscle. However, disopyramide lengthened the effective refractory period of hypoxic muscle to a much greater degree than that of oxygenated muscle. This resulted in a decrease of disparity in refractoriness. The above differential effects of disopyramide in oxygenated and hypoxic tissue may account for its effectiveness in postinfarction re-entrant arrhythmias.