MODULATION OF THE ELECTROPHYSIOLOGICAL EFFECTS OF ISCHEMIA-REPERFUSION BY METHYLISOBUTYL AMILORIDE

We studied the effect of the Na+/H+ exchanger inhibitor methylisobutyl amiloride (MIA. 1 mu M) on action potential characteristics and arrhy thmias induced by: (a) reperfusion following regional ischemia in rat hearts and (b) realkalization after lactate acidosis in rabbit hearts. We also determined the effect of MIA on the incidence of transient in ward currents (I-Tls) induced by acidosis-realkalization in rabbit car diocytes. Ligation of the LAD coronary artery for 10 min depolarized t he resting potential from -78 +/- 1.9 mV to -66.9 +/- 10 mV and depres sed the action potential but did not induce overt arrhythmias. Delayed afterdepolarizations were observed during ischemia in 50% of untreate d hearts whereas reperfusion produced severe ventricular tachyarrhythm ias in all of them, MIA reduced the incidence of arrhythmias to 27% an d their duration to less than 1 min, MIA increased action potential du ration by 38 +/- 4.1%, BaCl2 produced a similar APD lengthening and ha d an antifibrillatory effect. Acidic reperfusion induced bradycardia a nd reduced severity of arrhythmias. In rabbit hearts, MIA increased th e action potential duration by 61 +/- 4.3% and abolished arrhythmias o n realkalization. Eleven out of 18 cells developed transient inward cu rrents during acidosis-realkalization and seven of them underwent irre versible injury. MIA prevented the appearance of I-Tls, had no effect on I-CaL but decreased the outward component of I-K1 by 50%. Our resul ts suggest that the protective effect of MIA is in part due to changes in cellular electrical activity that modulate Na+ and Ca2+ entry via different pathways. (C) 1996 Academic Press Limited