4-Aminopyridine: effects on electrical activity during ischemia and reperfusion in perfused rat hearts

We investigated the effects of 2 and 4 mM 4-aminopyridine (4-AP,--blocker of the transient outward current I(to) on the electrophysiological response to regional ischemia and reperfusion. Spontaneously beating rat hearts were subjected to coronary occlusion (10 min) followed by reperfusion. The surface electrogram and the membrane potential from subepicardial left ventricular cells were recorded throughout. The basal effect of 4-AP was a dose dependent increase in the action potential duration (APD90) without changes in the resting potential or the heart rate. During early ischemia resting depolarization (from 87.4 +/- 1.9-70.1 +/- 2.5 mV in the controls) was enhanced by 4 mM, 4-AP (84.3 +/- 1.4 mV vs. 61.7 +/- 1.3 mV) whereas APD90 increased by 73.5%. These effects resulted in a marked reduction in the duration of diastolic intervals that led to conduction failure and aborted responses. A partial recovery was found by the end of ischemia concomitant with APD90 shortening in both, control and 4-AP treated hearts. On reperfusion, 4-AP did not influence the initial incidence of ventricular tachyarrhythmias but decreased their duration from 531.5 +/- 56.3-260.7 +/- 100 sec (2 mM) and to 75.6 +/- 10.5 sec (4 mM). These data confirm others obtained by Henry et al. in isolated cells indicating that ischemia induces sequential changes in several K+ conductances. In addition, they show that changes in action potential characteristics may exert beneficial effects on reperfusion arrhythmias by acting on the arrhythmic substrate without suppressing the trigger mechanism.