EFFECT OF E4031, A CLASS-III ANTIARRHYTHMIC DRUG, ON ISCHEMIA-INDUCEDAND REPERFUSION-INDUCED ARRHYTHMIAS IN ISOLATED RAT HEARTS

The delayed outward rectifier K+ channel has a role in the increase in automaticity of myocytes under pathophysiological conditions. The pur pose of the present study was to clarify the effect of blockade of out ward recitifier K+ channels by a class III antiarrhythmic drug, E4031, on ischemia-and reperfusion-induced arrhythmias. Ion fluxes, energy m etabolites and cardiac function were measured and the epicardial elect rocardiograms of Langendorff-perfused rat hearts were recorded during initial perfusion, global or regional ischemia and reperfusion. 10(-7) M of E4031 administered during the initial perfusion did not prolong the QT interval, but slowed the heart rate (Control: 222, E4031: 183 b pm, p < 0.05), increased myocardial Ca-45(2+) uptake (Control: 2.1, E4 031: 2.9 mu mol/g dwt, p < 0.05) and attenuated the loss of intracellu lar K+ during ischemia (Control: 238, E4031: 248 mu mol/g dwt, p < 0.0 5). E4031 tended to reduce ischemia-induced ventricular tachyarrhythmi as (Control: 60, E4031: 30%, n.s.), but reperfusion-induced ventricula r tachyarrhythmias were sustained longer by the administration of E403 1 (Control: 255, E4031: 623 sec, p < 0.05). Prior exposure to E4031 de creased the depletion of high energy phosphates during ischemia, but s uppressed their recovery during reperfusion. These results suggest tha t the attenuated loss of K+ from the ischemic myocardium and the decre ase in heart rate by E4031 contributed to the reduction of ischemia-in duced arrhythmias. However, the increase in myocardial Ca2+ uptake and altered energy metabolism may be responsible for the increase in repe rfusion-induced arrhythmias.