Effects of the I-K.ATP blockers glibenclamide and HMR1883 on cardiac electrophysiology during ischemia and reperfusion

Clinical evidence indicates an antiarrhythmic effect of sulfonylureas, whic h might be blunted by their vascular action. We wanted to investigate the e ffect of glibenclamide and the new sulfonylthiourea compound 1-[[5-[2-(5-ch loro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR1883 ) on cardiac electrophysiology in the course of regional ischemia and reper fusion. Isolated rabbit hearts (Langendorff-technique) were pretreated with either vehicle (n = 14), 3 mu mol/l glibenclamide (n = 7) or 3 mu mol/l HM R1883 (n = 7) before regional ischemia was induced by left coronary artery branch occlusion (45 min) followed by 45 min reperfusion. Unipolar epicardi al electrocardiograms were recorded from 256 epicardial AgCl electrodes. Co ronary ligation resulted in a decrease in coronary flow (CF) by 35% and in left ventricular pressure (LVP) by 40% in all series. The occluded zone was 23 +/- 3% in all series. Ischemia led to shortening of the epicardial acti vation-recovery interval (ARI) in the ischemic area, which was inhibited by both drugs especially in the early phase. In the non-ischemic area, ARIs r emained stable and there was no effect of the drugs. Ischemia led to an inc rease in the regional difference in ARI between ischemic center and border zone. This increase was significantly inhibited by both substances during l ate ischemia and early reperfusion (until 15 min reperfusion). In addition, the dispersion of ARIs was reduced by both drugs during late ischemia and reperfusion. Ventricular fibrillation was observed in 7/14 (control), 0/7 ( glibenclamide), and 0/7 (HMR1883). All ventricular fibrillation occurred du ring reperfusion. In glibenclamide but not in HMR1883-treated hearts recove ry of CF upon reperfusion was significantly depressed (control: 25.5 +/- 4; HMR1883: 23 +/- 2.5; glibenclamide: 16 +/- 1 ml/min, values at 2 min reper fusion), while the elevation of ST-segments of the electrograms in early is chemia was fully prevented by both treatments. We conclude that both gliben clamide and HMR1883 exert an antiarrhythmic effect in this model, and reduc e the shortening of the ARIs in the ischemic area, thus attenuating regiona l differences in ARIs between ischemic and non-ischemic area. Furthermore, unlike glibenclamide HMR1883 does not interfere with postischemic hyperemia . (C) 2000 Elsevier Science B.V. All rights reserved.