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

Abstract

Clinical evidence indicates an antiarrhythmic effect of sulfonylureas, which might be blunted by their vascular action. We wanted to investigate the effect of glibenclamide and the new sulfonylthiourea compound 1-[[5-[2-(5-chloro- o-anisamido)ethyl]-2-methoxyphenyl]-sulfonyl]-3-methylthiourea (HMR1883) on cardiac electrophysiology in the course of regional ischemia and reperfusion. Isolated rabbit hearts (Langendorff-technique) were pretreated with either vehicle ( n=14), 3 μmol/l glibenclamide ( n=7) or 3 μmol/l HMR1883 ( n=7) before regional ischemia was induced by left coronary artery branch occlusion (45 min) followed by 45 min reperfusion. Unipolar epicardial electrocardiograms were recorded from 256 epicardial AgCl electrodes. Coronary 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 activation–recovery interval (ARI) in the ischemic area, which was inhibited by both drugs especially in the early phase. In the non-ischemic area, ARIs remained stable and there was no effect of the drugs. Ischemia led to an increase in the regional difference in ARI between ischemic center and border zone. This increase was significantly inhibited by both substances during late 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 during reperfusion. In glibenclamide but not in HMR1883-treated hearts recovery of CF upon reperfusion was significantly depressed (control: 25.5±4; HMR1883: 23±2.5; glibenclamide: 16±1 ml/min, values at 2 min reperfusion), while the elevation of ST-segments of the electrograms in early ischemia was fully prevented by both treatments. We conclude that both glibenclamide and HMR1883 exert an antiarrhythmic effect in this model, and reduce the shortening of the ARIs in the ischemic area, thus attenuating regional differences in ARIs between ischemic and non-ischemic area. Furthermore, unlike glibenclamide HMR1883 does not interfere with postischemic hyperemia.