Reduction of Ischemic K⁺ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulfonylurea

Glibenclamide, one of the antidiabetic sulfonylureas, is known to block ATP-dependent K+ channels. We used this drug to determine to what extent K+ loss from acutely ischemic myocardium is mediated via these channels. We also investigated whether glibenclamide would infuence ischemic arrhythmias. Isolated rate hearts rendered globally ischemic showed no correlation between early lactate and K+ efflux rates. Cumulative K+ loss during 11 minutes of global ischemia (0.5 ml min-1g-1) was reduced, from 3.2 ± 0.3 to 2.5 ± 0.1 μeq/g (p < 0.025) by 1 μM glibenclamide and from 3.3 ± 0.2 to 1.9 ± 0.2 μeq/g (p < 0.005) by 10 μM glibenclamide, while lactate efflux was unaltered by the drug. Glibenclamide also exhibited potent antifibrillatory activity, abolishing irreversible ventricular fibrillation during regional ischemia (0/6 vs. 5/6 controls; p < 0.02) and during global ischemia (0/7 vs. 9/9 controls; p < 0.01). Heart rate, coronary flow rate, peak systolic pressure, and myocardial oxygen consumption were unaltered by the drug (1 μM). Similarly, glibenclamide (1 μM) did not alter myocardial ATP, phosphocreatine or lactate content, or glucose utilization. Ventricular fibrillation threshold during normoxia was also unaltered by glibenclamide (1 μM). We conclude that K+ loss during acute myocardial ischemia is mediated partly by ATP-dependent K+ channels, and not by a tightly coupled co-efflux with anionic lactate.