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 influence ischemic arrhythmias. Isolated rat 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-1 g-1) was reduced, from 3.2 +/- 0.3 to 2.5 +/- 0.1 mueq/g (p less than 0.025) by 1 microM glibenclamide and from 3.3 +/- 0.2 to 1.9 +/- 0.2 mueq/g (p less than 0.005) by 10 microM 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 less than 0.02) and during global ischemia (0/7 vs. 9/9 controls; p less than 0.01). Heart rate, coronary flow rate, peak systolic pressure, and myocardial oxygen consumption were unaltered by the drug (1 microM). Similarly, glibenclamide (1 microM) did not alter myocardial ATP, phosphocreatine or lactate content, or glucose utilization. Ventricular fibrillation threshold during normoxia was also unaltered by glibenclamide (1 microM). 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.
Kantor
P F
PF
Medical Research Council Ischemic Heart Disease Research Unit, University of Cape Town, South Africa.
Coetzee
W A
WA
Carmeliet
E E
EE
Dennis
S C
SC
Opie
L H
LH
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D003327:Coronary Disease / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D007773:Lactates; D019344:Lactic Acid; D011188:Potassium; D005905:Glyburide