The ATP-sensitive potassium channel blocker glibenclamide (glyburide) does not abolish preconditioning in isolated ischemic rat hearts.
Previous studies have indicated that the ATP-sensitive potassium channels blocker glibenclamide (glyburide) can abolish preconditioning in canine models of myocardial ischemia. Recently, an isolated rat heart model of preconditioning has been developed that may be ideal for studying the mechanisms of preconditioning. In the present study, we determined the effect of glyburide on preconditioning in isolated rat hearts. Rat hearts were isolated and retrogradely perfused with oxygenated Krebs'-Henseleit solution. They were then subjected to four periods of total global ischemia of 5-min duration, separated by 5-min reperfusion. The hearts were then subjected to 30-min global ischemia followed by 30-min reperfusion and contractile function and lactate dehydrogenase release determined. Non-preconditioned hearts sustained severe damage. Glyburide (1-100 microM) pretreatment had no effect on the severity of 30-min global ischemia and 30-min reperfusion. Preconditioning caused significant improvements in reperfusion contractile function (25-fold increase in left ventricular developed pressure) and reductions in reperfusion lactate dehydrogenase release and reperfusion end diastolic pressure (contracture). Glyburide had modest preischemic cardiodepressant and vasoconstrictor effects at 1-30 microM, whereas 100 microM caused a 50% reduction in preischemic coronary flow. Despite these effects, none of these concentrations of glyburide affected the efficacy of preconditioning. These studies indicate that preconditioning in isolated rat hearts does not occur via a glyburide- (and thus presumably ATP-sensitive potassium channel) sensitive mechanism.
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
Dzwonczyk
S
S
Sleph
P G
PG
Sargent
C A
CA
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005905:Glyburide