Glibenclamide does not prevent action potential shortening induced by ischemia in anesthetized rabbits but reduces ischemia-induced arrhythmias.
The possible ischemia-selective Class III anti-arrhythmic action (selective action potential widening in ischemia) of the IKATP blocker glibenclamide was assessed in anesthetized rabbits during ischemia induced by complete occlusion of a coronary artery. Coronary artery occlusion caused an initial prolongation in monophasic action potential (MAP) duration at 90% repolarization from 145 +/- 2.8 ms (mean +/- S.E.M., n = 14) to 162 +/- 4.5 ms (P < 0.05) 1 min after ischemia. This was followed by a rapid and sustained shortening to 104 +/- 4.9 ms 5 min after the onset of ischemia (P < 0.05 from both values). Glibenclamide (3, 6, 12 or 24 mg/kg, i.v.) caused a statistically significant, dose-related reduction in the rate of MAP shortening induced by ischemia, whereas 0.3 mg/kg was without effect. The effective dose for a 50% maximal effect (ED50) was 13 +/- 0.8 mg/kg (n = 28). Despite this, there was no effect on the final magnitude of MAP shortening. Five min after induction of ischemia, there were no longer any detectable effects of glibenclamide on MAP duration. Glibenclamide significantly reduced the incidence of ventricular fibrillation, although the effect was not dose related. No differences were found in the latency to ventricular fibrillation between groups. Ventricular fibrillation occurred 10.6 +/- 1.1 min (n = 19) after the start of ischemia. In a similar experiment, 0.3 mg/kg glibenclamide i.v. did not affect the rate of MAP shortening, the final magnitude of MAP shortening or the occurrence of arrhythmias caused by ischemia. Since the action potential widening effects of glibenclamide in ischemic tissue were not observed at the time when arrhythmias occurred, it is unlikely that an ischemia-selective Class III anti-arrhythmic action contributes to the limited antiarrhythmic actions of glibenclamide.
Barrett
T D
TD
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Walker
M J
MJ
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D001786:Blood Glucose / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography / Q000187:drug effects; D005905:Glyburide / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000150:complications*; D011817:Rabbits
D000889:Anti-Arrhythmia Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D005905:Glyburide