Modification by glibenclamide of the electrophysiological consequences of myocardial ischaemia in dogs and rabbits

Abstract

Glibenclamide has been shown to block ATP-dependent K+ channels in the heart and prevent the shortening of cardiac action potentials caused by hypoxia in vitro. The present study examines the ability of glibenclamide to modify the effect of acute ischaemia on monophasic action potential duration in pentobarbital-anaesthetized rabbits, and on monophasic action potential duration and ventricular fibrillation threshold in pentobarbital-anaesthetized dogs. Left ventricular endocardial monophasic action potential duration was measured using a contact electrode catheter, and ventricular fibrillation threshold was measured by the single pulse method. Ischaemia was produced in rabbits by occluding the circumflex coronary for 5 min and in dogs by occluding the left anterior descending coronary artery for 40 min. In rabbits, glibenclamide (0.3-3 mg/kg, i.v.) had no effect on baseline monophasic action potential duration, but attenuated action potential shortening during ischaemia in a dose-related manner. In dogs, monophasic action potential duration did not shorten during ischaemia in the vehicle group, but tended to increase in the glibenclamide group (0.5 mg/kg, i.v.) both before and during ischaemia (7 +/- 5% and 14 +/- 8%, respectively, NS). Likewise, ventricular effective refractory period was significantly increased by glibenclamide prior to ischaemia (5 +/- 1%). Ventricular fibrillation threshold tended to increase during 40 min of ischaemia in vehicle-treated dogs (40 +/- 29%, NS), but was unchanged during ischaemia in the glibenclamide-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of Ventricular Proarrhythmia with Selective Opening of the Myocardial Sarcolemmal versus Mitochondrial ATP-Gated Potassium Channel

“…It would stand to reason therefore, that blockade of the K-ATP channel should be antiarrhythmic during ischemia-reperfusion and/or hypoxiareoxygenation. This has been demonstrated in several different animal models (Wolleben et al, 1989;Kantor et al, 1990;Smallwood et al, 1990;Gwilt et al, 1992) in which glibenclamide, a nonselective K-ATP channel blocker, prevented the electrophysiological and arrhythmogenic consequences of myocardial ischemia. However, glibenclamide is many times more specific for the pancreatic K-ATP channel than it is for the myocardial K-ATP channel, resulting in release of insulin.…”

Clinical Pharmacology of Potassium Channel Openers

“…In contrast, pinacidil had the opposite effect (Cole et al 1991). In anesthetized rabbits, glibenclamide attenuated action potential shortening during ischaemia in a dose-MiniReview related manner, but did not reduce the susceptibility to electrically-induced ventricular fibrillation in dogs subjected to acute ischaemia (Smallwood et al 1990). These conflicting results make it an open question whether or not K t channel openers will be useful in acute myocardial ischaemia.…”

Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.

“…Glibenclamide prevents ventricular fibrillation in the ischemic rat heart, 81 -83 but not in the dog. 85 Block of K ATP channels during ischemia may even have deleterious effects, exacerbating myocardial stunning during reperfusion. 86 Such an undesirable effect is not unexpected considering the suggested physiological role of cardiac K ATP channels.…”