Effects of cromakalim or glibenclamide on arrhythmias and dispersion of refractoriness in chronically infarcted anesthetized dogs

Abstract

The proarrhythmic effects of the ATP-sensitive potassium channel modulators cromakalim (n = 10; 0.01 to 0.3 mg/kg i.v.), glibenclamide (n = 10; 0.3 to 10 mg/kg i.v.) or volume equivalents of vehicle (n = 10) were evaluated in post-infarcted anaesthetised dogs. Dogs were anaesthetised, subjected to an anterior-apical myocardial infarction, and allowed to recover. At 7.4 +/- 0.7 days post infarction, animals were anaesthetised again, electrophysiologic measurements (effective refractory periods, QT-intervals and ventricular fibrillation thresholds) were taken, and animals were tested for arrhythmias using a programmed electrical stimulation protocol. Only animals that did not have programmed electrical stimulation-inducible arrhythmias were used. Ventricular fibrillation thresholds were determined twice, once before the first dose then after the last dose of drug. At the end of the experiment, animals were subjected to ligation of the left circumflex coronary artery and survival was measured over the next two hours. Cromakalim significantly increased heart rate and decreased blood pressure. Although cromakalim significantly reduced effective refractory periods, it neither increased electrical dispersion, as determined by the standard deviation or coefficient of variance of the effective refractory period, nor did it enhance inducibility (0 out of 10 in both vehicle and cromakalim treated animals), change ventricular fibrillation thresholds, or reduce sudden death survival relative to vehicle. Glibenclamide did not increase electrical dispersion, but slightly increased the incidence of programmed electrical stimulation-induced arrhythmias (3 out of 10), and lowered ventricular fibrillation thresholds values. However, these changes were not statistically significant. Glibenclamide did not significantly affect survival relative to vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the Sarcolemmal KATP Channel Blocker HMR1098 on Arrhythmias Induced by Programmed Electrical Stimulation in Canine Old Myocardial Infarction Model: Comparison With Glibenclamide

“…On the other hand, D'Alonzo et al (21) reported that glibenclamide at 0.3 -10 mg / kg did not affect electrical dispersion, but increased the incidence of PES-induced VF and lowered the VF threshold in chronic infarct dogs. It is unknown whether these controversial observations are due to the differences in the experimental protocols or to the lack of selectivity of this agent.…”

Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus

“…The antiarrhythmic effects of glibenclamide during transient myocardial ischaemia were demonstrated in patients with type 2 diabetes and coronary artery disease by Cacciapuoti and coworkers, but no effect on spontaneously occurring ventricular arrhythmias was seen [45]. An experimental study on dogs failed to demonstrate the effects of glibenclamide on the dispersion of refractoriness [46].…”

Interspecies Differences and Extracellular Calcium Dependence in the Vasorelaxing Effect of Cromakalim in Isolated Human, Porcine, and Canine Coronary Arteries

“…The magnitude of effect, however, differs in the 2 species. One micromole per liter cromakalim, which is a therapeutically meaningful concentration, 21 produced 69.6% relaxation in porcine but only 8.6% relaxation in human coronary artery at 1.5 mmol/L [Ca 2þ ] o . This corresponds to the existence of an additional large conductance, cromakalim-activated potassium channel in the porcine coronary artery.…”