EFFECT OF POTASSIUM ON THE ACTION OF THE K-ATP MODULATORS CROMAKALIM,PINACIDIL, OR GLIBENCLAMIDE ON ARRHYTHMIAS IN ISOLATED-PERFUSED RAT-HEART SUBJECTED TO REGIONAL ISCHEMIA

Objective: The ATP sensitive potassium channel openers cromakalim (n = 10) and pinacidil (n = 10), and a blocker of this channel, glibenclam ide (n = 10), were studied in isolated perfused rat hearts subjected t o regional ischaemia at varying concentrations (2 to 8 mM) of external potassium ([K+](0)). Methods: Hearts were isolated and perfused on a Langendorff apparatus. Vehicle (0.1% DMSO), cromakalim (10 mu M), pina cidil (10 mu M), or glibenclamide (10 mu M) were given 10 min before i schaemia. The left coronary artery was then occluded for 15 min and re perfused for 5 min. Results: No agent caused more than a 10% change in heart rate. Both cromakalim and pinacidil increased (30%), and gliben clamide decreased (30%) coronary flow at 4 and 6 mM [K+](0). In the ve hicle group, increases in [K+](0) produced concentration dependent red uctions in arrhythmia scores by decreasing ventricular fibrillation. N o concentration dependent effects of [K+](0) on ischaemic ventricular tachycardia was observed. Under ischaemic conditions, potassium channe l openers and glibenclamide more markedly reduced ischaemic ventricula r tachycardia and fibrillation relative to the effects of increased [K +](0). Conclusions: Ischaemic ventricular fibrillation was inversely r elated to changes in [K+](0), whereas effects on ventricular tachycard ia were all-or-none. Neither potassium channel openers nor glibenclami de elicited significant proarrhythmic activity despite variations in [ K+](0). These data suggest that both potassium channel openers and gli benclamide display potential antiarrhythmic activity through their abi lity to abolish two distinct arrhythmogenic mechanisms during ischaemi a. It is also suggested that the underlying mechanisms of ventricular tachycardia and fibrillation are coupled during ischaemia in the rat.