SYMPATHETIC ACTIVATION, VENTRICULAR REPOLARIZATION AND I-KR BLOCKADE - IMPLICATIONS FOR THE ANTIFIBRILLATORY EFFICACY OF POTASSIUM CHANNEL BLOCKING-AGENTS

Objectives. The aim of the present study was to test, in vivo and in v itro, the influence of adrenergic activation on action potential prolo ngation induced by the potassium channel blocking agent d-sotalol. Bac kground. d-Sotalol is not effective against myocardial ischemia-depend ent ventricular fibrillation in the presence of elevated sympathetic a ctivity. Most potassium channel blockers, such as d-sotalol, affect on ly one of the two components of I-k (I-kr) but not the other (I-ks). I -ks is activated by isoproterenol. An unopposed activation of I-ks mig ht account for the Loss of antifibrillatory effect by d-sotalol in con ditions of high sympathetic activity. Methods. In nine anesthetized do gs we tested at constant heart rate (160 to 220 beats/min) the influen ces of left stellate ganglion stimulation on the monophasic action pot ential prolongation induced by d-sotalol. In two groups of isolated gu inea pig ventricular myocytes we tested the effect of isoproterenol (1 0(-9) mol/liter) on the action potential duration at five pacing rates (from 0.5 to 2.5 Hz) in the absence (n = 6) and in the presence (n = 8) of d-sotalol.Results. In control conditions, both in vivo and in vi tro, adrenergic stimulation did not significantly change action potent ial duration. d-Sotalol prolonged both monophasic action potential dur ation in dogs and action potential duration of guinea pig ventricular myocytes by 19% to 24%. Adrenergic activation, either left stellate ga nglion stimulation in vivo or isoproterenol in vitro, reduced by 40% t o 60% the prolongation of action potential duration produced by d-sota lol. Conclusions. Sympathetic activation counteracts the effects of po tassium channel blockers on the duration of repolarization and may imp air their primary antifibrillatory mechanism. An intriguing clinical i mplication is that potassium channel blockers may not offer effective protection from malignant ischemic arrhythmias that occur in a setting of elevated sympathetic activity.