RATE-DEPENDENT CLASS-III ANTIARRHYTHMIC ACTION, NEGATIVE CHRONOTROPY, AND POSITIVE INOTROPY OF A NOVEL IK BLOCKING DRUG, UK-68,798 - POTENT IN GUINEA-PIG BUT NO EFFECT IN RAT MYOCARDIUM

The electromechanical effects of UK-68,798 (UK), a novel class III antiarrhythmic drug, were studied in guinea pig and rat papillary muscles (PMs) and atria in vitro using conventional microelectrode technique. UK (10-8-10-6 M) prolonged the action potential duration (APD) by 21-58% and effective refractory period in parallel, without affecting the resting potential or maximum rate of depolarization in guinea pig PM stimulated at 1 Hz. UK increased the contractile force without prolonging the time to peak force or relaxation. In comparison, 5 ± 10-5 M d-sotalol was needed to induce the same electrophysiological effects as 10-8 M UK. UK prolonged the APD significantly less at 2 Hz than at 1 and 0.5 Hz. Early afterdepolarizations (EADs) developed in 2 of 11 preparations after 10-6 M at 0.5 Hz. No reversal of drug effect was seen after up to 2 h washout. UK (10-9-10-3 M) reduced the spontaneous heart rate and prolonged the sinus node recovery time of guinea pig right atria. No effects on rat PM or atria, even after 10-5 M, indicate a selective action of UK on the delayed rectifying outward potassium current, Ik. These results indicate a potent and selective, rate-dependent class III antiarrhythmic action of UK-68,798 linked with positive inotropy. Increased APD, bradycardia, and induction of EADs, however, represent a potential arrhythmogenic combination. © 1990 Raven Press, Ltd., New York.