Rate-Dependent Class III Antiarrhythmic Action, Negative Chronotropy, and Positive Inotropy of a Novel I: Potent in Guinea Pig but no Effect in Rat Myocardiumk: Potent in Guinea Pig but no Effect in Rat Myocardium Blocking Drug, UK-68,798: Potent in Guinea Pig but no Effect in Rat Myocardium

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Abstract

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 (10−8-10−6M) 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 ± 10−5Md-sotalol was needed to induce the same electrophysiological effects as 10−8M 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 10–6M at 0.5 Hz. No reversal of drug effect was seen after up to 2 h washout. UK (10−9-10−3M) 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 10−5M, 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.

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