Comparison of Direct Negative Chronotropic and Positive Inotropic Effects of Sematilide to Those of E-4031 and MS-551 and the Reverse Frequency-Dependent Prolongation of Cardiac Refractoriness of Sematilide

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Abstract
Direct cardiac effects of sematilide, a new class III antiarrhythmic drug, were compared with those of E-4031 and MS-551 in canine isolated blood-perfused heart preparations. Doses of sematilide, E-4031, and MS-551 causing a 10% decrease in the spontaneous sinoatrial beating rate were 58 ± 15, 9 ± 5, and 84 ± 10 μg (n = 5); those causing a 10% increase in developed tension of the papillary muscle were 485 ± 49, 17 ± 2, and 267 ± 50 μg (n = 6); and those causing a 10% prolongation of effective refractory period (ERP) of the atrioventricular node were 68 ± 10, 11 ± 2, and 53 ± 15 μg (n = 5), respectively. There were few effects on atrio-His or His-ventricular intervals. Also, in in situ open-chest dog hearts, the percent increases in ERP of the atrioventricular conduction system caused by 1 mg/kg of sematilide were 21 ± 3, 16 ± 2 and 9 ± 1% at cycle lengths of 800, 600, and 400 ms, respectively (p

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