CARDIAC ELECTROPHYSIOLOGIC AND INOTROPIC ACTIONS OF NEW AND POTENT METHANESULFONANILIDE CLASS-III ANTIARRHYTHMIC AGENTS IN ANESTHETIZED DOGS

The effects of cumulative intravenous (i.v.) administration of potent and selective methanesulfonanilide class III antiarrhythmic agents on cardiac electrophysiologic and hemodynamic parameters were compared with those of D-sotalol in chloralose-anesthetized dogs. The new class III agents tested were E-4031 [1-(2-(6-methyl-2-pyridyl)ethyl)-(4-methanesulfonamidobenzoyl)piperidine]; UK-66,914 [N-(4-(1-hydroxy-2-(4-(4-pyridinyl)-1-piperazinyl)ethyl)phenyl)methanesulfonamide], and UK-68,798 [1-(4-methanesulfonamidophenoxy)-2-(N-(4-methanesulfonamidophenethyl)-N-methylamino)ethane]. The class III agents produced significant and dose-dependent increases in ventricular refractoriness, with effective doses required to increase ventricular relative refractory period 20 ms above baseline (ED20, mu-g/kg i.v., with 95% confidence limits) of 5.2 (4.2-6.6) for UK-68,798, 17 (13-23) for E-4031, 75 (58-99) for UK-66,914, and 3,700 (2,600-5,800) for D-sotalol. Significant increases in the electrocardiographic QT and QTc intervals paralleled the increases in ventricular refractoriness for the four class III agents. Significant increases in left ventricular (LV) + dP/dt also paralleled increases in ventricular refractoriness and QT intervals for E-4031 (10-1,000-mu-g/kg i.v.), UK-66,914 (100-1,000-mu-g/kg i.v.), and UK-68,798 (30-1,000-mu-g/kg i.v.), but not for D-sotalol. No concomitant alterations in LV - dP/dt were observed for the new and potent methanesulfonanilide class III agents, resulting in significant increases in the ratio of LV + dP/dt/ - dP/dt for E-4031, UK-66,914, and UK-68,798. Potent and selective methanesulfonanilide class III agents therefore may augment cardiac contractility in addition to prolonging ventricular refractoriness.