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

Author:
WALLACE, AA  STUPIENSKI, RF  BROOKES, LM  SELNICK, HG  CLAREMON, DA  LYNCH, JJ  


Journal:
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY


Issue Date:
1991


Abstract(summary):

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)methanesu lfonamide], 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.


Page:
687---695


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