Positive inotropic effects of RP 62719, a new pure class III antiarrhythmic agent, on guinea pig myocardium

JP Beregi, D Escande, N Coudray, P Mery, M Mestre, D Chemla and Y Lecarpentier

Institut National de la Sante et de la Recherche Medicale, Unite 275, LOA-ENSTA-Ecole Polytechnique, Palaiseau.

The mechanical effects of RP 62719 [(-)1-[-2-(3,4-dihydro-2H-1- benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)-piperidine] were tested in vitro on guinea pig left ventricular papillary muscle. RP 62719 is a novel pure class III antiarrhythmic agent known to prolong the cardiac action potential duration by selectively blocking the inward rectifying K+ current. Mechanical parameters were determined from contraction and relaxation phases under isotonic and isometric conditions. At a concentration of 0.02 microM, RP 62719 did not produce significant effects on inotropy or lusitropy. At 0.2 and 2 microM, the drug improved contraction under both heavy and low loading conditions, as evidenced by a 30% increase in maximum unloaded shortening velocity (Vmax, P < .001), peak amplitude of shortening (delta L, P < .001), peak isometric active force normalized per cross-sectional area (AF/s, P < .001) and positive peak of the force derivative per mm2 (+dF/s, P < .001). At the same concentrations, positive lusitropic effects were evidenced by an increase in maximum lengthening velocity (maxVr) and negative peak of force derivative per mm2 (-dF/s, P < .001). At a higher concentration (20 microM), effects of RP 62719 on inotropy and lusitropy were less marked, thus accounting for the bell-shaped form of the dose-response curve. An increase in the extracellular Ca++ concentration from 2.5 to 3.75 mM improved inotropy to a similar extent (+30-50%) as did 2 microM RP 62719. However, lusitropy and mechanical coupling between contraction and relaxation were not modified in the same proportion under RP 62719 and under 3.75 mM Ca++.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 263, Issue 3, pp. 1369-1376, 12/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

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