POSITIVE INOTROPIC AND LUSOTROPIC ACTION OF RP-62719 - A NEW CLASS-III ANTIARRHYTHMIC AGENT

Antiarrhythmic drugs, especially the Class I family, exert a negative inotropic effect on the myocardium which is particularly undesirable i n patients with depressed left ventricular function. Thefore, research has been directed to the development of new, more specific molecules of the Class III family. The authors studies die mechanical effects of RP 62719 on guinea pig left ventricular papillary muscle. This new mo lecule is a pure Class III antiarrhythmic, known to lengthen the durat ion of the cardiac action potential by selectively blocking the potass ium current iK1 (inward rectifier K+ current). The mechanical paramete rs were determined during the phases of contraction and relaxation und er isotonic and isometric conditions. At 0.2 and 2 muM concentrations, RP 62719 improved cardiac contraction under both isotonic and isometr ic conditions with an increase of about 30 % of Vmax (p < 0.001), the maximum unloaded shortening velocity DELTA1 (p < 0.001), die peak isom etric active force normalized per cross-sectional area [AF/S (p < 0.00 1)]. At these two concentrations, a positive lusitropic effect (improv ed relaxation) was demonstrated by an increase in negative peak of der ivative per mm2 -dF/s and maximum lengthening velocity VR max (p < 0.0 1). At higher concentrations (20 muM), the inotropic and lusitropic ef fects were less marked with a bell-shaped form of the dose-effect curv e. This study indicates that RP 62719 has moderate but significant pos itive inotropic and lusitropic effects. These actions could provide si gnificant therapeutic advantages especially in patients cardiac failur e.