Cardiac profile of EGIS-9377, a novel cardiotonic agent as a Ca2+ sensitizer with bradycardiac activity

The cardiac profile of EGIS-9377 {2-(1-methylthio)-5-(2-morpholinoethylamin o)-8,9-dihydro-7H-thiopyrano[3,2-d] [1,2,4]triazolo[1,5-a]pyrimidine dihydr ochloride}, a newly synthesized cardiotonic agent, was compared with those of pimobendan and isoprenaline in cardiac preparations isolated from guinea pigs. The positive inotropic potency and efficacy of EGIS-9377 were equal to those of pimobendan in electrically paced papillary muscles, with each a gent maximally increasing force of contraction by 30-35% of the maximum eff ect of isoprenaline. The positive inotropic effects of EGIS-9377 and pimobe ndan were accompanied by an increase in the relaxation time of the isometri c contraction curve, whereas that of isoprenaline was associated with an ab breviation of this parameter: Pimobendan significantly increased the sponta neously beating frequency of right atria, and its positive chronotropic eff ect amounted to 40% of the maximum effect of isoprenaline. In contrast, EGI S-9377 exerted a significant negative chronotropic action, which resulted i n a 30% decrease in the basal frequency. In beta-escin-skinned trabecular m uscles, both EGIS-9377 and pimobendan substantially enhanced contractions i nduced by Ca2+. EGIS-9377 at concentrations to cause a significant negative chronotropic action produced a marked prolongation of action potential dur ation (APD) in guinea pig papillary muscle and greatly inhibited the delaye d rectifier potassium current (I-K) in guinea pig ventricular single cells. This suggests that the negative chronotropic effect of EGIS-9377 may, at l east in part, be due to the prolongation of APD as a result of the I-K inhi bition. The present results indicate that EGIS-9377 efficiently increases m yocardial contractile force possibly due to its Ca2+-sensitizing activity, and yet produces a substantial negative chronotropic action. This cardiac p rofile of EGIS-9377 is suggested to be a clinically favorable feature compa red with the inotropic agents having cyclic AMP generation or phosphodieste rase inhibition as their action mechanisms.