The positive inotropic activity of MS-857, a novel cardiotonic agent, was assessed in isolated atrial and ventricular muscle of several mammalian species. MS-857 (0.1-300 microM) increased the developed tension of the dog, rabbit, monkey, cat, and guinea pig ventricular muscles in a concentration-dependent manner. However, MS-857 failed to cause a positive inotropic effect in isolated rat ventricular muscle. In isolated guinea pig atria, MS-857 caused both positive inotropic and chronotropic effects. MS-857 was more selective for inotropy than for chronotropy as compared with either milrinone or 3-isobutyl-1-methylxanthine (IBMX). The positive inotropic and chronotropic effects of MS-857 do not appear to be mediated by direct stimulation of alpha- or beta-adrenoceptors, histamine H1- or H2-receptors, or by release of endogenous catecholamines. The inotropic response to isoproterenol or histamine was potentiated by a relatively low concentration of MS-857. MS-857 increased both developed tension and intracellular cyclic AMP level in isolated dog right ventricular muscle. The time course of the elevation in cyclic AMP level was paralleled by that of increase in developed tension. Carbachol inhibited the increase in developed tension and cyclic AMP level caused by MS-857. These findings support the idea that cyclic AMP may be involved in the positive inotropic effect of MS-857.
1-Methyl-3-isobutylxanthine Animals