A novel cardiotonic agent SCH00013 acts as a Ca++ sensitizer with no chronotropic activity in mammalian cardiac muscle

We investigated the inotropic effect of SCH00013 (4, 5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5, 6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one) on isolated dog and rabbit ventricular muscles and in indo-1 loaded rabbit ventricular cardiomyocytes. SCH00013 elicited a positive inotropic effect in a concentration-dependent manner (10(-6) to 10(-4) M) in both species in the presence of bupranolol. The positive inotropic effects of 10(-4) M SCH00013 on the dog and rabbit were 38% and 29% of the maximal response to isoproterenol. SCH00013 did not alter the rate of beating in isolated rabbit right atria. In indo-1 loaded rabbit ventricular cardiomyocytes, SCH00013 at 10(-4) M increased the systolic cell shortening by 52% above the base-line value in association with an insignificant increase in the systolic fluorescence ratio by 15% above the control. SCH00013 shifted the relationship between the Ca++ transients and cell shortening to the left as compared with that of elevation of [Ca++]o. In the dog and rabbit ventricular muscles, carbachol partially inhibited the positive inotropic effect of SCH00013. SCH00013 did not affect the positive inotropic effect of isoproterenol at 3 x 10(-6) M, but enhanced it at 3 x 10(-5) M. These results indicate that SCH00013 is a cardiotonic agent that primarily acts via an increase in myofibrillar Ca++ sensitivity with a moderate contribution of the cAMP-dependent mechanism at higher concentrations. SCH00013 has no chronotropic activity. The pharmacological profile of SCH00013 implies that the compound may be a promising cardiotonic agent for the treatment of congestive heart failure.