Vol. 287, Issue 1, 214-222, October 1998

A Novel Cardiotonic Agent SCH00013 Acts as a Ca⁺⁺ Sensitizer with No Chronotropic Activity in Mammalian Cardiac Muscle^1,2

Hiromi Sugawara and Masao Endoh

Department of Pharmacology, Yamagata University School of Medicine, 990-9585 Yamagata, Japan

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 (10⁶ to 10⁴ M) in both species in the presence of bupranolol. The positive inotropic effects of 10⁴ 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 10⁴ 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 × 10⁶ M, but enhanced it at 3 × 10⁵ 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.