EFFECTS OF A NOVEL CARDIOTONIC AGENT (+/-)-6-[3-(3,4-DIMETHOXYBENZYLAMINO)-2-HYDROXYPROPOXY]-2(1H)-QUINOLINONE (OPC-18790) ON CONTRACTILE-FORCE, CYCLIC-AMP LEVEL, AND AEQUORIN LIGHT TRANSIENTS IN DOG VENTRICULAR MYOCARDIUM

We studied the effects of a novel cardiotonic agent OPC-18790 [(+/-)-6-[3-(3,4-dimethoxybenzylamino)2-hydroxypropoxy]-2(1H)-quinolinone] on isometric contractions, intracellular aequorin light transients, and cyclic AMP levels in isolated dog ventricular trabeculae. The positive inotropic effect (PIE) of OPC-18790 (1-30 mu M) was consistently associated with an abbreviation of contractions and an increase in the amplitude of aequorin light transients. The maximum responses of Ca2+ transients and force to OPC-18790 were similar to 40% of the isoproterenol-induced maximum. Carbachol (3 mu M) markedly attenuated the increases in force, light transients, and cyclic AMP accumulation induced by OPC-18790. These results indicate that OPC-18790 is a cardiotonic agent with moderate effectiveness, and that the PIE of OPC-18790 may be produced mainly by an increase in intracellular Ca2+ transients induced by cyclic AMP accumulation. For a given increase in amplitude of Ca2+ transients, OPC-18790 produced a more pronounced increase in force of contraction (FOC) than did isoproterenol, suggesting that OPC-18790 does not produce as great a decrease in Ca2+ sensitivity of contractile proteins as does isoproterenol. These observations indicate that among cardiotonic agents acting through cyclic AMP pathway, regulation of contractility produced by the selective cyclic AMP phosphodiesterase III (PDE-III) inhibitor OPC-18790 is qualitatively different from the regulation induced by isoproterenol that acts on cyclic AMP generation in intact myocardial cells.