New Positive Inotropic Agent OPC-8212 Modulates Single Ca2+ Channels in Ventricular Myocytes of Guinea Pig

Abstract

The effects of a new positive inotropic drug, OPC-8212 (a quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1 -piperazinyl]-2(1H)-quinolinone), on whole-cell and single-channel calcium currents of guinea pig ventricular myocytes were studied by the patch-clamp method. OPC-8212 increased whole-cell calcium currents in a concentration-dependent manner. The concentration-response curve was fitted by a single binding site model that has an ED50 of 2.7 microM. At the single-channel level, OPC-8212 increased calcium currents mainly by increasing the probability of channel opening on depolarization; the open times were slightly increased, but single-channel conductance did not change. The actions of OPC-8212 on single calcium channel currents were compared with those of forskolin, isoproterenol, and caffeine, agents that cause positive inotropic effects associated with an increase in cytoplasmic cyclic AMP level, and with those of the dihydropyridine calcium channel agonist (-)Bay K 8644, an agent that has a positive inotropic effect but does not act through cyclic AMP. OPC-8212 increased calcium currents in a manner that resembled the actions of forskolin, isoproterenol, and caffeine rather than the actions of (-)Bay K 8644. We suggest that activation of calcium currents by OPC-8212 is mediated by an elevation of intracellular cyclic AMP. Since OPC-8212 produces bradycardia and antitachycardiac effects in animals and humans, unlike agents that increase cyclic AMP, additional effects on other currents are likely.