A dihydropyridine (Bay k 8644) that enhances calcium currents in guinea pig and calf myocardial cells. A new type of positive inotropic agent.

Abstract

Bay k 8644 is a structural analog of nifedipine with positive inotropic activity. The mechanism of drug action was evaluated by measuring the effects of Bay k 8644 on twitch tension, action potential configuration, and calcium channel currents in myocardial cells. Bay k 8644 increases twitch tension in guinea pig atria without changing the time course of tension development. The drug does not occlude the effect of isoproterenol on twitch tension. The effects of Bay k 8644 on atrial twitch tension are highly dependent on the frequency of stimulation. Maximal inotropic effects are observed at approximately 0.5 Hz, but no inotropic effect occurs at 0.003 Hz (a rested-state contraction). Since positive inotropic effects only occur with frequent electrical stimulation, they are not due to an intracellular action or to mechanisms that elevate cell calcium in quiescent muscle, such as inhibition of the Na,K-ATPase. Bay k 8644 increases the action potential duration of calf ventricular muscle and Purkinje fibers. Effects on action potential duration are occluded by 1 microM nisoldipine, which specifically blocks calcium channels. The interaction of Bay k 8644 with calcium channels in calf Purkinje fibers was studied using the two-microelectrode voltage clamp technique. Strontium was used as a charge carrier to minimize current through calcium-activated channels and to avoid changes in calcium conductance due to changes in intracellular calcium. Bay k 8644 increases strontium currents and alters the time- and voltage-dependence of channel opening. The greatest percent increase in strontium current occurs for weak depolarizations. For strong depolarizations, strontium current is increased most at the beginning of a test pulse. The drug-induced changes in calcium channel gating are inconsistent with a calcium- or cyclic adenosine monophosphate-mediated effect, and indicate a novel mechanism of action on calcium channels. Thus, Bay k 8644 is the first positive inotropic agent shown to act specifically and directly on calcium channels.