Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium

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Abstract
Excitability, maximum velocity of depolarization (MVD), conduction velocity, discharge rate and the duration of transmembrane action potentials as a function of frequency of stimulation were studied in isolated cardiac tissues exposed to the optical isomers of verapamil and D 600. In isolated papillary muscles depression of the MVD and the conduction velocity depend on concentration (1–8 μg/ml) of (+)-verapamil and (+)-D 600. (+)-Verapamil and (+)-D 600 (1–30 μg/ml) increase frequency-dependently the threshold intensity of electrical stimuli needed to elicit conducted action potentials. (-)-Verapamil and (-)-D 600 are about one order of magnitude less effective than the corresponding (+)-isomers. Both (+)- and (-)-isomers slightly prolong the transmembrane action potential at 90% repolarization level, particularly at low frequencies. In addition, the (-)-isomers induce a frequency-dependent depression of the plateau phase. The results indicate that, at least in ventricular myocardium, the (+)-isomers of verapamil and D 600 have a quite specific inhibitory effect on the fast Na-inward current and, therefore, may contribute to some extent to the anti-dysrhythmic potency of the racemic drugs. In isolated cat SA-nodes, both (+)- and (-)-isomers of verapamil and D 600 (0.2–1.0 μg/ml) reduce the discharge rate to the point of complete suppression of automaticity; different mechanisms are responsible for the effects. The (-)-isomers (0.3–0.6 μg/ml) slightly reduce the slope of the slow diastolic depolarization, while causing a more effective depression of MVD and nodal conduction velocity until partial or complete nodal conduction blocks occur. The (+)-isomers (1–2μg/ml) do not affect MVD or nodal conduction, but obviously shift the threshold voltage for the fast depolarization to less negative voltages. Cessation of automaticity occurs with a stable membrane potential and the ability to generate conducted action potentials by electrical stimulation persists.