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We studied the effects of a new antiarrhythmic and antianginal agent, bepridil, on the intracellular calcium transient and contraction of cultured neonatal rat ventricular cells, and compared the effects with those caused by an authentic Ca2+ -entry blocker, D600 (methoxyverapamil). The Ca2+ transient was measured by using dual-wavelength microfluorometry of fura-2. The contraction was measured as a shortening of cell aggregates with the use of a video image-analyzing system. Both bepridil (1-30 microM) and D600 (1-30 microM) decreased the peak systolic amplitude of the Ca2+ transient in a concentration- and frequency-dependent manner. Bepridil, but not D600, significantly shortened the half-decay time of the Ca2+ transient and prolonged the time course of the contraction. D600 decreased the contraction in parallel with the decrease in the peak Ca2+ transient, whereas bepridil exerted no significant effect on the contraction. Bepridil (10 microM) induced a leftward shift (to lower amplitude of peak systolic Ca2+ transient) of the relation between the magnitude of contraction and the peak systolic Ca2+ transient, which was obtained by changing external Ca2+ concentration. In contrast, D600 (10 microM) did not affect the relation. The results suggest that the negative inotropic effect of bepridil (caused by its Ca2+ channel-blocking effect) is offset by its simultaneous increase in the sensitivity of contractile protein(s) to intracellular Ca2+, which may be a unique characteristic of this antiarrhythmic agent in a clinical setting.

1 Effects of harmaline and other harmala alkaloids on the contractions induced in the vascular smooth muscle ofrabbit aorta and intestinal smooth muscle of taenia isolated from guinea-pig caecum were examined. 2 In rabbit isolated aorta, harmaline inhibited the sustained contraction induced by 65.4 mM K' with an ICo (concentration needed for 50% inhibition) of 4.6 x 10-5 M. This inhibitory effect on high K+- 4 Harmaline, at the concentrations needed to inhibit the muscle contraction, inhibited the increase in 45Ca2+ uptake induced by high K', noradrenaline and carbachol in aorta and taenia.5 Harmaline did not change the cellular Na+ and ATP contents in resting and high K+ stimulated taenia. 6 Other harmala alkaloids also inhibited the contractions in these smooth muscles. The order of the inhibitory potency was 6-methoxyharman = harmine > harmaline = 2-methylharmine = harmane > 6-methoxyharmalan > harmalol = harmol for the contractions induced by high K+ in aorta and taenia and by carbachol in taenia, and 2-methylharmine > 6-methoxyharman > 6-methoxyharmalan = harmol = harmalol = harmane > harmine > harmaline for the contraction induced by noradrenaline in aorta. 7 These results suggest that harmaline inhibits the contractile response ofrabbit aorta and guinea-pig taenia by inhibiting different types of Ca2`channel. The structure-activity relationship indicates that the potency and selectivity of the inhibitory effects on these channels are varied by modification of the structure of this alkaloid.

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