A novel benzothiazine Ca2+ channel antagonist, SEMOTIADIL (cas 116476-13-2), inhibits cardiac L-type Ca2+ currents

Add time:08/18/2019    Source:sciencedirect.com

The influence of semotiadil fumarate, a novel vasoselective Ca2+ channel antagonist with a benzothiazine skeleton, was measured on the high-threshold Ca2+ current ICa, L in guinea-pig ventricular myocytes prepared by coronary perfusion with collagenase solution. Patch- and voltage-clamp methods were used to measure ICa, L. Diltiazem, nifedipine and amlodipine were studied for comparison. Semotiadil could be shown to inhibit ICa, L in a dose-dependent manner in concentrations similar to those of diltiazem but was less effective than amlodipine and nifedipine. The IC50 for nifedipine and amlodipine was in the range between 0.1 and 1 μM, and that of semotiadil and diltiazem was between 10 and 100 μM. Recovery from inactivation of ICa, L in the control and under the influence of nifedipine (0.01 μM) and amlodipine (0.1 μM) was complete after 1 s. Semotiadil (0.1 μM) and diltiazem (1 μM) prolonged the time to full recovery to 20 s. This significant delay in the recovery of ICa, L produced by semotiadil indicates a mode of action similar to that of the verapamil type of Ca2+ channel antagonists and makes a clear distinction between it and the dihydropyridines, which have no effect on the recovery process. The rate dependence of the effect in combination with a distinct influence of the holding potential underlines the use dependence of the mechanism underlying the effect of semotiadil. The well-known high vasoselectivity of semotiadil in combination with a relatively low Ca2+ channel antagonistic influence on the heart makes semotiadil an interesting candidate for the treatment of coronary heart diseases. © 1997 Elsevier Science B.V. All rights reserved.

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