EFFECTS OF SEMOTIADIL FUMARATE, A NOVEL CA2+ ANTAGONIST, ON CYTOSOLIC CA2+ LEVEL AND FORCE OF CONTRACTION IN PORCINE CORONARY-ARTERIES

1 The mechanisms of action of semotiadil fumarate, a novel Ca2+ antagonist, were examined by measuring the cytosolic Ca2+ level ([Ca2+](i)) and force of contraction in porcine coronary arteries, and by determining [H-3]-pyrilamine binding to bovine cerebellar membranes. 2 Semotiadil or verapamil (0.1 and 1 mu M) inhibited both the high KCl-induced increases in [Ca2+](i) and force in a concentration-dependent manner. 3 Histamine(30 mu M) produced transient increases followed by sustained increases in [Ca2+](i) and force, which were inhibited by semotiadil and verapamil (1 and 10 mu M). The agents were different in that semotiadil reduced the maximum [Ca2+](i) and force responses to histamine, but not pD(2) values, whereas verapamil did reduce the pot values for histamine, but not the maximum responses. 4 Verapamil (10 mu M), but not semotiadil, inhibited histamine-induced increases in [Ca2+](i) and force in Ca2+-free solution. Neither semotiadil nor verapamil affected the increases in [Ca2+](i) and force induced by caffeine. Semotiadil even at the higher concentration (10 mu M) did not displace specific binding of [H-3]-pyrilamine to bovine cerebellar membranes. 5 These results suggest that semotiadil inhibits both KCl- and histamine-induced contractions mainly by blocking voltage-dependent L-type Ca2+ channels.