Calcium and calmodulin antagonists binding to calmodulin and relaxation of coronary segments

JD Johnson and DA Fugman

Ca++ antagonist drugs (also known as Ca++ channel blockers) and the calmodulin antagonists trifluoperazine (TFP) and W-7 [N-(6-aminohexyl)- 5-chloro-1-naphthalenesulfonamide] were capable of half-maximally relaxing porcine coronary segments at 1.5 X 10(-10) M for felodipine, 6.5 X 10(-8) M for verapamil, 2.6 X 10(-7) M for diltiazem, 7 X 10(-7) M for prenylamine, 7 X 10(-6) M for TFP and 45 X 10(-6) M for W-7. Their correspondent binding to calmodulin was half-maximal at 2.8 X 10(- 6), 30 X 10(-6), 80 X 10(-6), 5 X 10(-7), 5.0 X 10(-6) and 11 X 10(-6) M, respectively. Only prenylamine, TFP and W-7 were capable of relaxing coronaries over the same concentration range in which they bind to calmodulin. The relaxations produced by these calmodulin antagonists and prenylamine could not be overcome by contractile agonists which release Ca++ from internal stores (histamine and serotonin), whereas the relaxations produced by felodipine, verapamil and diltiazem were readily reversed by either of these agonists. This is consistent with TFP and W-7 and to some degree prenylamine-inducing vasodilation by calmodulin antagonism and with felodipine, verapamil and diltiazem vasodilating through Ca++ antagonism of Ca++ channels at the level of the cell membrane.

Volume 226, Issue 2, pp. 330-334, 08/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics