Calcium channel blockers: correlation among receptor binding, calcium uptake and contractility in vitro

S Papaioannou, S Panzer-Knodle and PC Yang

Ten known calcium channel blockers were studied for inhibition of K+- induced 45Ca++ uptake into rabbit aortic smooth muscle cells in culture, and for displacement of [3H]nitrendipine [2,6-dimethyl-3- carbomethoxy-5-carbomethoxy-4-(3-nitro)phenyl-1, 4-dihydroxypyridine] binding to rat ventricular membrane preparations, in order to relate their effects on receptor binding with their inhibitory activities on 45Ca++ uptake and on contractile responses of vascular smooth muscle. Steady-state 45Ca++ uptake increased with K+ concentration in a dose- dependent manner. With 25 to 50 mM K+, Ca++ uptake was 0.6 nmol of Ca++ per one million cells. All calcium channel blockers inhibited K+- induced 45Ca++ uptake and [3H]nitrendipine binding in a dose-dependent fashion. The enatiomeric dihydropyridines 202-791 [isopropyl-4-(2,1,3- benzoxadiazol-4-yl)-1,4-dihydro-2, 6-dimethyl-5-nitro-3- pyridinecarboxylate] exhibited marked stereoselectivity in both studies, the agonist (+)-202-791 significantly enhancing 45Ca++ uptake at 15 to 50 mM K+. The similarity between the order of potency in inhibiting 45Ca++ uptake and displacing [3H]nitrendipine resulted in a highly significant linear (1:1) correlation. An equally significant correlation was also established for the 10 blockers between their inhibitory potencies on 45Ca++ uptake and the contractile response of rabbit aortic strips as cited in the literature. These findings support the hypothesis that calcium channel blockers block contraction of vascular muscle by inhibiting cellular calcium uptake through voltage- dependent calcium channels as a result of binding to receptors associated with these channels. The aortic cells possess channels that are functionally similar to those found in intact vascular tissue.

Volume 241, Issue 1, pp. 91-96, 04/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics