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Organic calcium-antagonists and calcium ionophores

par Malaisse, Willy ;Somers, Guido;Valverde, Isabel;Couturier, Etienne
Référence Arzneimittel-Forschung, 31, I, page (628-633)
Publication Publié, 1981

Article révisé par les pairs

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Résumé :

Verapamil, suloctidil and other organic calcium-antagonists inhibit translocation from an aqueous medium into a hydrophobic domain mediated by 8-[1-(ethyl-1-carboxy-pyrrole-2)]-4-(2-methylene-4-carboxy-5-methylamino-ben zoxazole)-spiro(5,5)hendecan-3,9,11-trimethyl-6,7-dioxane (A23187). The magnitude of this inhibition depends on the verapamil/ionophore concentration ratio, the slope of the dose-action relationship (in semilogarithmic coordinates) being comparable with distinct drugs of vastly different biological potency. Like in intact cells, calcium itself protects against the inhibitory effect of the calcium-antagonists, an effect which apparently depends on a direct interaction with the calcium-binding site of the ionophoretic molecule. Verapamil also inhibits calcium and sodium translocation mediated by 3-methyl-5-bromo-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl -5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl }salicylic acid (X537A). The relative efficiency of suloctidil and its analogues or metabolites to inhibit calcium translocation correlates with their potency to inhibit smooth muscle contraction. These findings suggest that the interference of organic calcium-antagonists with native ionophoretic processes represents a fundamental event in the expression of their biological action.