Ca2+ channel antagonist actions in bladder smooth muscle: comparative pharmacologic and [3H]nitrendipine binding studies

Abstract

The actions of a series of 15 Ca²⁺ channel antagonists including D-6(X), nifedipine, and diltiazem were examined against K⁺ depolarization and muscarinic receptor induced responses in guinea pig bladder smooth muscle. Responses of bladder are very dependent upon extracellular Ca²⁺ and sensitive to the Ca²⁺ channel antagonists, the tonic component more than the phasic component of response. Regardless of stimulant, K⁺ or methylfurmethide (MF), or component of response, the same rank order of antagonist activities is expressed, suggestive of a single structure–activity relationship and the existence of a single category of binding site which may, however, exist in several affinity states. High affinity binding of [³H]nitrendipine (K_D = 1.1 × 10⁻¹⁰ M) occurs in bladder membranes, and similar high affinity binding was found in microsomal preparations from other smooth muscles including guinea pig and rat lung, rat vas deferens, uterus, and stomach. [³H]nitrendipine binding in the bladder was sensitive to displacement by other 1,4-dihydropyridines, paralleling their pharmacologic activities and showing excellent agreement with binding data previously obtained for guinea pig ileal smooth muscle. Comparison of pharmacologic data for inhibition of K⁺- and MF-induced responses by a common series of Ca²⁺ channel antagonists in bladder and ileum revealed excellent correlations. Neither pharmacologic nor binding studies suggest significant differences in Ca²⁺ channel antagonist properties in smooth muscle from bladder and intestine.