Prolonged depolarization increases the pharmacological effect of dihydropyridines and their binding affinity for calcium channels of vascular smooth muscle.

Experiments were performed on isolated rat mesenteric arteries with the calcium-antagonistic dihydropyridine derivative PN 200-110 in order to examine how its time-dependent effect on K+-evoked contraction might be related to voltage sensitive binding. (+)-PN 200-110 is a potent blocker of the K+-contraction in mesenteric artery. Inhibition of the K+-contraction was time-dependent and dose-effect curves were shifted to the left with the duration of depolarization. The (-)-isomer of PN 200-110 was less potent than the (+)-isomer but its action was also time-dependent. (+)-[3H]PN 200-110 binding has been determined in arteries bathed in physiological or high K+-solutions. Nonspecific binding measured in the presence of 10(-6) M nifedipine was not different in polarized and in depolarized arteries but specific binding was increased markedly after 30 min of depolarization. Specific binding data were well fitted by one hyperbolic curve describing a one-to-one binding to a single class of sites. Maximum binding capacity was unchanged whereas apparent dissociation constant was significantly lower in depolarized arteries. Depolarization also shifted to the left displacement curves of (+)-[3H]PN 200-110 by (+)- and (-)-PN 200-110. These results indicate that time-dependent effect of dihydropyridines in vascular smooth muscle is related to increased affinity of depolarized arteries for those drugs, suggesting that calcium channels in vascular smooth muscle are modulated by membrane potential in a way similar to that reported for cardiac muscle.