Receptor sites involved in the action of calcium blocking agents

The affinities of calcium blocking agents (CBAs) for membrane binding sites and for calmodulin were compared to their potencies at inhibiting contraction of various isolated arteries. Two allosterically linked binding sites, the dihydropyridine (DHPS) and benzothiazepine-phenylakylamine (BS) one, were characterized. In spite of a correlation between the affinities of a number of hydrophobic CBAs and calmodulin antagonists for DHPS and for calmodulin, these drugs displayed higher affinities for BS. Furthermore, their potency at inhibiting calcium-induced contraction in depolarized rat aorta rings was correlated to their affinity for the latter site. These results suggest that binding to membrane sites was the basis of the inhibition of depolarization-elicited contraction by all CBAs, including calmodulin antagonists. Differences in sensitivity to CBAs depending on the artery and whether they were depolarized or stimulated by noradrenaline were shown in further experiments on rat cerebral artery and resistance arterioles. These differences in sensitivity did not correspond to differences in the apparent affinity of the drugs. This suggests that the receptors of CBAs (and therefore the associated calcium channels) involved in the responses to depolarization and to the agonist were identical.