INTERACTIONS OF CALMODULIN ANTAGONISTS WITH CALCIUM-ANTAGONISTS BINDING-SITES

Calmodulin antagonists have calcium entry blocking properties. In order to quantitatively investigate the interactions of these drugs with calcium channels, their effect on [H-3]nitrendipine and [H-3]d-cis-diltiazem binding to rat cerebral cortex membrane preparations was compared to their inhibitory effect on the activation of cyclic nucleotide phosphodiesterase by calmodulin. The potency of most antagonists to inhibit [H-3]nitrendipine binding was correlated with their calmodulin inhibitory potency. However, bepridil (K0.5 = 280 nM), chlorpromazine (K0.5 = 3-mu-M), triflupromazine (K0.5 = 1.5-mu-M), imipramine (K0.5 = 3-mu-M) and propranolol (K0.5 = 14-mu-M) were much more active on [H-3]d-cis-diltiazem binding than on either [H-3]nitrendipine binding or calmodulin, suggesting that these compounds bind to higher affinity sites on the calcium antagonist target protein. Moreover, the potencies of these compounds to compete with [H-3]d-cis-diltiazem and to inhibit calcium-induced contractions in depolarized smooth muscle were correlated (R = 0.76, p < 0.02). These data suggest that low concentrations of these hydrophobic drugs which have calcium and calmodulin antagonistic properties inhibit smooth muscle contraction through calcium entry blockade, not calmodulin antagonism.