Differences in Ca2+ entry blockers revealed by effects on adenosine- and adrenergic- receptors and cyclic AMP levels of [2-3H]adenine-prelabeled vesicles prepared from guinea pig brain.

Three major classes of Ca2+ entry blockers, classified according to effects on cardiac and vascular smooth muscle, were tested. Vesicles prepared from cerebral cortex and stimulated by adenosine and epinephrine constituted adenosine and alpha-adrenergic receptor systems respectively. Vesicles prepared from cerebellum and stimulated by epinephrine constituted the beta-adrenergic receptor system. Experiments with adenosine were also performed with vesicles formed or incubated in the absence of exogenous Ca2+. The results indicate that Ca2+ entry blockers had a variety of effects, even within classes of drugs. Vascular-selective group A Ca2+ entry blockers such as nifedipine and nisoldipine antagonized adenosine, but the structurally-related drug nitrendipine was inactive. Inhibition was competitive with adenosine and independent of exogenous Ca2+. In contrast to receptor-binding studies requiring high ratios of the drugs to adenosine receptor radioligands, nifedipine and nisoldipine were inhibitory at equimolar concentrations with adenosine. Non-selective group A Ca2+ entry blockers such as diltiazem and verapamil were inactive against adenosine. Group B Ca2+ entry blockers, prenylamine and perhexilene, increased cyclic AMP (cAMP) levels of vesicles stimulated by adenosine but not by epinephrine or under basal conditions. This effect was observed only in vesicles that had been formed in the presence of Ca2+. Ca2+ entry blockers also exhibited effects on adrenergic receptors unrelated to effects on adenosine. Verapamil and prenylamine acted as alpha-adrenergic antagonists and only prenylamine acted as a beta-adrenergic antagonist. However, the vesicle system also revealed indirect blocking actions of nifedipine on adrenergic receptor systems. The actions of the Ca2+ entry blockers are discussed in relation to the special usefulness of nifedipine in the treatment of patients with defective atrioventricular conduction and also in relation to the unique ability of group B Ca2+ entry blockers to selectively inhibit Ca2+ and calmodulin activated phosphodiesterase. However, some caution must be applied in drawing conclusions relating to the cardiovascular actions of these drugs from data generated in a neuronally-derived model.