The interaction of calcium antagonists (slow channel blockers) with myocardial alpha adrenoceptors

Abstract

Verapamil, D-600, diltiazem and nifedipine belong to the newly recognized class of drugs known collectively as “calcium antagonists” [ 3] “slow channel inhibitors” [ 6] or “calcium entry blockers” [ 9]. These substances were originally classed as “calcium antagonists” on the basis of two requirements: 1. (a) their ability to inhibit the slow Ca 2+ current; and 2. (b) the reversal of this inhibitory effect by Ca 2+. These and other more recently developed calcium antagonists are now being widely used as research tools, often on the assumption that their inhibitory effect is specific for the slow current and that this is their sole pharmacological property. Such an assumption can no longer be justified however, because many of these compounds exhibit other properties [ 5]. For example, high concentrations of verapamil and D-600 inhibit the fast Na + current [ 11] and D-600, even when used in micromolar concentrations, slows the outward K + current. D-600 also inhibits the uptake of dopamine, noradrenaline, serotonin and choline into rat brain synaptosomes and interacts with muscarinic receptors [ 8]. Recent studies have shown that verapamil, nifedipine, and D-600 interact with rat brain α-adrenoceptors, thereby reducing their specific α-ligand binding activity [ 2, 14, 15]. D-600 apparently exerts a similar effect on α-adrenoceptors in rat cardiac membranes [ 4]. This effect of D-600 contrasts [ 4] with that of the inorganic slow channel antagonists, Ma 2+ and Ni 2+, because although these cations are also powerful inhibitors of the slow Ca 2+ current they enhance the specific ligand binding activity of α-adrenoceptors. It seems possible, therefore, that the interaction of slow channel inhibitors with α-adrenoceptors may involve a heteregeneous response, with not all of the slow channel inhibitors behaving in the same way. To investigate this possibility we have compared the inhibitory effect of several different slow channel blockers on α-adrenoceptor binding activity. 3H-prazosin binding was used to identify α 1 receptors in rat cardiac membranes, and 3H-clonidine to identify α 2-adrenoceptors in rat brain homogenates. The slow channel inhibitors used were the d and l isomers of verapamil, racemic D-600, nifedipine and nicardipine (RS69216), and the d-cis form of diltiazem.