Calcium antagonists and alpha-receptors.

Abstract

Distinct mechanisms of vasoconstriction mediated by either a1 - or a2- adrenoceptor stimulation have been identified. A differential role of extracellular calcium has been explored in both vasoconstrictor processes in different animal species both in vivo and in vitro . In order to achieve this goal the following drug classes have been used: selective agonists of a1 - (methoxamine and (-)-phenylephrine) and a2- adrenoceptors (B-HT 920), organic and inorganic calcium entry blockers (nifedipine and derivatives, verapamil and divalent metal cations) as well as Na2-EDTA. The general principle has been established that the organic and inorganic calcium slow channel blockers as well as Na2-ED TA selectively interfered with the vasoconstriction triggered by vascular a2-adrenoceptors thereby depressing both maximum and slope of the log dose-vasopressor response curve. On the other hand, vasoconstriction initiated by the stimulation of a1-adrenoceptors remained largely unaffected by these measures. It is not likely that the calcium entry blockers at issue behave as ordinary a2-adrenoceptor antagonists in view of their very moderate affinity for this class of adrenoceptors. Blockade of a transmembrane influx of extracellular calcium is presumably the mechanism underlying the interaction observed. This is supported by the linear relationship which could be established between the potency of the various calcium entry blockers to inhibit a2-adrenoceptor-mediated vasoconstriction and their activity to impair K+-induced (calcium-dependent) contraction of blood vessels. On the basis of these results the hypothesis is formulated that, in contrast to a1-adrenoceplor-induced vasoconstriction, the vasoconstrictor process initiated by a2-adrenoceptors is carried by an influx of extracellular calcium. By inhibiting this inward current of calcium, the so-called calcium entry blockers selectively attenuate this a2-adrenoceptor-mediated vasoconstriction. It is tempting to explain the vasodilator potency of calcium entry blockers by the aforementioned mechanism, although the functionality of vascular a2-adrenoceptors in the maintenance of peripheral resistance remains to be established.