Abstract
In experimental animals, calcium entry blockers (CEBs) preferentially depress systemic pressor responses to selective α2 stimulation. The reasons for such a behavior have been widely discussed. This paper reviews our experience in this regard. Either verapamil or nitrendipine, unrelated CEBs, antagonized pressor responses to selective α2 stimulation in pithed rats, but a similar effect was exerted by non-CEB vasodilators such as hydralazine or sodium nitroprusside in the same animal preparation. Furthermore, the CEB nitrendipine, at concentrations preferentially active against systemic α2-mediated pressor responses, antagonized either α1 or α2 local vasoconstriction in autologous blood, constant flow autoperfused rat hindlimb, showing that mechanisms other than calcium entry blockade “per se” underlay that effect, such as differences in α-adrenoceptor reserve. To evaluate that possibility, dose-response curves to the α-selective agonist methoxamine were obtained after partial α-adrenoceptor inactivation through the alkylating agent phenoxybenzamine. In those conditions, the α1-mediated pressor resistance disappeared, strongly suggesting the importance of adrenoceptor reserve in explaining agonist-antagonist interactions, and, in particular, differences in α1 versus α1 sensitivity to CEBs in rats. In man, verapamil infused intraarterially at systemically ineffective rates antagonized arteriolar forearm vasoconstriction to selective local α1 and α2 stimulation through the partial agonists methoxamine and B-HT 933, showing that in humans—well as in rats—CEBs do not antagonize preferentially α2-mediated vasoconstriction. Furthermore, verapamil, at the same infusion rates active against methoxamine and B-HT 933, was ineffective against the full agonist norepinephrine, a nonselective α stimulant, suggesting the relevance of adrenoceptor reserve mechanisms even in humans. Thus, in humans—but also in rats—CEBs do not preferentially exert α2 antagonism, although nonspecific and nonselective α-adrenolytic properties might contribute, under some circumstances, to their pharmacodynamic effect.
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