Differential effect of calcium entry blockers on alpha 1-adrenoceptor-mediated vasoconstriction in vivo

The effects of the calcium entry blockers nifedipine, (-)-verapamil and the dihydropyridine derivative PY 108-068 were evaluated on the increase in diastolic pressure of pithed normotensive rats caused by the selective alpha 1-adrenoceptor agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, (-)-amidephrine and St 587 [(2-chloro-5-trifluoromethylphenylimino)-2-imidazolidine] as well as by the mixed alpha 1/alpha 2-adrenoceptor agonists clonidine and DPI [(3,4-dihydroxyphenylimino)-2-imidazolidine]. The calcium entry inhibitors (up to 3 mg/kg) caused 3- to 5-fold, parallel rightward shifts of the log dose-pressor effect curves to cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine and (-)-amidephrine accompanied by only a slight depression of the maximal pressor response. In contrast, the calcium entry inhibitors produced a dose-dependent profound depression of both maximum and slope of the log dose-pressor response curves to St 587 and clonidine. For DPI about 10- and 100-fold parallel displacements to the right without reduction of the maximum were found following treatment with 1 and 3 mg/kg of nifedipine, respectively. Infusion of vasopressin to counteract the vasodilatory action produced by the calcium entry inhibitors did not significantly change the pattern of interference observed under the conditions of decreased baseline diastolic pressure. The results indicate that alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat, which is characterized by its sensitivity to blockade by prazosin and its relative insensitivity to antagonism by yohimbine or rauwolscine, can be subdivided into two distinct processes which are differentially influenced by blockade of calcium entry.(ABSTRACT TRUNCATED AT 250 WORDS)