Effects of the irreversible alpha-adrenoceptor antagonists phenoxybenzamine and benextramine on the effectiveness of nifedipine in inhibiting alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction in pithed rats.

In pithed normotensive rats, i.v. injection of the selective alpha 1-adrenoceptor agonist cirazoline produced vasoconstriction which was largely resistant to inhibition by nifedipine. On the other hand, the pressor effects of the selective alpha 1-adrenoceptor agonists St 587 and Sgd 101/75 were much more effectively blocked by nifedipine, although not as effectively as the pressor effects to the selective alpha 2-adrenoceptor agonist B-HT 920. The sensitivity to inhibition of vasoconstriction in pithed rats to the different agonists increased in the order cirazoline much less than St 587 less than Sgd 101/75 less than B-HT 920. Phenoxybenzamine (3-300 micrograms/kg, i.v., -60 min) irreversibly antagonized the vasoconstriction to cirazoline, St 587, Sgd 101/75 and B-HT 920. After treatment of the rats with phenoxybenzamine the potency and efficacy of nifedipine in antagonizing vasoconstriction to alpha 1-, but not to alpha 2-adrenoceptor activation was dose-dependently enhanced. The potency of nifedipine to inhibit alpha 1-adrenoceptor-mediated vasoconstriction by cirazoline, St 587 and Sgd 101/75 was increased maximally to the level of efficacy at which nifedipine antagonized B-HT 920-induced vasoconstriction. The dose of phenoxybenzamine required to maximally increase the potency and efficacy of nifedipine to antagonize vasoconstriction of the alpha 1-adrenoceptor agonists was inversely related to the level of sensitivity to blockade by nifedipine of the vasoconstriction they produced. In contrast, pretreatment of rats with the irreversible antagonist, benextramine (10 mg/kg, i.v., -100 to -60 min) did not increase the potency or efficacy of nifedipine to antagonize vasoconstriction to cirazoline, St 587, Sgd 101/75 or B-HT 920, despite irreversible blockade of alpha 1- and alpha 2-adrenoceptors. These data suggest that phenoxybenzamine, but not benextramine, selectively inhibits the alpha 1-adrenoceptor mediated vasoconstrictor mechanism that is independent of influx of extracellular calcium. Moreover, the results show that the existence of receptor reserve or the number of alpha 1-adrenoceptors activated does not determine the relative contribution of calcium influx-independent mechanisms in alpha 1-adrenoceptor-mediated vasoconstriction.