Effects of thiol chelation on alpha1-adrenoceptor-induced vasoconstriction in vivo.

The aims of this study were to determine whether systemic injections of the lipophobic thiol chelator, para-hydroxymercurobenzoic acid (PHMBA) would reduce the vasoconstrictor responses elicited by the α 1 -adrenoceptor agonist, phenylephrine, in urethane-anesthetized rats by chelation of thiol residues in α 1 -adrenoceptors in vascular smooth muscle rather than voltage-sensitive Ca 2 + -channels (Ca 2 + V E R S U S -channels). The magnitudes and durations of the vasoconstrictor responses elicited by phenylephrine were markedly reduced after the injections of PHMBA. In contrast, the maximal phenylephrine-induced responses were not affected whereas the durations of these responses were markedly attenuated after injection of the Ca 2 + V E R S U S -channel blocker, nifedipine. Nifedipine elicited pronounced and sustained falls in mean arterial blood pressure and vascular resistances in PHMBA-treated rats. Moreover, the vasodilator actions of the nitric oxide-donor, sodium nitroprusside were minimally attenuated by PHMBA whereas they were markedly attenuated by nifedipine. These findings support evidence that the vasoconstrictor responses due to activation of α 1 -adrenoceptors are initiated by mobilization of intracellular pools of Ca 2 + whereas they are sustained by opening of Ca 2 + V B R S U S -channels. These findings also suggest that PHMBA diminishes the vasoconstrictor effects of phenylephrine by chelation of thiol residues in α 1 -adrenoceptors rather than by blockade of Ca 2 + V E R S U S -channels, and that chelation of these thiol residues prevents agonist occupation and/or activation of these receptors and subsequent mobilization of intracellular pools of Ca 2 + .