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 alpha1-adrenoceptor agonist, phenylephrine, in urethane-anesthetized rats by chelation of thiol residues in alpha1-adrenoceptors in vascular smooth muscle rather than voltage-sensitive Ca(2+)-channels (Ca(2+)VERSUS-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+)VERSUS-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 alpha1-adrenoceptors are initiated by mobilization of intracellular pools of Ca(2+) whereas they are sustained by opening of Ca(2+)VERSUS-channels. These findings also suggest that PHMBA diminishes the vasoconstrictor effects of phenylephrine by chelation of thiol residues in alpha1-adrenoceptors rather than by blockade of Ca(2+)VERSUS-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+).
Hoque
Azizul
A
Department of Cardiology, University of Louisville, Louisville, KY, USA.
Owen
Joy R
JR
Bates
James N
JN
Lewis
Stephen J
SJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006902:Hydroxymercuribenzoates / Q000494:pharmacology*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013439:Sulfhydryl Reagents / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D006902:Hydroxymercuribenzoates; D018340:Receptors, Adrenergic, alpha-1; D013439:Sulfhydryl Reagents; D014665:Vasodilator Agents; C030601:4-hydroxymercuribenzoate; D010656:Phenylephrine; D009543:Nifedipine; D009638:Norepinephrine