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Potential role of nitration and oxidation reactions in the effects of peroxynitrite on the function of beta-adrenoceptor sub-types in the rat.

Abstract：

:This study examined the hemodynamic responses elicited by the beta-adrenoceptor agonist, isoproterenol (1 and 10 microg/kg, i.v.) before and after administration of (i) peroxynitrite (10 x 10 micromol/kg, i.v.), (ii) the thiol chelator, para-hydroxymercurobenzoic acid (pHMBA, 75 micromol/kg, i.v.), and (iii) the electron acceptor, nitroblue tetrazolium (NBT, 10 micromol/kg, i.v.) in pentobarbital-anesthetized rats. The tachycardia elicited by the lower dose of isoproterenol was diminished whereas the tachycardia elicited by the higher dose was not attenuated after administration of peroxynitrite. The falls in hindquarter and renal vascular resistances elicited by both doses of isoproterenol were substantially diminished whereas the isoproterenol-induced falls in mesenteric vascular resistance were not changed after administration of peroxynitrite. All of the isoproterenol-induced responses were markedly attenuated after administration of pHMBA or NBT. These findings suggest that the oxidation and/or nitration of beta-adrenoceptors impair the ability of isoproterenol to bind to and/or activate these G protein-coupled receptors. beta1-, beta2- and beta3-adrenoceptors contain extracellular cysteine residues susceptible to oxidation (i.e., disulfide-bridge formation) whereas only the beta1- and beta2-adrenoceptors contain extracellular tyrosine residues susceptible to nitration. These findings also suggest that sustained impairment of beta1- and beta2-adrenoceptor function by peroxynitrite is due to nitration of extracellular tyrosine residues in these receptors. By analogy, beta3-adrenoceptors may not be permanently affected by peroxynitrite because these receptors are devoid of extracellular tyrosine residues.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Lewis SJ,Hoque A,Walton TM,Kooy NW

doi

10.1016/j.ejphar.2005.06.027

keywords:

subject

Has Abstract

pub_date

2005-08-22 00:00:00

pages

187-94

issue

2-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(05)00681-3

journal_volume

518

pub_type

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Potential role of nitration and oxidation reactions in the effects of peroxynitrite on the function of beta-adrenoceptor sub-types in the rat.