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

Stephen J. Lewis, Azizul Hoque, Tina M. Walton, Neil W. Kooy

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

This study examined the hemodynamic responses elicited by the β-adrenoceptor agonist, isoproterenol (1 and 10 μg/kg, i.v.) before and after administration of (i) peroxynitrite (10 × 10 μmol/kg, i.v.), (ii) the thiol chelator, para-hydroxymercurobenzoic acid (pHMBA, 75 μmol/kg, i.v.), and (iii) the electron acceptor, nitroblue tetrazolium (NBT, 10 μmol/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 β-adrenoceptors impair the ability of isoproterenol to bind to and/or activate these G protein-coupled receptors. β1-, β2- and β3-adrenoceptors contain extracellular cysteine residues susceptible to oxidation (i.e., disulfide-bridge formation) whereas only the β1- and β2-adrenoceptors contain extracellular tyrosine residues susceptible to nitration. These findings also suggest that sustained impairment of β1- and β2-adrenoceptor function by peroxynitrite is due to nitration of extracellular tyrosine residues in these receptors. By analogy, β3-adrenoceptors may not be permanently affected by peroxynitrite because these receptors are devoid of extracellular tyrosine residues.

Original languageEnglish (US)
Pages (from-to)187-194
Number of pages8
JournalEuropean Journal of Pharmacology
Volume518
Issue number2-3
DOIs
StatePublished - Aug 22 2005

Keywords

  • (Rat)
  • Heart rate
  • Nitration
  • Peroxynitrite
  • Redox
  • Vasodilation
  • β-adrenoceptors

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