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 language | English (US) |
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Pages (from-to) | 187-194 |
Number of pages | 8 |
Journal | European Journal of Pharmacology |
Volume | 518 |
Issue number | 2-3 |
DOIs | |
State | Published - Aug 22 2005 |
Externally published | Yes |
Bibliographical note
Funding Information:This work was supported in part by American Heart Association (Iowa Affiliate) Grant IA-97-GB-29.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
Keywords
- (Rat)
- Heart rate
- Nitration
- Peroxynitrite
- Redox
- Vasodilation
- β-adrenoceptors