Potential role of nitration and oxidation reactions in the effects of peroxynitrite on the function of beta-adrenoceptor sub-types in the rat.
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.
Lewis
Stephen J
SJ
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7389, USA. slewis@vet.uga.edu
Hoque
Azizul
A
Walton
Tina M
TM
Kooy
Neil W
NW
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006902:Hydroxymercuribenzoates / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D009580:Nitroblue Tetrazolium / Q000494:pharmacology; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D006902:Hydroxymercuribenzoates; D009566:Nitrates; D011943:Receptors, Adrenergic, beta; C030601:4-hydroxymercuribenzoate; D030421:Peroxynitrous Acid; D009580:Nitroblue Tetrazolium; D007545:Isoproterenol