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This Article Full Text Full Text (PDF) All Versions of this Article: 290/1/L136    most recent 00230.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Nozik-Grayck, E. Articles by Piantadosi, C. A. Search for Related Content PubMed PubMed Citation Articles by Nozik-Grayck, E. Articles by Piantadosi, C. A.

S-nitrosoglutathione inhibits ₁-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery

¹Department of Pediatrics, University of Colorado Health Science Center, Denver, Colorado; and Departments of ²Medicine and ³Pediatrics, Duke University Medical Center, Durham, North Carolina

Submitted 27 May 2005 ; accepted in final form 23 August 2005

Endogenous nitric oxide donor compounds (S-nitrosothiols) contribute to low vascular tone by both cGMP-dependent and -independent pathways. We have reported that S-nitrosoglutathione (GSNO) inhibits 5-hydroxytryptamine (5-HT)-mediated pulmonary vasoconstriction via a cGMP-independent mechanism likely involving S-nitrosylation of its G protein-coupled receptor (GPCR) system. Because catecholamines, like 5-HT, constrict lung vessels via a GPCR coupled to G_q, we hypothesized that S-nitrosothiols modify the ₁-adrenergic GPCR system to inhibit pulmonary vasoconstriction by receptor agonists, e.g., phenylephrine (PE). Rat pulmonary artery rings were pretreated for 30 min with and without an S-nitrosothiol, either GSNO or S-nitrosocysteine (CSNO), and constricted with sequential concentrations of PE (10^–8–10^–6 M). Effective cGMP-dependence was tested in rings pretreated with soluble guanylate cyclase inhibitors {either 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or LY-83583} or G kinase inhibitor (KT-5823), and a thiol reductant [dithiothreitol (DTT)] was used to test reversibility of S-nitrosylation. Both S-nitrosothiols attenuated the PE dose response. The GSNO effect was not prevented by LY-83583, ODQ, or KT-5823, indicating cGMP independence. GSNO inhibition was reversed by DTT, consistent with S-nitrosylation or other GSNO-mediated cysteine modifications. In CSNO-treated lung protein, the ₁-adrenergic receptor was shown to undergo S-nitrosylation in vitro using a biotin switch assay. Studies of ₁-adrenergic receptor subtype expression and receptor density by saturation binding with ¹²⁵I-HEAT showed that GSNO decreased ₁-adrenergic receptor density but did not alter affinity for antagonist or agonist. These data demonstrate a novel cGMP-independent mechanism of reversible ₁-adrenergic receptor inhibition by S-nitrosothiols.

nitric oxide; S-nitrosylation; G protein-coupled receptor; guanosine 3',5'-cyclic monophosphate

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