S-nitrosoglutathione inhibits α1-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery
- 1 January 2006
- journal article
- Published by American Physiological Society in American Journal of Physiology-Lung Cellular and Molecular Physiology
- Vol. 290 (1), L136-L143
- https://doi.org/10.1152/ajplung.00230.2005
Abstract
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 Gq, we hypothesized that S-nitrosothiols modify the α1-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 α1-adrenergic receptor was shown to undergo S-nitrosylation in vitro using a biotin switch assay. Studies of α1-adrenergic receptor subtype expression and receptor density by saturation binding with 125I-HEAT showed that GSNO decreased α1-adrenergic receptor density but did not alter affinity for antagonist or agonist. These data demonstrate a novel cGMP-independent mechanism of reversible α1-adrenergic receptor inhibition by S-nitrosothiols.Keywords
This publication has 32 references indexed in Scilit:
- Protein S-nitrosylation: purview and parametersNature Reviews Molecular Cell Biology, 2005
- Protein S-Glutathiolation Triggered by DecomposedS-NitrosoglutathioneBiochemistry, 2004
- S-Nitrosating Nitric Oxide Donors Induce Long-Lasting Inhibition of Contraction in Isolated ArteriesJournal of Pharmacology and Experimental Therapeutics, 2003
- β-Adrenoceptor Dysfunction After Inhibition of NO SynthesisHypertension, 2000
- Nitric Oxide Modulates β2-Adrenergic Receptor Palmitoylation and SignalingPublished by Elsevier BV ,1999
- A Molecular Redox Switch on p21Published by Elsevier BV ,1997
- Variation in mRNA expression of alpha-adrenergic, neurokinin and muscarinic receptors amongst four arteries of the ratJournal of the Autonomic Nervous System, 1997
- S‐Nitrosylation of m2 Muscarinic Receptor Thiols Disrupts Receptor‐G‐Protein CouplingaAnnals of the New York Academy of Sciences, 1995
- Nitric oxide regulates angiotensin II receptors in vascular smooth muscle cellsEuropean Journal of Pharmacology: Molecular Pharmacology, 1995
- Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscleNature, 1994