Pulmonary vasoconstriction by serotonin is inhibited by S-nitrosoglutathione.
Nitric oxide (NO) functions as an endothelium-derived relaxing factor by activating guanylate cyclase to increase cGMP levels. However, NO and related species may also regulate vascular tone by cGMP-independent mechanisms. We hypothesized that naturally occurring NO donors could decrease the pulmonary vascular response to serotonin (5-HT) in the intact lung through chemical interactions with 5-HT(2) receptors. In isolated rabbit lung preparations and isolated pulmonary artery (PA) rings, 50-250 microM S-nitrosoglutathione (GSNO) inhibited the response to 0.01-10 microM 5-HT. The vasoconstrictor response to 5-HT was mediated by 5-HT(2) receptors in the lung, since it could be blocked completely by the selective inhibitor ketanserin (10 microM). GSNO inhibited the response to 5-HT by 77% in intact lung and 82% in PA rings. In PA rings, inhibition by GSNO could be reversed by treatment with the thiol reductant dithiothreitol (10 mM). 3-Morpholinosydnonimine (100-500 microM), which releases NO and O simultaneously, also blocked the response to 5-HT. Its chemical effects, however, were distinct from those of GSNO, because 5-HT-mediated vasoconstriction was not restored in isolated rings by dithiothreitol. In the intact lung, neither NO donor altered the vascular response to endothelin, which activates the same second-messenger vasoconstrictor system as 5-HT. These findings, which did not depend on guanylate cyclase, are consistent with chemical modification by NO of the 5-HT(2) G protein-coupled receptor system to inhibit vasoconstriction, possibly by S-nitrosylation of the receptor or a related protein. This study demonstrates that GSNO can regulate vascular tone in the intact lung by a reversible mechanism involving inhibition of the response to 5-HT.
Nozik-Grayck
Eva
E
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. grayc001@mc.duke.edu
McMahon
Timothy J
TJ
Huang
Yuh-Chin T
YC
Dieterle
Christine S
CS
Stamler
Jonathan S
JS
Piantadosi
Claude A
CA
D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000502:physiology*; D011817:Rabbits; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D012702:Serotonin Antagonists; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D012701:Serotonin; D026422:S-Nitrosoglutathione; D007650:Ketanserin; D019204:GTP-Binding Proteins; D004229:Dithiothreitol