Pulmonary vasoconstriction by serotonin is inhibited by S-nitrosoglutathione

Published

Journal Article

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-HT2 receptors. In isolated rabbit lung preparations and isolated pulmonary artery (PA) rings, 50-250 μM S-nitrosoglutathione (GSNO) inhibited the response to 0.01-10 μM 5-HT. The vasoconstrictor response to 5-HT was mediated by 5-HT2 receptors in the lung, since it could be blocked completely by the selective inhibitor ketanserin (10 μM). 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 μM), which releases NO and O2- 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-HT2 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.

Duke Authors

Cited Authors

  • Nozik-Grayck, E; McMahon, TJ; Huang, YCT; Dieterle, CS; Stamler, JS; Piantadosi, CA

Published In

Volume / Issue

  • 282 / 5 26-5

International Standard Serial Number (ISSN)

  • 1040-0605

Citation Source

  • Scopus