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Articles in PresS, published online ahead of print November 30, 2001
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00081.2001
Submitted on March 13, 2001
Accepted on November 28, 2001
1 Departments of Pediatrics and Medicine, Duke University Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: grayc001{at}mc.duke.edu.
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 both isolated rabbit lung preparations and isolated pulmonary artery (PA) rings, S-nitrosoglutathione (GSNO) (50 to 250 µM) inhibited the response to 5-HT (0.01 to 10 mM). 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 (DTT) (10 mM). SIN-1 (100 - 500 µM), which releases NO and superoxide simultaneously, also blocked the response to 5-HT. Its chemical effects, however, were distinct from GSNO because 5-HT-mediated vasoconstriction was not restored in isolated rings by DTT. 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.
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