Functional Interactions between 5-Hydroxytryptamine Receptors and the Serotonin Transporter in Pulmonary Arteries
- Ian Morecroft,
- Lynn Loughlin,
- Margaret Nilsen,
- Janet Colston,
- Yvonne Dempsie,
- John Sheward,
- Anthony Harmar and
- Margaret R. MacLean
- Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (I.M., L.L., M.N., J.C., Y.D., M.R.M.); and the Division of Neuroscience, University of Edinburgh, Edinburgh, Scotland, United Kingdom (J.S., A.H.)
- Address correspondence to:
Dr. Margaret R MacLean, West Medical Building, Institute of Biomedical and Life Sciences, University of Glasgow, G12 8QQ, Scotland. E-mail m.maclean{at}bio.gla.ac.uk
Abstract
Pulmonary arterial 5-hydroxytryptamine (serotonin) (5-HT) transporter (SERT)-, 5-HT receptor expression, and 5-HT-induced vasoconstriction can be increased in pulmonary hypertension. These variables were studied in normoxic and hypoxic Fawn-Hooded (FH) and Sprague-Dawley (SD) rats. Furthermore, we compared the functional effects of SERT inhibitors and 5-HT receptor antagonists against 5-HT-induced vasoconstriction of pulmonary arteries. SERT and 5-HT1B expression was greater in FH rat lungs than in SD rats, as was 5-HT-mediated vasoconstriction. The 5-HT2A receptor antagonist ketanserin and the 5-HT1B receptor antagonist SB224289 (1′-methyl-5-[[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-spiro-[furo] 2, 3-f]indole-3,4′-piperidine]) inhibited responses to 5-HT in all vessels. The combined 5-HT1B receptor/SERT antagonist LY393558 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide) was the most potent inhibitor of constriction in all vessels. SERT inhibitors citalopram and fluoxetine inhibited responses to 5-HT in SD vessels. However, these inhibitors potentiated responses to 5-HT in FH vessels. After exposure of rats to 2 weeks of hypoxia, there was increased 5-HT-mediated vasoconstriction and a profound decrease in SERT expression in both the FH and SD rat lung. Accordingly, citalopram had no effect on 5-HT-induced constriction in SD rat vessels and markedly less effect in FH rat vessels. Ketanserin, SB224289, and LY393558 inhibited responses to 5-HT in all hypoxic rat vessels. LY393558 was the most potent antagonist, and there was synergy between the effects of fluoxetine and SB224289 when given simultaneously. The results suggest that, in FH rats, SERT inhibitors may increase pulmonary vasoconstriction, but this can be inhibited by simultaneous 5-HT1B receptor antagonism. There is synergy between the inhibitory effects of 5-HT1B receptor antagonists and SERT inhibitors on 5-HT-induced pulmonary vasoconstriction.
Footnotes
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This work was funded by The British Heart Foundation. Some of this work has been published in abstract form [MacLean MR and Morecroft I (2004) Uptake inhibitors on 5-HT-induced contraction in Fawn Hooded rat pulmonary arteries. Am J Respir Crit Care Med169:A511].
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doi:10.1124/jpet.104.081182.
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ABBREVIATIONS: PAH, pulmonary arterial hypertension; 5-HT, 5-hydroxytryptamine (serotonin); SERT, serotonin transporter; FH, Fawn-Hooded; SD, Sprague-Dawley; RVP, right ventricular pressure; RV, right ventricle/right ventricular; SB224289, 1′-methyl-5-[[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-spiro[furo[2,3-f]indole-3,4′-piperidine]; LY393558, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide.
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- Received November 22, 2004.
- Accepted January 13, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
