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, Margaret R MacLean

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)539-548
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number2
DOIs
Publication statusPublished - 2005

Keywords

  • 5-hydroxytryptamine receptors
  • serotonin transporter
  • pulmonary arteries

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