Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats.: 5-HT Transporter Inhibition Prevents PH

Abstract : BACKGROUND: Progression of pulmonary hypertension (PH) is associated with increased lung expression of the serotonin transporter (5-HTT), which leads to hyperplasia of the pulmonary artery smooth muscle cells (PA-SMCs). Given the postulated causal relation between 5-HTT overexpression and PH, we herein investigated whether the highly selective 5-HTT inhibitor fluoxetine prevented and/or reversed PH induced by monocrotaline (MCT) in rats. Selective 5-HT(1B/1D), 5-HT(2A), and 5-HT(2B) receptor antagonists were used for comparative testing. METHODS AND RESULTS: MCT injection (60 mg/kg SC) was followed by an early peak in lung 5-HTT expression on day 1, which preceded the onset of PH. Established PH on day 15 was associated with a sustained 5-HTT increase. Continued fluoxetine treatment completely prevented PA-SMC proliferation and PH development and also suppressed the late 5-HTT increase, without affecting the early peak. The 5-HT receptor antagonists did not affect PH. Fluoxetine (10 mg . kg(-1) . d(-1) PO) started 3 weeks after MCT injection completely reversed established PH, normalizing PA pressure and structure. MCT-induced PH was also associated with increased expression of various cytokines, but only interleukin-1beta and monocyte chemotactic protein-1 increased at the early phase and stimulated 5-HTT expression by cultured PA-SMCs. CONCLUSIONS: Upregulation of lung 5-HTT induced by MCT appears necessary to initiate the development of pulmonary vascular remodeling, whereas a sustained increase in 5-HTT expression may underlie both the progression and the maintenance of MCT-induced PH. Complete reversal of established PH by fluoxetine provides a rationale for new therapeutic strategies in human PH.
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Contributeur : Christophe Guignabert <>
Soumis le : dimanche 11 juillet 2010 - 16:05:23
Dernière modification le : mercredi 21 mars 2018 - 18:57:29
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Christophe Guignabert, Bernadette Raffestin, Rima Benferhat, William Raoul, Patricia Zadigue, et al.. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats.: 5-HT Transporter Inhibition Prevents PH. Circulation, American Heart Association, 2005, 111 (21), pp.2812-9. 〈10.1161/CIRCULATIONAHA.104.524926〉. 〈inserm-00499643〉

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