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(Circulation. 2005;111:2812-2819.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats

Christophe Guignabert, PhD; Bernadette Raffestin, MD, PhD; Rima Benferhat, MS; William Raoul, PhD; Patricia Zadigue; Dominique Rideau; Michel Hamon, PhD; Serge Adnot, MD, PhD; Saadia Eddahibi, PhD

From the Département de Physiologie (C.G., R.B., P.Z., D.R., S.A., S.E.), INSERM U492, AP-HP, CHU Henri Mondor, Créteil; the Département de Physiologie (B.R.), Université René Descartes, Hôpital Ambroise Paré, AP-HP, UER Paris ouest, Boulogne; and INSERM U288 (M.H.), NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.

Correspondence to Saadia Eddahibi, PhD, INSERM U492, Faculté de Médecine, Créteil, France. E-mail saadia.eddahibi{at}creteil.inserm.fr

Received November 26, 2003; de novo received August 24, 2004; revision received November 26, 2004; accepted January 11, 2005.

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-1ß and monocyte chemotactic protein-1 increased at the early phase and stimulated 5-HTT expression by cultured PA-SMCs.

Conclusion— 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.

Key Words: pulmonary heart disease • remodeling • muscle, smooth

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