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Published ahead of print on May 28, 2003, doi:10.1164/rccm.200210-1212OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 487-493, (2003)
© 2003 American Thoracic Society

Original Article

Serotonin Transporter Inhibitors Protect against Hypoxic Pulmonary Hypertension

Elisabeth Marcos, Serge Adnot, Minh Hien Pham, Anne Nosjean, Bernadette Raffestin, Michel Hamon and Saadia Eddahibi

Département de Physiologie, INSERM U 492, AP-HP, CHU Henri Mondor, Créteil; Département de Physiologie, Université Versailles-Saint Quentin en Yvelines, Hôpital Ambroise Paré, AP-HP, UFR Paris-Ile de France, Ouest, Boulogne; and INSERM U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris Cedex 13, France

Correspondence and requests for reprints should be addressed to Saadia Eddahibi, INSERM U492, Faculté de Médecine, CHU Henri Mondor, 94010 Créteil, France. E-mail: saadia.eddahibi{at}creteil.inserm.fr

Pulmonary hypertension (PH) results from constriction and remodeling of pulmonary vessels. Serotonin contributes to both phenomena through different signaling pathways. The mitogenic effect of serotonin on pulmonary vascular smooth muscle cells is mediated by the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), whereas its constricting effect is mediated by 5-HT1B/1D and 5-HT2A receptors. Here, we investigated the respective roles of 5-HTT and 5-HT receptors on the development of chronic hypoxic PH in mice. During exposure to hypoxia (10% O2 for 2 weeks), the animals received one of the specific 5-HTT inhibitors citalopram and fluoxetine (10 mg/kg/day), the selective 5-HT1B/1D receptor antagonist GR127935 (2 and 10 mg/kg/day), or the 5-HT2A receptor antagonist ketanserin (2 mg/kg/day). Mice treated with the 5-HTT inhibitors showed less right ventricle hypertrophy (ratio of right ventricle/left ventricle + septum = 36.7 ± 2.0% and 35.8 ± 1.3% in citalopram- and fluoxetine-treated mice, respectively, vs. 41.5 ± 1.5% in vehicle-treated mice) and less pulmonary vessel muscularization (p < 0.01) than those receiving the vehicle. Neither GR127935 nor ketanserin affected these parameters. These data indicate that 5-HTT plays a key role in hypoxia-induced pulmonary vascular remodeling. The effects of serotonin transporter inhibitors on PH in humans deserve investigation.

Key Words: pulmonary hypertension • serotonin transporter • chronic hypoxia • serotonin receptors




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