This Article Full Text Full Text (PDF) All Versions of this Article: 200210-1212OCv1 168/4/487    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marcos, E. Articles by Eddahibi, S. Search for Related Content PubMed PubMed Citation Articles by Marcos, E. Articles by Eddahibi, S.

Serotonin Transporter Inhibitors Protect against Hypoxic Pulmonary Hypertension

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-HT_1B/1D and 5-HT_2A 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-HT_1B/1D receptor antagonist GR127935 (2 and 10 mg/kg/day), or the 5-HT_2A 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

This article has been cited by other articles:

				S. Rich and M. Rabinovitch Diagnosis and Treatment of Secondary (Non-Category 1) Pulmonary Hypertension Circulation, November 18, 2008; 118(21): 2190 - 2199. [Full Text] [PDF]

				A. Chaouat, R. Naeije, and E. Weitzenblum Pulmonary hypertension in COPD Eur. Respir. J., November 1, 2008; 32(5): 1371 - 1385. [Abstract] [Full Text] [PDF]

				K. Boutet, D. Montani, X. Jais, A. Yaici, O. Sitbon, G. Simonneau, and M. Humbert Review: Therapeutic advances in pulmonary arterial hypertension Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 249 - 265. [Abstract] [PDF]

				A. E. Linder, W. Ni, T. Szasz, R. Burnett, J. Diaz, T. J. Geddes, D. M. Kuhn, and S. W. Watts A Serotonergic System in Veins: Serotonin Transporter-Independent Uptake J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 714 - 722. [Abstract] [Full Text] [PDF]

				V. Jakoubek, J. Bibova, J. Herget, and V. Hampl Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1638 - H1644. [Abstract] [Full Text] [PDF]

				E. Fornaro, D. Li, J. Pan, and J. Belik Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1035 - 1040. [Abstract] [Full Text] [PDF]

				O. Sanchez, E. Marcos, F. Perros, E. Fadel, L. Tu, M. Humbert, P. Dartevelle, G. Simonneau, S. Adnot, and S. Eddahibi Role of Endothelium-derived CC Chemokine Ligand 2 in Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1041 - 1047. [Abstract] [Full Text] [PDF]

				A. E. Linder, W. Ni, J. L. Diaz, T. Szasz, R. Burnett, and S. W. Watts Serotonin (5-HT) in Veins: Not All in Vain J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 415 - 421. [Abstract] [Full Text] [PDF]

				S. Laudi, S. Trump, V. Schmitz, J. West, I. F. McMurtry, H. Mutlak, U. Christians, J. Weimann, U. Kaisers, and W. Steudel Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L630 - L638. [Abstract] [Full Text] [PDF]

				R. F. Wideman, M. E. Chapman, K. R. Hamal, O. T. Bowen, A. G. Lorenzoni, G. F. Erf, and N. B. Anthony An Inadequate Pulmonary Vascular Capacity and Susceptibility to Pulmonary Arterial Hypertension in Broilers Poult. Sci., May 1, 2007; 86(5): 984 - 998. [Abstract] [Full Text] [PDF]

				O. Distler and A. Pignone Pulmonary arterial hypertension and rheumatic diseases--from diagnosis to treatment Rheumatology, October 1, 2006; 45(suppl_4): iv22 - iv25. [Abstract] [Full Text] [PDF]

				K. R. Stenmark, K. A. Fagan, and M. G. Frid Hypoxia-Induced Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms Circ. Res., September 29, 2006; 99(7): 675 - 691. [Abstract] [Full Text] [PDF]

				D. Zolkowska, R. B. Rothman, and M. H. Baumann Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 604 - 610. [Abstract] [Full Text] [PDF]

				W. Ni, K. Lookingland, and S. W. Watts Arterial 5-Hydroxytryptamine Transporter Function Is Impaired in Deoxycorticosterone Acetate and N{omega}-Nitro-L-Arginine But Not Spontaneously Hypertensive Rats Hypertension, July 1, 2006; 48(1): 134 - 140. [Abstract] [Full Text] [PDF]

				M. de Caestecker Serotonin Signaling in Pulmonary Hypertension Circ. Res., May 26, 2006; 98(10): 1229 - 1231. [Full Text] [PDF]

				J. Callebert, J. M. Esteve, P. Herve, K. Peoc'h, C. Tournois, L. Drouet, J. M. Launay, and L. Maroteaux Evidence for a Control of Plasma Serotonin Levels by 5-Hydroxytryptamine2B Receptors in Mice J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 724 - 731. [Abstract] [Full Text] [PDF]

				S. Eddahibi and S. Adnot From functional to genetic studies of a candidate gene for pulmonary hypertension: any point? Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 693 - 694. [Full Text] [PDF]

				Y. Liu and B. L. Fanburg Serotonin-Induced Growth of Pulmonary Artery Smooth Muscle Requires Activation of Phosphatidylinositol 3-Kinase/Serine-Threonine Protein Kinase B/Mammalian Target of Rapamycin/p70 Ribosomal S6 Kinase 1 Am. J. Respir. Cell Mol. Biol., February 1, 2006; 34(2): 182 - 191. [Abstract] [Full Text] [PDF]

				C. Guignabert, B. Raffestin, R. Benferhat, W. Raoul, P. Zadigue, D. Rideau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats Circulation, May 31, 2005; 111(21): 2812 - 2819. [Abstract] [Full Text] [PDF]

				K. Nouette-Gaulain, M. Malgat, C. Rocher, J.-P. Savineau, R. Marthan, J.-P. Mazat, and F. Sztark Time course of differential mitochondrial energy metabolism adaptation to chronic hypoxia in right and left ventricles Cardiovasc Res, April 1, 2005; 66(1): 132 - 140. [Abstract] [Full Text] [PDF]

				H. W. Farber and J. Loscalzo Pulmonary Arterial Hypertension N. Engl. J. Med., October 14, 2004; 351(16): 1655 - 1665. [Full Text] [PDF]

				M. Humbert, O. Sitbon, and G. Simonneau Treatment of Pulmonary Arterial Hypertension N. Engl. J. Med., September 30, 2004; 351(14): 1425 - 1436. [Full Text] [PDF]

				D. J. Welsh, M. Harnett, M. MacLean, and A. J. Peacock Proliferation and Signaling in Fibroblasts: Role of 5-Hydroxytryptamine2A Receptor and Transporter Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 252 - 259. [Abstract] [Full Text] [PDF]

				M. Humbert, N. W. Morrell, S. L. Archer, K. R. Stenmark, M. R. MacLean, I. M. Lang, B. W. Christman, E. K. Weir, O. Eickelberg, N. F. Voelkel, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 13S - 24S. [Abstract] [Full Text] [PDF]

				E. Marcos, E. Fadel, O. Sanchez, M. Humbert, P. Dartevelle, G. Simonneau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension Circ. Res., May 14, 2004; 94(9): 1263 - 1270. [Abstract] [Full Text] [PDF]

				M. R. MacLean, G. A. Deuchar, M. N. Hicks, I. Morecroft, S. Shen, J. Sheward, J. Colston, L. Loughlin, M. Nilsen, Y. Dempsie, et al. Overexpression of the 5-Hydroxytryptamine Transporter Gene: Effect on Pulmonary Hemodynamics and Hypoxia-Induced Pulmonary Hypertension Circulation, May 4, 2004; 109(17): 2150 - 2155. [Abstract] [Full Text] [PDF]

				M. J. Tobin Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003 Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313. [Full Text] [PDF]

				S. Eddahibi, A. Chaouat, N. Morrell, E. Fadel, C. Fuhrman, A.-S. Bugnet, P. Dartevelle, B. Housset, M. Hamon, E. Weitzenblum, et al. Polymorphism of the Serotonin Transporter Gene and Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease Circulation, October 14, 2003; 108(15): 1839 - 1844. [Abstract] [Full Text] [PDF]