Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension.
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.
Marcos
Elisabeth
E
INSERM U492, Faculté de Médecine, CHU Henri Mondor, 94010 Créteil, France.
Adnot
Serge
S
Pham
Minh Hien
MH
Nosjean
Anne
A
Raffestin
Bernadette
B
Hamon
Michel
M
Eddahibi
Saadia
S
D000704:Analysis of Variance; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002908:Chronic Disease; D015283:Citalopram / Q000627:therapeutic use; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D000860:Hypoxia / Q000517:prevention & control*; D007650:Ketanserin / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010069:Oxadiazoles / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D018709:Statistics, Nonparametric
D002352:Carrier Proteins; D015283:Citalopram; D005473:Fluoxetine; D007650:Ketanserin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C090701:GR 127935