Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension

Am J Respir Crit Care Med. 2003 Aug 15;168(4):487-93. doi: 10.1164/rccm.200210-1212OC. Epub 2003 May 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Chronic Disease
  • Citalopram / therapeutic use
  • Disease Models, Animal
  • Fluoxetine / therapeutic use
  • Hypertension, Pulmonary / prevention & control*
  • Hypertrophy, Right Ventricular / prevention & control
  • Hypoxia / prevention & control*
  • Ketanserin / therapeutic use
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Transport Proteins*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Muscle, Smooth, Vascular / drug effects
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Oxadiazoles / therapeutic use
  • Piperazines / therapeutic use
  • Pulmonary Artery / drug effects
  • Receptors, Serotonin / drug effects
  • Serotonin Antagonists / therapeutic use*
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors / therapeutic use
  • Statistics, Nonparametric

Substances

  • Carrier Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Oxadiazoles
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, mouse
  • Fluoxetine
  • Citalopram
  • GR 127935
  • Ketanserin