Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats.
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.


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


CONCLUSIONS
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.
Guignabert
Christophe
C
Département de Physiologie, INSERM U492, AP-HP, CHU Henri Mondor, Créteil, France.
Raffestin
Bernadette
B
Benferhat
Rima
R
Raoul
William
W
Zadigue
Patricia
P
Rideau
Dominique
D
Hamon
Michel
M
Adnot
Serge
S
Eddahibi
Saadia
S
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D016686:Monocrotaline / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D051381:Rats; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
D005473:Fluoxetine; D016686:Monocrotaline; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors