Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats.
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(₂A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(₂B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.
Dumitrascu
R
R
University of Giessen Lung Center, Germany.
Kulcke
C
C
Königshoff
M
M
Kouri
F
F
Yang
X
X
Morrell
N
N
Ghofrani
H A
HA
Weissmann
N
N
Reiter
R
R
Seeger
W
W
Grimminger
F
F
Eickelberg
O
O
Schermuly
R T
RT
Pullamsetti
S S
SS
D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008090:Lisuride / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016040:Lung Transplantation; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*
D018491:Dopamine Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; C006208:dironyl; D016686:Monocrotaline; D008090:Lisuride