Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats.
OBJECTIVE
The purpose of the present study was to determine if sarpogrelate hydrochloride (SPG), a serotonin 5HT2A receptor antagonist, prevented the development of chronic hypoxia-induced pulmonary hypertension (PH) and hypertensive pulmonary vascular remodeling.


METHODS
Forty-one male Sprague-Dawley rats were exposed to hypobaric hypoxia (380 mmHg, 10 % oxygen) or room air and administered 50 mg/kg SPG or vehicle by gavage once daily from day -2 to day 14. The mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodelings were assessed morphometrically by light microscopy. Serotonin-induced contraction was determined in isolated pulmonary artery rings from 24 rats. In another set of rats, Western blotting, real-time polymerase chain reaction and immunofluorescent staining (n = 9) for lung tissue were performed.


RESULTS
Chronic hypoxia induced a rise in mean PAP and RVH, increased the percentage of muscularized arteries in peripheral pulmonary arteries and medial wall thickness in small muscular arteries, and potentiated serotonin-induced contraction, each of which was significantly (p < 0.05) ameliorated by SPG. Chronic hypoxia significantly increased the expression of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) protein levels, cyclic guanosine monophosphate, and matrix metalloproteinase-13 (MMP-13) mRNA levels in whole lung tissues. SPG increased peNOS expression in the immunofluorescent staining of peripheral pulmonary arteries from chronic hypoxic rats and decreased the MMP-13 mRNA in lung tissue in chronic hypoxic rats.


CONCLUSIONS
The administration of SPG ameliorated the development of chronic hypoxic PH and hypertensive pulmonary vascular changes.
Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Erquan
E
Zhang
Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.|Faculty of Medical Engineering, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie, 510-0293, Japan.
Junko
J
Maruyama
Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Ayumu
A
Yokochi
Department of Pediatrics, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Yoshihide
Y
Mitani
Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.|Department of Pediatrics, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Hirofumi
H
Sawada
Department of Institute of Human Research Promotion and Drug Development, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Masakatsu
M
Nishikawa
Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie, 510-0293, Japan.
Ning
N
Ma
Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. k-maru@clin.medic.mie-u.ac.jp.
Kazuo
K
Maruyama
D000818:Animals; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000187:drug effects; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology*
D044402:Receptor, Serotonin, 5-HT2A; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; D052250:Nitric Oxide Synthase Type III
Hypoxia; Nitric oxide; Pulmonary hypertension; Sarpogrelate hydrochloride; Serotonin 2A receptor