Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats.
OBJECTIVE
It has been reported that serotonin (5-HT) is involved in the development of pulmonary arterial hypertension (PAH) with pulmonary vascular remodeling. The purpose of the present study was to examine the role of a 5-HT2A receptor antagonist, sarpogrelate hydrochroride, in preventing or reversing monocrotaline (MCT)-induced PAH in rats.


METHODS
Rats were injected with 40 mg/kg of MCT subcutaneously and randomized to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for 3 weeks. Animals treated with MCT and survived for 3 weeks were assigned to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for next 3 weeks. The animals had pressure measurement of the pulmonary artery, and then underwent histologic, immunohistochemical, and Western blot analyses of the lung tissue. Survival rate was also assessed after treatment.


RESULTS
Sarpogrelate immediately following MCT injection suppressed PAH with severe pulmonary vascular remodeling and right-sided heart failure. The survival rate was significantly increased in the sarpogrelate-treated group compared with the placebo group (71% vs. 44%, p<0.05). Intense expression of P-selectin was found on the endothelium of the pulmonary arteries in the placebo group, and it was markedly attenuated in the sarpogrelate-treated group. The numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen (PCNA)-positive cells in the lung tissue were significantly increased in the placebo group, and the increases in these cells were prevented by sarpogrelate. Endothelial nitric oxide synthase (eNOS) expression in the lung tissue was markedly decreased in the placebo group, but it was prevented by sarpogrelate (p<0.001). In contrast, late treatment with sarpogrelate failed to reverse established PAH.


CONCLUSIONS
Specific 5-HT2A receptor blockade with sarpogrelate immediately after MCT inhibited PAH and prolongs survival in rats. These effects were accompanied by anti-inflammatory and anti-proliferative effects in the lung tissue and marked improvement of pulmonary vascular endothelial dysfunction and activation.
Hironaka
Eiji
E
Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Hongo
Minoru
M
Sakai
Akio
A
Mawatari
Eiichiro
E
Terasawa
Fumiko
F
Okumura
Nobuo
N
Yamazaki
Akie
A
Ushiyama
Yoshihisa
Y
Yazaki
Yoshikazu
Y
Kinoshita
Osamu
O
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019007:P-Selectin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D013386:Succinates / Q000627:therapeutic use*; D015996:Survival Rate
D019007:P-Selectin; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat