Erquan Zhang1, Junko Maruyama1,2, Ayumu Yokochi1, Yoshihide Mitani3, Hirofumi Sawada1,3, Masakatsu Nishikawa4, Ning Ma5, Kazuo Maruyama6. 1. Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. 2. Faculty of Medical Engineering, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie, 510-0293, Japan. 3. Department of Pediatrics, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. 4. Department of Institute of Human Research Promotion and Drug Development, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. 5. Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie, 510-0293, Japan. 6. 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.
Abstract
PURPOSE: 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.
PURPOSE: 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 hypoxicrats and decreased the MMP-13 mRNA in lung tissue in chronic hypoxicrats. CONCLUSIONS: The administration of SPG ameliorated the development of chronic hypoxic PH and hypertensive pulmonary vascular changes.
Authors: Yidan D Zhao; David W Courtman; Yupu Deng; Lakshmi Kugathasan; Qiuwang Zhang; Duncan J Stewart Journal: Circ Res Date: 2005-02-03 Impact factor: 17.367