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Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats

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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.

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Acknowledgments

This study was supported in part by Grants-In-Aid for Scientific Research from the Japanese Association for the Promotion of Science. The authors thank Ms. A Okada and N Hiramtsu for the technical and secretarial assistance.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Erquan Zhang, Junko Maruyama, Ayumu Yokochi, Hirofumi Sawada & Kazuo Maruyama

  2. Department of Pediatrics, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Yoshihide Mitani & Hirofumi Sawada

  3. Department of Institute of Human Research Promotion and Drug Development, Mie University school of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Masakatsu Nishikawa

  4. Faculty of Medical Engineering, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie, 510-0293, Japan

    Junko Maruyama

  5. Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie, 510-0293, Japan

    Ning Ma

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  1. Erquan Zhang
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Correspondence to Kazuo Maruyama.

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Zhang, E., Maruyama, J., Yokochi, A. et al. Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats. J Anesth 29, 715–723 (2015). https://doi.org/10.1007/s00540-015-2015-y

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  • DOI: https://doi.org/10.1007/s00540-015-2015-y

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