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Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: Role of endogenous endothelin-1

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Abstract

Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosenthan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.

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Authors and Affiliations

  1. Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, 305, Tsukuba-shi, Ibaraki, Japan

    Kazuhiko Matsumaru, Hiromasa Kashimura, Mahmudul Hassan, Akira Nakahara, Hiroshi Muto, Naomi Tanaka & Hisayuki Fukutomi

  2. Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, 305, Tsukuba-shi, Ibaraki, Japan

    Katsutoshi Goto

  3. Pharmaceutical Research Laboratory, Hitachi Chemical Co. Ltd., Ibaraki, Japan

    Takashi Hayashi & Riko Iwata

Authors
  1. Kazuhiko Matsumaru
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  2. Hiromasa Kashimura
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  3. Mahmudul Hassan
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  4. Akira Nakahara
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  5. Takashi Hayashi
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  7. Katsutoshi Goto
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  9. Naomi Tanaka
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  10. Hisayuki Fukutomi
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Matsumaru, K., Kashimura, H., Hassan, M. et al. Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: Role of endogenous endothelin-1. J Gastroenterol 32, 164–170 (1997). https://doi.org/10.1007/BF02936362

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  • DOI: https://doi.org/10.1007/BF02936362

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