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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 19, 2005; DOI: 10.1124/jpet.105.093195

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Received for publication July 25, 2005.
Revised October 14, 2005.
Accepted for publication October 17, 2005.

Roles of COX-2 and Prostacyclin/IP Receptors in Mucosal Defense against Ischemia/Reperfusion Injury in Mouse Stomach

Tohru Kotani 1, Atsushi Kobata 1, Eiji Nakamura 1, Kikuko Amagase 1, Koji Takeuchi 1*

1 Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University

* Address correspondence to: E-mail: takeuchi{at}mb.kyoto-phu.ac.jp

Abstract

We examined the roles of cyclooxygenase (COX) isozymes, prostaglandins (PGs) and their receptors in the mucosal defense against ischemia/reperfusion (I/R)-induced gastric lesions in mice. Male C57BL/6 mice, including wild-type animals and those lacking EP1-, EP3- or IP-receptors, were used after 18 hr fasting. Under urethane anesthesia, the celiac artery was clamped (ischemia) for 30 min, then reperfusion was achieved for 60 min through removal of the clamp, and the stomach was examined for lesions. I/R produced hemorrhagic gastric lesions in wild-type mice. The severity of lesions was significantly increased by pretreatment with indomethacin (a nonselective COX inhibitor) and rofecoxib (a selective COX-2 inhibitor) but not SC-560 (a selective COX-1 inhibitor). The expression of COX-2 mRNA was up-regulated in the stomach following I/R but not either sham-operation or ischemia alone. The ulcerogenic response was markedly aggravated in IP-receptor knockout mice but not those lacking EP1- or EP3-receptors. I/R increased the levels of 6-keto-PGF1{alpha} and PGE2 in the stomach of wild-type mice, and this response was attenuated by indomethacin and rofecoxib but not SC-560. Pretreatment of wild-type mice with iloprost, a prostacyclin (PGI2) analogue, significantly prevented the I/R-induced gastric lesions in the absence and presence of indomethacin or rofecoxib. PGE2 also reduced the severity of I/R-induced gastric lesions, yet the effect was much less pronounced than that of iloprost. These results suggest that endogenous PGs derived from COX-2 play a crucial role in gastric mucosal defense during I/R, and this action is mainly mediated by PGI2 through the activation of IP receptors.


Key words: IP receptors, IP-receptor knockout mouse, cyclooxygenase-2, endogenous prostaglandins, gastric injury induced by ischemia-reperfusion, prostacyclin


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