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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Roles of Endogenous Prostaglandins and Cyclooxygenase Isozymes in Healing of Indomethacin-Induced Small Intestinal Lesions in Rats

Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan

The role of prostaglandins (PGs)/cyclooxygenase (COX) in the healing of indomethacin-induced small intestinal ulcers was examined in rats. Animals were given indomethacin (10 mg/kg s.c.) and killed 1, 2, 3, 5, and 7 days later. Indomethacin (2 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC560; COX-1 inhibitor; 3 mg/kg), and rofecoxib (COX-2 inhibitor; 3 mg/kg) were given p.o. once daily for 6 days, during the first 3 days or last 3 days of the experimental period. All COX inhibitors given for 6 days significantly impaired the healing of these ulcers. Healing was also impaired by rofecoxib given for the first 3 days or by SC560 given for the last 3 days. The expression of COX-2 mRNA in the intestine was up-regulated after ulceration, persisting for 3 days and dissipating thereafter. Mucosal PGE₂ contents decreased within 3 h after ulceration, recovered 24 h later, and increased above normal 13 days later. The PGE₂ content at 4 days after ulceration was decreased by rofecoxib but not SC560, whereas that at 7 days was suppressed by SC560 but not rofecoxib. Vascular content in the ulcerated mucosa decreased when the healing was impaired by COX inhibitors. The deleterious effect of indomethacin on healing was mimicked by a prostacyclin E receptor (EP) 4 antagonist and reversed by coadministration of PGE₂ as well as an EP4 agonist. In conclusion, endogenous PGs play a role in the healing of intestinal ulcers through EP4 receptors, yet the COX isozyme involved differs depending on the stage of healing; COX-2 in the early stage and COX-1 in the late stage.

Address correspondence to: Dr. Koji Takeuchi, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan. E-mail: takeuchi{at}mb.kyoto-phu.ac.jp

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