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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Cyclooxygenase-1 and -2, Phospholipase C, and Protein Kinase C in Prostaglandin-Mediated Gastroprotection

Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Bochum, Germany (B.M.P., N.S., K.E.); and Department of Experimental and Clinical Pharmacology, University of Graz, Graz, Austria (B.A.P.)

Oral administration of the nonselective cyclooxygenase (COX) inhibitor indomethacin (20 mg/kg), the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (20 mg/kg), or the COX-2 inhibitor rofecoxib (1–20 mg/kg) antagonized the gastroprotective effects of 16,16-dimethyl-prostaglandin (PG) E₂ (75 ng/kg p.o.) and 20% ethanol in rats. The effects of the COX inhibitors were reversed by the activator of ATP-sensitive potassium (K_ATP) channels cromakalim (0.3–0.5 mg/kg p.o.). The protective effects of 16,16-dimethyl-PGE₂ and 20% ethanol were counteracted by the phospholipase C inhibitor 1-(6-((17-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U-73122), but not its inactive analog 1-(6-((17-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-2,5-pyrrolidine-dione (U-73343) (1 mg/kg each i.v.). Likewise, the protein kinase C inhibitors chelerythrine (0.7 mg/kg i.v.) and staurosporine (3 µg/kg i.v.) inhibited gastroprotection. Effects of these enzyme inhibitors were not reversed by cromakalim. Submaximally effective doses of SC-560 (0.2 mg/kg p.o.) and rofecoxib (0.02 mg/kg p.o.) were additive and abolished the protection induced by 20% ethanol. The findings show that inhibition of COX-1 or COX-2 antagonizes not only adaptive gastroprotection by 20% ethanol but also the protective effect of exogenous PG in a cromakalimsensitive manner. Endogenous PG obviously add to the protective activity of exogenous PG. Gastroprotection by PG involves phospholipase C, protein kinase C, and K_ATP channels. Activation of K_ATP channels does not exert protection when the activity of phospholipase C or protein kinase C is suppressed.

Address correspondence to: Dr. Brigitta M. Peskar, Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Universitaetsstr. 150, D-44801 Bochum, Germany. E-mail: brigitta.m.peskar{at}ruhr-uni-bochum.de

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