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) E 2 (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-PGE 2 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 g/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.Orally administered 16,16-dimethyl-prostaglandin (PG) E 2 as well as endogenous PG released by 20% ethanol have been shown to be gastroprotective against 70% or absolute ethanol in rats (Robert et al., 1983(Robert et al., , 1985Gretzer et al., 1998). The gastroprotection by various agents, including 20% ethanol, is not only inhibited by indomethacin but also by the blocker of ATP-sensitive potassium (K ATP ) channels glibenclamide (Peskar et al., 2002). These findings suggest that the mechanism of action of endogenous PG involves the activation of K ATP channels. Similarly, the gastroprotective effect of exogenous PG is antagonized by glibenclamide (Peskar et al., 2002). The specificity of the antagonism has been demonstrated by the use of the K ATP channel activator cromakalim, which reverses the glibenclamide effects (Standen et al., 1989;Quayle et al., 1995). We have now further investigated the isoenzyme specificity and mechanisms of action of PG in gastroprotection. For this purpose, we have studied the effects of the nonselective cyclooxygenase (COX) inhibitor indomethacin, the COX-1 selective inhibitor SC-560 (Smith et al., 1998), and the COX-2 selective inhibitor rofecoxib (Chan et al., 1999) on gastroprotection conferred by 16,16-dimethyl-PGE 2 as well as endogenous PG, which mediate adaptive gastroprotection. Because it has been...
