Role of cyclooxygenase-1 and-2, phospholipase C, and protein kinase C in prostaglandin-mediated gastroprotection

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-((17beta-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-((17beta-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 mug/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 cromakalim-sensitive 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.