DIFFERENT EFFECTS OF INDOMETHACIN AND NABUMETONE ON PROSTAGLANDIN-MEDIATED GASTRIC RESPONSES TO CENTRAL VAGAL ACTIVATION IN RATS

Intracisternal injection of a stable thyrotropin-releasing hormone (TR H) analog increases gastric prostaglandins release and mucosal resista nce to injury through central vagal pathways. The effects of two nonst eroidal anti-inflammatory drugs, indomethacin (INDO) and nabumetone on intracisternal injection of various doses of TRH-induced gastric acid secretion and changes in mucosal resistance were investigated in uret hane-anesthetized rats. Doses of INDO (5 mg/kg) and nabumetone (13.75 mg/kg) producing similar acute anti-inflammatory response in the carra geenin-induced paw edema were injected i.p. in all studies. INDO poten tiated the acid secretion induced by intracisternal injection of TRH a t 25, 50 and 200 ng by 5.1-, 1.9- and 1.4-fold, respectively, whereas nabumetone did not modify the secretory response to TRH. Moderate eros ions were observed in 100% of rats treated with the combination of IND O and TRH (200 ng) whereas no erosions were observed when TRH or INDO were given alone or TRH in combination with nabumetone. TRH at 7 ng re duced mucosal damage induced by intragastric administration of ethanol (60%, 1 ml/kg) by 63%. The mucosal protective action of TRH was aboli shed by INDO but not altered by nabumetone pretreatment. These data in dicate that at comparable anti-inflammatory doses, nabumetone, unlike INDO, neither blocks the protection against ethanol injury induced by low doses of TRH injected intracisternally nor potentiates the gastric acid secretion or lesions induced by higher dose of TRH. We speculate that these differences reflect reduced inhibition of gastric prostagl andins by nabumetone.