Involvement of endogenous cholecystokinin and somatostatin in gastroprotection induced by intraduodenal fat

Duodenal fat such as oleate is known to influence gut functions by release of cholecystokinin (CCK), but the contribution of CCK endogenously released by duodenal fat or by diversion of pancreatic juice from the duodenum in t he mechanism of mucosal integrity and gastroprotection has been little stud ied. This study was designed to compare the effect of CCK-8 and intraduoden al (i.d.) instillation of sodium oleate, or diversion of the pancreatic bil iary secretions that are known to release CCK, on the gastric mucosal lesio ns induced by topical application of 100% ethanol or acidified aspirin (ASA ) in rats with or without the pretreatment with a CCK-A receptor antagonist , loxiglumide, or with L-365,260 to block CCK-B receptors. In addition, the effect of suppression of prosta glandin (PG) biosynthesis by indomethacin (5 mg/kg i.p.), inhibition of nitric oxide (NO)-synthase by L-NAME (5 mg/kg i.v.), or blockade of sensory nerves by capsaicin (125 mg/kg s.c.) on the protective activity of sodium oleate was determined. Sodium oleate (50-200 mM i.d.), or diversion of pancreatic juice from the duodenum for 3 h that p roduced significant rise in plasma CCK levels, significantly reduced gastri c lesions induced by 100% ethanol to an extent similar to that induced by e xogenous CCK-S (5 nmol/kg s.c.). The protective effect of oleate or diversi on of pancreatic juice was accompanied by an increase in gastric blood flow (GBF). Both protection and accompanying hyperemia were completely abolishe d by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an an tagonist of CCK-B receptors, had no effect. Oleate given i.d. significantly attenuated acidified ASA-induced gastric lesions and gastric secretion whi le increasing the luminal concentration of somatostatin. These effects were significantly reduced by loxiglumide but not by L-365,260. In contrast, CC K-8, which stimulated gastric acid secretion, failed to affect the lesions induced by acidified ASA and the decrease in the GBF produced by this ulcer ogen. Indomethacin, which suppressed PG generation by similar to 90%, faile d to influence the protective activity of oleate or CCK-8 against ethanol-i nduced lesions, whereas L-NAME, vagotomy, or sensory denervation significan tly attenuated this protection and accompanying hyperemia. Addition to L-NA ME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK-S and duodenal oleate against gastric lesions induced by et hanol or acidified ASA. We conclude that endogenous CCK released by oleate or diversion of pancreatic secretion exerts a potent gastroprotective actio n on the stomach involving predominantly CCK-A receptors and depending on v agal activity, and hyperemia mediated by NO and sensory nerves but unrelate d to acid secretory effects and endogenous PG.