Acceleration of ulcer healing by cholecystokinin (CCK): role of CCK-A receptors, somatostatin, nitric oxide and sensory nerves

CCK exhibits a potent cytoprotective activity against acute gastric lesions , but its role in ulcer healing has been little examined. In this study we determined whether exogenous CCK or endogenously released CCK by camostate, an inhibitor of luminal proteases, or by the diversion of pancreatico-bili ary secretion from the duodenum, could affect ulcer healing. In addition, t he effects of antagonism of CCK-A receptors (by loxiglumide, LOX) or CCK-B receptors (by L-365,260), an inhibition of NO-synthase by NG-nitro-L-argini ne (L-NNA), or sensory denervation by large neurotoxic dose of capsaicin on CCK-induced ulcer healing were examined. Gastric ulcers were produced by s erosal application of acetic acid and animals were sacrificed 9 days after ulcer induction. The area of ulcers and blood flow at the ulcer area were d etermined. Plasma levels of gastrin and CCK and luminal somatostatin were m easured by RIA and mucosal biopsy samples were taken for histological evalu ation and measurement of DNA synthesis. CCK given s.c. reduced dose depende ntly the ulcer area; the threshold dose of CCK being 1 nmol/kg and the dose inhibiting this area by 50% being 5 nmol/kg. This healing effect of CCK wa s accompanied by a significant increase in the GBF at ulcer margin and the rise in luminal NO production, plasma gastrin level and DNA synthesis. Conc urrent treatment with LOX, completely abolished the CCK-8-induced accelerat ion of the ulcer healing and the rise in the GBF at the ulcer margin, where as L-365,260 remained without any influence. Treatment with camostate or di version of pancreatic juice that raised plasma CCK level to that observed w ith administration of CCK-8, also accelerated ulcer healing and this effect was also attenuated by LOX but not by L-365,260. Inhibition of NO-synthase by L-NNA significantly delayed ulcer healing and reversed the CCK-8 induce d acceleration of ulcer healing, hyperemia at the ulcer margin and luminal NO release, and these effects were restored by the addition to L-NNA of L-a rginine but not D-arginine. Capsaicin denervation attenuated CCK-induced ul cer healing, and the accompanying rise in the GBF at the ulcer margin and d ecreased plasma gastrin and luminal release of somatostatin when compared t o those in rats with intact sensory nerves. Detectable signals for CCK-A an d B receptor mRNAs as well as for cNOS mRNA expression were recorded by RT- PCR in the vehicle control gastric mucosa. The expression of CCK-A receptor mRNA and cNOS mRNA was significantly increased in rats treated with CCK-8 and camostate, whereas CCK-B receptor mRNA remained unaffected. We conclude that CCK accelerates ulcer healing by the mechanism involving upregulation of specific CCK-A receptors, enhancement of somatostatin release, stimulat ion of sensory nerves and hyperemia in the ulcer area, possibly mediated by NO. (C) 1999 Elsevier Science BN. All rights reserved.