CCK1 and CCK2 receptors regulate gastric pepsinogen secretion

The present study investigated (1) the pharmacological profile of cholecyst okinin (CCK) receptor subtypes involved in the regulation of gastric pepsin ogen secretion, (2) the influence of gastric acidity on peptic responses in duced by CCK-8-sulfate (CCK-8S) or gastrin-I; and (3) the mechanisms accoun ting for the effects of CCK-like peptides on pepsinogen secretion. In anaes thetized rats, i.v. injection of CCK-8S or gastrin-I increased both pepsino gen and acid secretion. The pepsigogue effect of CCK-8S was higher than tha t of gastrin-I, whereas acid hypersecretion after CCK-8S was lower than tha t induced by gastrin-I. Peptic output following CCK-8S was partly blocked b y i.v, injection of the CCK, receptor antagonist, devazepide (- 75.3%), or the CCK 2 receptor antagonist, L-365,260 [3R(+)-N-(2,3-dihydro-1-methyt-7-o xo-5-phenyl-1H-1,4-benzodiazepine-3yl)-N'-(3-methyl-phenyl)urea; - 27.9%], but was fully prevented by combined administration of devazepide and L-365, 260. The gastric acid hypersecretory effect of CCK-8S was enhanced by devaz epide (+ 84.5%) and blocked by r-365,260. In contrast, the gastric secretor y actions of gastrin-I were insensitive to devazepide, but abolished by L-3 65,260. Excitatory effects of CCK-8S and gastrin-I were not modified by vag otomy or atropine, whereas cimetidine or alpha-fluoromethylhistidine (irrev ersible blocker of histidine decarboxylase) partly prevented acid hypersecr etion induced by both peptides without affecting their pepsigogue effects. After pretreatment with omeprazole, both CCK-8S and gastrin-I failed to sti mulate acid secretion, while they increased pepsinogen output. In rats with gastric perfusion of acid solutions, CCK-8S or gastrin-I increased peptic output in a pH-indepxndent manner either with or without pretreatment with omeprazole. Ablation of capsaicin-sensitive sensory nerves as well as appli cation of lidocaine to the gastric mucosa failed to modify the excitatory e ffects of CCK-8S or gastrin-I on pepsinogen and acid secretion. Blockade of the nitric oxide (NO) synthase pathway by N-G-nitro-L-arginine-methyl este r prevented the pepsigogue actions of both CCK-8S and gastrin-I (-61.8% and -71.7%, respectively), without affecting the concomitant increase in acid output. In addition, both these peptides significantly increased the releas e of NO breakdown products into the gastric lumen. The present results sugg est that: (1) both CCK, and CCK, receptors mediate the peptic secretory res ponses induced by CCK-like peptides; (2) the excitatory inputs of CCK-8S an d gastrin-I to chief cells are not driven through acid-dependent mechanisms or capsaicin-sensitive afferent sensory nerves; and (3) under in vivo cond itions, the stimulant actions of CCK-like peptides on pepsinogen secretion are mediated, at least in part, by an increase in NO generation. (C) 1999 E lsevier Science B.V. All rights reserved.