CCK1 and CCK2 receptors regulate gastric pepsinogen secretion

Eur J Pharmacol. 1999 May 28;373(1):71-84. doi: 10.1016/s0014-2999(99)00212-5.

Abstract

The present study investigated (1) the pharmacological profile of cholecystokinin (CCK) receptor subtypes involved in the regulation of gastric pepsinogen secretion, (2) the influence of gastric acidity on peptic responses induced by CCK-8-sulfate (CCK-8S) or gastrin-I; and (3) the mechanisms accounting for the effects of CCK-like peptides on pepsinogen secretion. In anaesthetized rats, i.v. injection of CCK-8S or gastrin-I increased both pepsinogen and acid secretion. The pepsigogue effect of CCK-8S was higher than that of gastrin-I, whereas acid hypersecretion after CCK-8S was lower than that induced by gastrin-I. Peptic output following CCK-8S was partly blocked by i.v. injection of the CCK1 receptor antagonist, devazepide (-75.3%), or the CCK2 receptor antagonist, L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 yl)-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 devazepide (+84.5%) and blocked by L-365,260. In contrast, the gastric secretory actions of gastrin-I were insensitive to devazepide, but abolished by L-365,260. Excitatory effects of CCK-8S and gastrin-I were not modified by vagotomy or atropine, whereas cimetidine or alpha-fluoromethylhistidine (irreversible blocker of histidine decarboxylase) partly prevented acid hypersecretion induced by both peptides without affecting their pepsigogue effects. After pretreatment with omeprazole, both CCK-8S and gastrin-I failed to stimulate 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-independent manner either with or without pretreatment with omeprazole. Ablation of capsaicin-sensitive sensory nerves as well as application of lidocaine to the gastric mucosa failed to modify the excitatory effects 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 ester 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 release of NO breakdown products into the gastric lumen. The present results suggest that: (1) both CCK1 and CCK2 receptors mediate the peptic secretory responses induced by CCK-like peptides; (2) the excitatory inputs of CCK-8S and gastrin-I to chief cells are not driven through acid-dependent mechanisms or capsaicin-sensitive afferent sensory nerves; and (3) under in vivo conditions, the stimulant actions of CCK-like peptides on pepsinogen secretion are mediated, at least in part, by an increase in NO generation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / pharmacology
  • Anesthetics, Local / pharmacology
  • Animals
  • Benzodiazepinones / pharmacology
  • Capsaicin / pharmacology
  • Devazepide / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Gastric Acid / metabolism
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / enzymology*
  • Gastric Mucosa / metabolism
  • Gastrins / pharmacology
  • Histidine Decarboxylase / antagonists & inhibitors
  • Hormone Antagonists / pharmacology
  • Lidocaine / pharmacology
  • Male
  • Methylhistidines / pharmacology
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitrates / metabolism
  • Nitric Oxide / metabolism
  • Nitrites / metabolism
  • Nootropic Agents / pharmacology
  • Omeprazole / pharmacology
  • Pepsinogens / metabolism*
  • Perfusion
  • Phenylurea Compounds / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Cholecystokinin / agonists
  • Receptors, Cholecystokinin / antagonists & inhibitors
  • Receptors, Cholecystokinin / physiology*
  • Sincalide / analogs & derivatives
  • Sincalide / pharmacology
  • Somatostatin / pharmacology
  • Vagotomy

Substances

  • 8-sulfocholecystokinin octapeptide
  • Acids
  • Anesthetics, Local
  • Benzodiazepinones
  • Enzyme Inhibitors
  • Gastrins
  • Hormone Antagonists
  • Methylhistidines
  • Nitrates
  • Nitrites
  • Nootropic Agents
  • Pepsinogens
  • Phenylurea Compounds
  • Receptors, Cholecystokinin
  • Nitric Oxide
  • L 365260
  • Somatostatin
  • alpha-fluoromethylhistidine
  • gastrin I
  • Lidocaine
  • Histidine Decarboxylase
  • Devazepide
  • Omeprazole
  • Sincalide
  • Capsaicin
  • NG-Nitroarginine Methyl Ester