POSITIVE MODULATION OF PEPSINOGEN SECRETION BY GASTRIC-ACIDITY AFTER VAGAL CHOLINERGIC STIMULATION

Parallel increments of gastric acid and pepsinogen secretion generally occur after the application of cholinergic stimuli. However, it still remains to be established whether the changes in acid output associat ed with cholinergic stimulation play a role in regulation of the conco mitant peptic secretory activity. In the present study, an anesthetize d rat model was used for the evaluation of pepsinogen secretion in ord er to pursue a dual purpose: I)to assess the relative functional relev ance of direct and acid-dependent control exerted by cholinergic pathw ays on pepsinogen output; 2) to characterize the mechanisms through wh ich changes in acidity within the stomach lumen may affect the peptic secretory activity of gastric mucosa. Bethanechol, 2-deoxy-D-glucose o r electrical vagal stimulation caused parallel and atropine-sensitive increments of peptic and acid secretions. Omeprazole, a selective inhi bitor of gastric H+:K+-adenosintriphosphatase, blocked the increase in acid but not pepsinogen secretion induced by bethanechol. However, 2- deoxy-D-glucose or electrical vagal stimulation failed to increase eit her pepsinogen or acid secretion in omeprazole-pretreated rats. When t ested in animals pretreated with both omeprazole and physostigmine (a drug able to prevent the enzymatic breakdown of vagally released ACh t hrough the blockade of acetylcholinesterase), 2-deoxy-D-glucose or ele ctrical vagal stimulation significantly increased pepsinogen secretion without affecting acid secretion. In omeprazole-pretreated rats, perf usion of the gastric lumen with acid solutions caused a pH-dependent a nd atropine-sensitive increase in peptic output only when applied in c ombination with electrical vagal stimulation. Functional ablation of c apsaicin-sensitive sensory neurons did not modify the gastric secretor y responses induced by bethanechol or electrical vagal stimulation. Ho wever, after topical application of lidocaine to the gastric mucosal s urface, bethanechol stimulated both peptic and acid outputs, whereas e lectrical vagal stimulation only evoked acid secretion without affecti ng basal peptic output. The present results indicate that the activati on of muscarinic receptors by vagally released ACh is not sufficient b y itself to stimulate pepsinogen secretion and that a facilitatory act ion mediated by acid secretion is necessary to allow an increment of p eptic output in response to vagal cholinergic stimuli. it is suggested that such facilitatory input is driven to chief cells by local intram ural reflexes that involve capsaicin-insensitive intrinsic nerves.