P. Del Soldato

Effects of autonomic nervous system on gastric damage by ethanol in the rat

To study whether or not the autonomic nervous system influences the defense mechanisms of the gastric mucosa, groups of Sprague-Dawley rats were given stimulants and inhibitors of the different components of the vagus and celiac nerves before administration of absolute or 70% w/v ethanol. The effects of vagotomy and sympathectomy on “adaptive cytoprotection” were studied, as were the effects of blocking the muscarinic receptors and stimulation of β-adrenergic receptors. We found that: (1) cholinomimetic agents and norepinephrine make the damage caused by 70% ethanol worse; (2) atropine is the only agent that fully protects against absolute ethanol; (3) vagotomy and sympathectomy abolish the effects of atropine and adaptive cytoprotection; and (4) β-adrenergic stimulation replaces conditions that allow adaptive cytoprotection and the protection by anticholinergics. These results suggest that two different reflexes are triggered by ethanol: when low concentrations are given, the β-adrenergic-mediated effect is prevalent, with protection of the mucosa; when high concentrations are given, the cholinergic- mediated effect is prevalent with damage of the mucosa.

Protection of gastric mucosa in rats. Differences between vagotomy, atropine, and PGE2.

We have studied the protective effects of truncal vagotomy, atropine, and PGE2 against gastric mucosal injury produced by necrotizing agents (0.2 N NaOH, 0.6 N HCl, absolute ethanol), acetylsalicylic acid (ASA) and HCl, or serotonin (5HT). Vagotomy, atropine, and PGE2 prevent the effects of different noxious agents. Vagotomy is protective only against 5HT and against ASA+0.15 N or 0.35 N HCl, whereas atropine and PGE2 are also protective against the necrotizing agents. The effectiveness of vagotomy against ASA+0.35 N HCl does not depend on the inhibition of acid secretion and supports the hypothesis that removal of the vagal drive counteracts the effect of H+ back-diffusion.

Studies of the factors that influence acetylsalicylic acid-induced gastric damage in stressed rats.

The ability of H2-receptor antagonists (cimetidine, ranitidine, tiotidine) and antimuscarinic agents (atropine and pirenzepine) to prevent gastric damage induced by acetylsalicylic acid (ASA) was determined in stressed rats. The results obtained were as follows: 1) H2-receptor antagonists were ineffective; 2) antimuscarinic agents significantly reduced the gastric pathology in a dose-related manner. These findings are discussed in an attempt to elucidate the mechanism(s) involved in the pathogenesis of ASA-induced gastric damage in stressed rats.

A rat model based on the histamine H2-receptor-activation-induced gastric pathology

Summary On the basis of a universally recognized hypothesis about the involvement of H2-receptors in the pathogenesis of peptic ulcer, an appropriate rat model has been designed with dimaprit as the specific H2-receptor agonist. Cimetidine and ranitidine, known to comparatively inhibit H2-receptors are shown to be quite effective in preventing gastric damage, in a dose-related manner. The influence of compounds known to interfere with acid secretion processes or histamine H2-receptors on dimaprit induced damage was studied in the attempt of assessing the specificity and selectivity of this ulcer model.

Pharmacodynamic evaluation of selective antimuscarinic properties of pirenzepine in the rat

Summary Central and peripheral antimuscarinic properties of pirenzepine following either oral or intravenous administration were evaluated in the rat, in comparison to atropine. Pirenzepine, unlike atropine, was shown to be devoid of central effects and to possess a marked selectivity toward the gastric muscarinic receptors. This selectivity is mainly directed toward the stomach: gastric ulcer and acid secretion inhibition can be achieved at lower doses than other secretions (salivation, lachrymation). Particularly, the oral ED 50 values of pirenzepine for inhibiting oxotremorine induced gastric ulcer and salivation were 0.4 mg/kg and 30 mg/kg, respectively orally, 13 and 620 μg/kg respectively by intravenous administration. On the other hand the ED 50 values of atropine for inhibiting the same parameters were 30 μg/kg and 550 μg/kg orally and 5.8 and 4.2 μg/kg intravenously. The ratios of the intravenous ED 50 values inhibiting the other measured symptoms to the therapeutic (anti-ulcer) effect were: o 1) pirenzepine — 11 for lachrymation, 48 for salivation, greater than 2308 for tremors, 2) atropine — 1.1 for lachrymation, 0.7 for salivation, 14 for tremors. These findings are discussed, in the attempt to correlate them with data of binding affinity studies.