Mode of Action of a Gastric‐secretion Antagonist

Abstract

We embarked on the present study with the object of throwing light on the mode of action of gastrin. In this study a compound with specific antigastrin properties would seem to be useful. The actions of the pure natural peptides, gastrins I and II, in stimulating and inhibiting gastric acid secretion, as stimulants of pepsin and pancreatic secretion, and of gastric and small intestinal tone and motility, have been recorded by Tracy & Gregory (1964). Little is known of the mechanisms by which the gastrins display these numerous actions. As to the mode of action of gastrin in exciting acid secretion, pertinent facts have recently appeared. It was disclosed that injection of gastrin, as well as feeding, distension, and vagus stimulation, produced a striking and long lasting elevation of the histamine forming capacity (HFC) within the region of the parietal cells (Kahlson, Rosengren, Svahn & Thunberg, 1964;Kahlson, Rosengren & Thunberg, 1967). These authors further found that the mucosal histamine formed at high rates was sufficient to stimulate acid secretion, that additional histamine was formed only in the region containing parietal cells, that the elevation of HFC was not merely a concomitant of the process of secretion per se, and that the elevation of HFC occurred in all species studied.The authors believe that gastrin acts by evoking a mobilization of histamine and a concurrent acceleration of HFC, thus providing adequate amounts of histamine available for effective stimulation of acid secretion, so a specific antigastrin was expected to hinder the elevation of mucosal HFC without lowering the sensitivity of the parietal cells to histamine. The present experiments reveal that the newly synthesized compound antigastrin (Cook & Bianchi, 1967), 2-phenyl-2-(2-pyridyl)-thioacetamide (SC-15396) inhibits acid secretion not by interfering with the elevation of mucosal HFC induced by gastrin but by rendering the parietal cells less sensitive to histamine. The lack of specificity is shown further by the present finding that antigastrin reduces the secretory response of the peptic cells to stimulation by gastrin and histamine. METHODS AnimalsThe rats used weighed about 200 g, and belonged to two strains; a strain bred at this Institute for gastric secretory studies, and Sprague-Dawley rats for determination of histamine forming capacity (HFC) of the glandular part of the gastric mucosa. Urinary histamine was estimated in the latter strain.

Elicidation by a H‐2‐receptor antagonist of the significance of mucosal histamine mobilization in exciting acid secretion.

“…This effect of Metiamide could be due to increased gastrin secretion facilitated by the increase in pH of the gastric juice, as previously noted e.g. after 'antigastrin' (Kahlson, Rosengren & Svensson, 1968;Kobayashi & Maudsley, 1968;HAkanson & Liedberg, 1971). The discrepancy between the in vivo and in vitro determinations of histamine mobilization by pentagastrin in the presence of Metiamide is perhaps attributed to the reported activation of the histamine methyl transferase by small doses of the H2-receptor antagonist (Barth, Niemayer & Lorenz 1973).…”

Inhibition of gastric secretion by atropine in conscious rats

“…Its site of action is presumably the parietal cell proper. In a previous study from this laboratory it was demonstrated that the alleged 'Antigastrin' SC-15396, 2-phenyl-2-(2-pyridyl)-thioacetamide, acts by greatly reducing the sensitivity of the parietal and peptic cells to a variety of secretorily effective modes of stimulation (Kahlson, Rosengren & Svensson, 1968). At the present stage it appears reasonable to assume that atropine also, in a non-specific way, lowers the responsiveness of the parietal cell to stimulating influences.…”

The secretory pattern of three stomach preparations in the rat

“…Rats in which augmented interdigestive secretion occurred were excluded from further use. The absence of visual motor response in the pouch, and its presence in the main stomach under electrical stimulation of the vagus nerves in the neck, was also taken as evidence of effective vagal denervation (Kahlson, Rosengren & Svensson, 1968).…”