G. Bertaccini

Evidence that acetylcholine released by gastrin and related polypeptides contributes to their effect on gastrointestinal motility.

Abstract Gastrin- and cholecystokinin-like polypeptides have been found to release acetylcholine from the Auerbach plexus of longitudinal muscle strips of guinea pig ileum. The evidence is consistent with the view that contractions of intestine in response to these peptides are due to the acetylcholine released. Tetrodotoxin inhibited actions of peptides both on acetylcholine release and on mechanical responses of intestine; however, hexamethonium failed to affect their actions, indicating that their site of action is situated on non-nicotinic receptors of ganglionic cells. C-terminal octapeptide amide of cholecystokinin-pancreozymin and caerulein produced significant acetylcholine release in concentrations as low as 9 × 10 −10 and 7.5 × 10 −10 M, respectively. Human gastrin I was much less effective, its threshold concentration being 7 × 10 −8 M. Both exogenous and endogenous noradrenaline reduced both the acetylcholine release and the contractions of longitudinal muscle produced by peptides. Noradrenaline acted at a presynaptic site and its action was mediated through α receptors. It is concluded that gastrointestinal hormones may play a role as hormonal factors in regulating gastrointestinal motility, and their effect is continuously controlled by the tonic activity of the sympathetic nervous system which reduces acetycholine release.

Acetylcholine-releasing effect of gastrin and related polypeptides

Abstract The effect of gastrin and related polypeptides on acetylcholine release from the Auerbach plexus of guinea pig longitudinal muscle strip were studied. Gastrin, octapeptide amide of cholecystokinin, pentagastrin and caerulein released acetylcholine from longitudinal muscle strip. Noradrenaline and tetrodotoxin prevented both release of acetylcholine and contraction of the intestine produced by gastrin and related polypeptides.

Cholinergic-like effects of the new histamine H2-receptor antagonist ranitidine

The new H2-receptor blocker ranitidine, together with the effect on histamine H2-receptors, possesses a series of cholinergic-like actions: it provokes atropine-sensitive contractions of several isolated smooth muscle preparations from different animal species and it potentiates the stimulant effect of acetylcholine. Moreover it contracts human lower esophageal sphincterin vivo, an effect which is completely prevented by small doses of atropine. Finally, ranitidine potentiates the stimulant effect of bethanechol and of carbachol on salivary glands of the rat while leaving unaffected the secretagogue effect of physalaemin which is known to be completely independent of the cholinergic system. In thein vivo experiments the doses of ranitidine capable of eliciting cholinergic-like effects were of the same order of magnitude as those necessary to cause the H2-receptor blockade.

The actions of bombesin on gastric secretion of the dog and the rat

1 Bombesin stimulated acid secretion from the denervated fundic pouch of the dog. Whereas the concentration of hydrochloric acid in bombesin‐produced juice was always higher than in control juice this did not occur for pepsin, the concentration of which remained below the basal values. The threshold dose of bombesin was 5–30 ng/kg by the subcutaneous route and 0·05–0·2 (μg/kg)/h by intravenous infusion. At low doses bombesin was more active than caerulein, even on a molar basis, and at high dose levels was as active as caerulein. In contrast to gastrin and caerulein, bombesin elicited a moderate secretory response also following rapid intravenous injection. 2 The acid secretion provoked by bombesin was almost completely inhibited by atropine and reduced by approximately 50% by hexamethonium. 3 Bombesin did not stimulate acid secretion in the lumen‐perfused preparation of the rat stomach when administered by subcutaneous injection (up to 10 μg/kg) or by intravenous infusion (up to 10 (μg/kg)/hour). An irregular increase in acid output was observed only following rapid intravenous injection and this was of doubtful significance. 4 The mechanism of the secretagogue action of bombesin on the dog stomach is discussed.

An update on histamine H3 receptors and gastrointestinal functions

The distribution and functions of histamine H3 receptors in the gastrointestinal tract is reviewed with particular reference to the effects on gastric acid secretion, mucosal protection, and intestinal motility. Histamine H3 receptor activation has negative effects on acid secretion induced by indirect secretagogues in cats, dogs, and rabbits; less clear effects were found in rats. An inhibitory effect on histamine release induced by different stimuli was observed in rats, rabbits, and dogs after H3 receptor agonists, thus supporting the idea that H3 receptors occur in ECL cells. (R)-α-methylhistamine has a marked protective effect against gastric lesions induced by ethanol in rats, being slightly less effective against aspirin and stress. H3 receptor activation decreases the intestinal motility induced by electrical stimulation in a variety of gut preparations, reducing both cholinergic and NANC neurotransmitter release. In this tissue the inhibitory effects mediated by histamine H3 receptors seem to be coupled, via a G protein, to a restriction of Ca2+ access into the nerve terminal; other mechanisms, however, have been suggested in the gastric mucosa. Histamine H3 receptors have already been subdivided into two receptor subtypes, H3A and H3B, the former being the subtype predominant in the gastrointestinal tissue. The increasing availability of selective agonists and antagonists of H3 receptors will unravel possible novel actions and physiological roles of histamine.

The effect of physalaemin and related polypeptides on salivary secretion.

In the course of a systematic pharmacological study on active polypeptides occurring in nature, it was observed that eledoisin, found in the posterior salivary glands of two molluscan species, Eledone moschata and E. aldrovandi (Erspamer & Falconieri Erspamer, 1962) and physalaemin, found in the skin of a South-American amphibian Physalaemus fuscumaculatus (Bertaccini, Erspamer & Cei, 1965) injected intravenously or subcutaneously into dogs caused, besides a marked hypotension, a profuse atropine-resistant salivation. This effect was present both in normal and anaesthetized animals, suggesting that it was independent from nausea and vomiting which always followed administration of large doses of eledoisin or physalaemin in unanaesthetized dogs. It was deemed of interest to extend the research to other animal species and to investigate more thoroughly this side-effect of the polypeptides. Attention was paid mainly to physalaemin, the most powerful polypeptide so far described in nature, in order to elucidate the mechanism of its sialogenous action.

HISTAMINE H2‐ANTAGONISTS MODIFY GASTRIC EMPTYING IN THE RAT

1 Histamine H2‐receptor antagonists were tested for their effect on gastric emptying in the rat. 2 At low doses all the compounds were inactive except for burimamide which delayed and ranitidine which accelerated gastric emptying. 3 At high doses burimamide, metiamide, Cimetidine and oxmetidine delayed, whereas ranitidine accelerated gastric emptying; tiotidine remained ineffective. 4 Changes in emptying rate were not accompanied by changes in emptying pattern which, with all the compounds examined, proceeded, as in the controls, by apparent first order kinetics. 5 The mechanism of the ranitidine‐induced acceleration of gastric emptying seemed to be connected with an interference with the cholinergic system, whereas the mechanism of cimetidine‐ and oxmetidine‐induced slowing of gastric emptying was apparently related to cholinolytic and possibly also relaxant effects of the compounds. 6 These different effects of the various H2‐blockers are consistent with the idea that changes in emptying rate are independent of H2‐receptor blockade.

Presence of caerulein in extracts of the skin of Leptodactylus pentadactylus labyrinthicus and of Xenopus laevis

1 The South American amphibian Leptodactylus pentadactylus labyrinthicus and the South African amphibian Xenopus laevis contain in their skin a polypeptide indistinguishable from caerulein prepared from the Australian amphibian Hyla caerulea. 2 The caerulein content of different batches of Leptodactylus pentadactylus labyrinthicus skins varies from 10 to 500–600 μg/g tissue. Drying of the skin causes either a moderate decrease or a slight increase in the caerulein content. Methanol extraction gives considerably higher yields of caerulein than acetone extraction. 3 Caerulein or caerulein‐like polypeptides also occur in the skin of several other species of Leptodactylus together with 5‐hydroxyindole alkylamines and imidazole alkylamines. Yet other species of Leptodactylus lack caerulein‐like polypeptides and 5‐hydroxyindole alkylamines. 4 It is suggested that caerulein and caerulein‐like polypeptides may have some function either in the regulation of secretory processes of the skin or in the exchange of water and electrolytes through the skin, or in both.

Cholecystokinetic activity of the new peptide Caerulein in man

Summary Caerulein was tested in 42 normal individuals and in 10 cholecystopathic subjects for its cholecystokinetic activity. The threshold cholecystokinetic dose was 0.5 to 1 ng per kg. The magnitude of the effect was satisfactorily dose dependent up to 20 ng per kg and lasted approximately 90 min. It seemed to be accompanied by a parallel spasmolytic effect on the Oddis sphincter. Harmful side effects were rarely, if ever, present. The possible importance of this new cholecystokinetic agent as a diagnostic agent in diseases of the biliary tract is discussed.

The Histamine H3 Receptor

Histamine is widely distributed in the body, although with marked quantitative differences in the various species and tissues, and it produces a variety of biological effects by interacting with specific receptors on the surface of target cells.