N-Methyl, 5-Methyl Histamine Evokes a Higher Maximal Rate of Gastric Acid Secretion than Histamine

Abstract

Histamine H2 receptor antagonists counteract those actions of histamine, such as stimulation of gastric acid secretion, that are not blocked by the older antihistaminics, histamine H1 receptor antagonists (1). Accordingly, histamine receptors are now classified on the basis of which of these two types of blockers counteract the action in question. By this classification, stimulation of gastric acid secretion by histamine is an H2 action since it is inhibited by H2 but not by H1 antihistaminics. Similarly, analogs of histamine with histamine-like action can be classified according to the degree of selectivity they show for H1 or H2 receptors. Two monomethyl derivatives of histamine, one with a methyl group on the imidazole ring, 5-methyl histamine (2), and one with a methyl group on the side chain nitrogen, N-methyl histamine (3), have been shown to have selectivity for histamine H2 receptors including gastric acid secretion. We report here that the dimethyl derivative corresponding to each of these two monomethyl histamines evokes higher maximal acid secretion than histamine in cats with gastric fistulas.Methods. N-me thyl-2-( 5-me thyl-4-imida-zoly1)ethylamine (in this presentation called N-methyl, 5-methyl histamine and abbreviated DMH for dimethyl histamine) was synthesized and purified by methods that will be described elsewhere. Preliminary studies showed that DMH was about 1000 times more potent for an H2 action, stimulation of auricular rate, than for an H1 action, contraction of guinea pig ileum (4). The tests reported here were done in cats (3to 9-kg body weight) with plastic cannulas in the stomach forming a permanent gastric fistula ( 5 ) . Gastric juice was collected continuously and divided into 15-min samples. Acid concentration was measured by elec-trometric titration to pH 7.0 with 0.2 M NaOH. All drugs were given intravenously through an indwelling catheter inserted into a leg vein at the start of each test. Each dose of stimulant was given for 30 min and was immediately followed by the next higher dose. The significance of differences between means was determined by Student's t test for paired values.Results. The first set of tests (Fig. 1A) compared acid secretory responses to graded doses of DMH and histamine. The maximal response to DMH was significantly ( P cO.02) greater than to histamine.The second set of tests (Fig. 1B) compared the acid secretory response to graded doses of histamine given alone with the response to the same doses of histamine given against a background of a constant dose of a histamine H 1 receptor antagonist, pyrilamine. The maximal response to histamine plus pyrilamine was significantly ( P <0.02) greater than to histamine alone.The third set of tests (Fig. 1C) compared the acid secretory response to graded doses of DMH alone with the response to DMH given against a background of a constant dose of histamine. The dose of histamine was double the dose needed for maximal response. The maximal response to DMH was significantly lower ( P C0.02) in the presence of the back...

Inhibition of acid formation and stimulation of somatostatin release by cholecystokinin‐related peptides in rabbit gastric glands.

“…Interestingly, the addition of histamine seems to further increase the release of somatostatin, implying that histamine, besides its ability to stimulate acid secretion, may also evoke inhibition of gastric acid secretion. Such a dual action of histamine has in fact already been suggested from 25 2 in vivo experiments with a histamine analogue (Impicciatore, Bertaccini, Mossini, Hansen & Grossman, 1977). It is a well-known observation that the aminopyrine uptake in gastric glands following histamine stimulation decreases on prolonged ( > 20-30 min) incubation.…”

OCCURRENCE OF H,‐ AND H2‐HISTAMINE RECEPTORS IN THE GUINEA‐PIG GALL BLADDER in situ

“…The introduction of a specific H1-receptor agonist, 242-aminoethyl)thiazolene (Levi, Ganellin, Allen & Willms, 1975;Durant, Ganellin & Parsons, 1975), of H2-specific agonists, N-methyl-2-(5-methyl-4-imidazolyl)ethylamine (Impicciatore Bertaccini, Mossini, Hansen & Grossman, 1977) and - [S-[3(N, N dimethylamino)propyl]isothiourea] (Parsons, Owen, Ganellin & Durant, 1977) and on the other hand the discovery of a specific H2-receptor blocking agent, cimetidine (Brimblecombe, Duncan, Durant, Emmet, Ganellin & Parsons, 1975), provided important tools in the identification and analysis of the histamine receptors. The aim of this research was to investigate the actions of histamine on the guinea-pig gall bladder in situ in which it exerts a dose-dependent spasmogenic effect (Bertaccini De Caro, Endean, Erspamer & Impicciatore, 1968) and to identify the receptors involved.…”