The Role of Histamine in Gastric Hydrochloric Acid Secretion

Lin, T. M.; Alphin, R. S.; Henderson, Francis G.; Benslay, D. N.; Chen, K. K.

doi:10.1111/j.1749-6632.1962.tb45284.x

Cited by 36 publications

(5 citation statements)

References 41 publications

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“…This observation is of particular significance since side-chain methylated derivatives of histamine are known to be more potent than histamine in eliciting acid secretion in the dog (Lin, Alphin, Henderson, Benslay & Chen, 1962;Code, Maslinski, Mossini & Navert, 1971) and also in the isolated guinea-pig stomach (Holton, Impicciatore & Spencer, 1975). Since N-methyl and N-dimethyl histamine are not metabolized by diamine oxidase (Lin et al 1962;Hill & Bardsley, 1975) we studied the catabolism of histamine during diamine oxidase blockade concomitantly by two independent methods in order to obtain information on a formation of these side-chain methylated compounds. The method determining [14C]histamine loss gave the same figure as that determining formation of ["4C]methylhistamine indicating no in vitro formation of '4C-N-methyl and N-dimethylhistamine.…”

Section: Discussionmentioning

confidence: 99%

Histamine metabolism of the guinea‐pig gastric mucosa.

Bergmark¹,

Granérus²,

Henningsson³

et al. 1976

The Journal of Physiology

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1. The mobilization of gastric mucosal histamine as reflected by changes in formation and content has been studied in guinea‐pigs on feeding and after injections of pentagastrin or 2‐deoxy‐D‐glucose. 2. Re‐feeding fasting guinea‐pigs as well as injections of pentagastrin or 2‐deoxy‐D‐glucose raised the rate of mucosal histamine formation; pentagastrin induced a fourfold rise. 3. Some properties of the enzyme catalysing the formation of histamine were examined. The results indicated that this enzyme is histidine decarboxylase, L‐histidine carboxy‐lyase, E.C. 4.1.1. 22. 4. The enzyme imidazole‐N‐methyl transferase, E.C. 2.1.1.8, which carries out methylation of the imidazole ring to yield 1‐methyl‐4‐(beta‐aminoethyl)imidazole (methylhistamine), was found in high amounts in the mucosa. The enzyme did not change upon stimulation of the mucosa. 5. The metabolism of histamine within the gastric mucosa is discussed in relationship to a suggested role of the amine in exciting acid secretion.

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Section: Discussionmentioning

confidence: 99%

Histamine metabolism of the guinea‐pig gastric mucosa.

Bergmark¹,

Granérus²,

Henningsson³

et al. 1976

The Journal of Physiology

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“…A group of 8 dogs was treated by two batches of either Makrodex| Haemaccel| Gelifundol | and Plasmasteril| or by gelatin cross-finked by succinic acid anhydride (Neoplasmagel| Braun Melsungen), phosphatidyl serine (100 gg/kg i.v., PS, Lipid Products, South Nutfield), Makrodex | + PS and Plasmasteril| + PS. In the test persons plasma histamine [3], heart rate (ECG) and blood pressure (sphygmomanometric) were determined [4]. In the dogs whole blood histamine by the combined method [2] and blood pressure (Statham) were measured and the macroscopical and microscopical pathology was investigated.…”

Section: Methodsmentioning

confidence: 99%

“…2-Methyl-histamine preferentially stimulates histamine Hcreceptors, whereas 5(4)-methyl-histamine is a selective HE-receptor stimulating agonist.In order to determine the effect of substitution at C-5(4) of the imidazole nucleus on the interaction with H t and H2-receptors, various aliphatic, alicyclic and aromatic substituents were introduced at this position.Since the side chain methylated N~-methyl-histamine is active at both histamine receptors [2], being particularly more potent than histamine in evoking the stimulation of gastric acid secretion in the dog [3,4] and in the cat [5], N ~-methylated derivates of the C-5(4) substituted histamines were also prepared.In an attempt to demonstrate the stereoselectivity of atrial H2-receptors 5-amino-4,5,6,7-tetrahydrobenzimidazole [6] (ATHB), a racemic compound in which the histamine side chain is fixed by integration into a ring system, was resoluted into its optical isomers which were then investigated on their H t-and H2-activity. …”

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confidence: 99%

Structure-activity relationship of histamine H2-receptor agonists

et al. 1978

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Methylation of histamine at the imidazole nucleus leads to most selective agonists [1, 2]. 2-Methyl-histamine preferentially stimulates histamine Hcreceptors, whereas 5(4)-methyl-histamine is a selective HE-receptor stimulating agonist.In order to determine the effect of substitution at C-5(4) of the imidazole nucleus on the interaction with H t and H2-receptors, various aliphatic, alicyclic and aromatic substituents were introduced at this position.Since the side chain methylated N~-methyl-histamine is active at both histamine receptors [2], being particularly more potent than histamine in evoking the stimulation of gastric acid secretion in the dog [3,4] and in the cat [5], N ~-methylated derivates of the C-5(4) substituted histamines were also prepared.In an attempt to demonstrate the stereoselectivity of atrial H2-receptors 5-amino-4,5,6,7-tetrahydrobenzimidazole [6] (ATHB), a racemic compound in which the histamine side chain is fixed by integration into a ring system, was resoluted into its optical isomers which were then investigated on their H t-and H2-activity. MethodsOptically active dibenzoyl-tartaric acid was used for resolution of the racemic mixture. The absolute configuration was determined by optical-rotatory-dispersion measurements [7] of the optically active N-phthalimido-4,5,6,7-tetrahydrobenzimidazoles.All compounds were tested on isolated strips of guinea-pig ileum (Ha) [1,8] and on the isolated spontaneously beating guinea-pig right atrium (HE) [1]. ResultsThe intrinsic activities, pD2-values, the agonist activities relative to histamine and the activity ratios estimated at both types of receptors were reported.N~-Methyl-histamine is distinctly more potent than histamine in stimulating atrial HE-receptors.Among several active derivates the C-5(4) methyl and ethyl-analogues of histamine and of N~-methyl-histamine are selective H2-receptor agonists with full intrinsic activity. Among them the N~,5(4)-dimethyl-histamine proved to be active with the same degree of selectivity as the known H xagonist 5 (4)-methyl-histamine.Of the two optical isomers of ATHB the S(-)-enantiomer is apparently more active at atrial H2-receptors than its R(+)-antipode, both equally showing little activity at ileal H t-receptors. ConclusionsAs demonstrated by the results the active C-5(4) substituted histamines and N'~-methyl-histamines are to various extents selective H2-receptor agonists.

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“…This failure may have been due to inadkquate doses of histamine or antihistaminic, to species differences, or to unidentified factors. Lin (7) showed that a histamine H1 receptor antagonist increased the acid secretion in response to histamine in an anesthetized cat but he did not establish that the maximal response was increased.…”

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confidence: 97%

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

Impicciatore

Bertaccini

Mossini

et al. 1977

Experimental Biology and Medicine

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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...

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The Role of Histamine in Gastric Hydrochloric Acid Secretion

Cited by 36 publications

References 41 publications

Histamine metabolism of the guinea‐pig gastric mucosa.

Histamine metabolism of the guinea‐pig gastric mucosa.

Structure-activity relationship of histamine H2-receptor agonists

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

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