Affinity For Histamine Research Articles

An in vitro characterization of gamma-glutamylhistamine synthetase: a novel enzyme catalyzing histamine metabolism in the central nervous system of the marine mollusk, Aplysia californica.

The properties of the histamine metabolizing enzyme, gamma-glutamylhistamine synthetase (gamma-GHA synthetase) were studied in Aplysia ganglia in vitro. This enzyme catalyzes the incorporation of histamine into peptide linkage with L-glutamate to form a peptidoamine, gamma-glutamylhistamine (gamma-GHA). gamma-GHA synthetase is a soluble enzyme with an apparent Km of 653 microM for histamine and 10.6 mM for L-glutamate. Synthesis of gamma-GHA is energy-dependent, having an absolute requirement for ATP. Magnesium ions and dithiothreitol are also essential for activity. Of a variety of gamma-glutamyl compounds and glutamate analogs tested, only L-glutamate was effectively incorporated into peptide linkage with histamine. Similarly, the enzyme has a higher affinity for histamine than for numerous imidazole analogs. In addition, 3,4-dihydroxyphenylethylamine (dopamine), 5-hydroxytryptamine, octopamine, and several other amines tested are effective inhibitors of gamma-GHA synthesis. Ganglia, nerve trunks, and the capsule surrounding the ganglion had the highest synthetase activity. The specific activity of the enzyme in muscle, heart, and hemolymph was less than 10% of that in ganglia. Differences in substrate specificity and effect of inhibitors distinguish gamma-GHA synthetase from gamma-glutamyl transpeptidase, glutamine synthetase, and carnosine synthetase.

Histamine H1-receptor binding sites in guinea pig brain membranes: regulation of agonist interactions by guanine nucleotides and cations.

Abstract: Agonist, but not antagonist, interactions with histamine H2‐receptors labeled by [3H]mepyramine are regulated selectively by sodium, divalent cations, and guanine nucleotides. Sodium decreases the affinity of histamine and the agonist 2‐amino‐ethylpyridine for [3H]mepyramine sites in guinea pig brain membranes up to 10‐fold. The effect of sodium is exerted to a lesser extent by lithium, while potassium and rubidium are much weaker. Guanine nucleotides also decrease the affinity of histamine for H1 binding sites about twofold. GTP and its nonmetabolized analogue GMP‐PNP as well as GDP exert similar effects, while GMP, ATP, ADP, and AMP are inactive. The effects of GTP and sodium on histamine interactions with H1‐receptors are additive. By contrast, certain divalent cations enhance the potency of histamine at H1‐receptors. Manganese is most potent, while magnesium is almost as active as manganese and calcium is essentially inactive. Sodium, divalent cations, and guanine nucleotides have negligible effects on the interactions of antihistamines with H1‐receptors.

Chemistry and Storage Function of Mast Cell Granules

The mast cell reacts to allergens and other degranulating agents with sequential exocytosis. Beginning in the cell periphery with fusions between granule membranes and the plasma membrane, the process proceeds inwards and sidewards with intergranule fusions that result in the formation of vacuoles and more or less extensive cavities. The fusion processes are accompanied by morphological changes in part of the granules, which lose their surrounding membranes, swell, and become less electron-dense. Part of these changed granules are dispersed around the cell; others remain inside the formed cavities. Because all formed cavities are in communication with the extracellular space, all changed granules, regardless of whether they are inside or outside the cell, become exposed to the extracellular cation-containing fluid. The matrix of the basophil granules is composed mainly of a heparin-protein complex with the properties of a weak cation exchange material in which protein carboxyls serve as histamine binding ionic sites. Because the affinities for histamine and sodium at the granule sites are equal and the concentration of sodium present in the extracellular fluid (150 mM) is about 100 times higher than that required for saturation of the granule binding sites (1–10 mM), histamine is immediately released by cation exchange when, during exocytosis and degranulation, the changed mast cell granules devoid of their surrounding membranes are exposed to the extracellular fluid.

CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FORMATION IN GUINEA‐PIG BRAIN SLICES: EFFECT OF H1‐ AND H2‐HISTAMINERGIC AGONISTS

Abstract—A variety of histamine analogs elicit accumulations of radioactive cyclic AMP in guinea‐pig neocortical and hippocampal slices labelled during a prior incubation with [14C]adenine. The H1agonist, 2‐aminoethylthiazole, elicits accumulation of cyclic AMP in neocortical and hippocampal slices both in the absence or presence of adenosine. The presence of adenosine increases the maximum response to 2‐aminoethylthiazole and decreases the EC50 by nearly 10‐fold. In the absence of adenosine the effects of 2‐aminoethylthiazole are antagonized in hippocampal slices by both d‐brompheniramine and metiamide, while in the presence of adenosine only d‐brompheniramine is an effective antagonist. The H2‐agonist, 4‐methylhistamine, elicits a somewhat smaller accumulation of cyclic AMP than does 2‐aminoethylthiazole in both cortical and hippocampal slices. In the presence of adenosine the response to 4‐methylhistamine is enhanced, but is markedly lower than that seen with the combination of adenosine and 2‐aminoethylthiazole. The dose‐response relationship for 4‐methylhistamine in the presence of adenosine appears in hippocampal slices to consist of two components. The response to 4‐methylhistamine in the absence of adenosine is blocked by metiamide, while in the presence of adenosine the response is partially blocked by both H1 and H2‐antagonists. The accumulation of cyclic AMP elicited by histamine is greatly increased by adenosine but the EC50 is not significantly decreased. The results suggest that (i) both H1‐ and H2‐receptors regulate cyclic AMP‐formation in the central nervous system, (ii) the synergism between adenosine and histamine is mediated primarily by interaction with H1‐receptors and (iii) that adenosine greatly increases the affinity of the H1‐receptors for both H1 and H2‐agonists without affecting its affinity for histamine.

Effects of temperature on the responses to noradrenaline, isoprenaline and histamine on isolated rabbit mesenteric artery.

On the rabbit mesenteric artery, the elevation of temperature from 25 degrees up to 42 degrees diminished the affinity of histamine, whereas that of noradrenaline to the alpha-adrenoceptors remained unchanged. The presence of beta-adrenoceptors could not be demonstrated.

Ionic binding of histamine in mast cell granules.

AbstractHistamine‐containing granu!es were isolated from rat mast cells by differential centrifugation. The histamine was released on suspension of the granules in a medium containing sodium. By using radioactive sodium (22Ta) the release of histamine was shown to be due to an exchange with sodium at ionic sites in the granules. The affinity of histamine was calculated to he about 10 times that o sodium. The pH dependence of the release of histamine and the uptake of sodium agrees with an ionic binding to weak acid groups [carboxylic groups] and not to strong acid groups (sulphate groups) as previously stated. Whether these hindins groups belong to the heparin or the protein in the granules remains to be decided.

The sulfomucopolysaccharides from a mast cell tumor of the mouse

Sulfomucopolysaccharides prepared from a murine mast cell tumor were fractionated by chromatography on Ecteola, by precipitation with cetyltrimethylammonium bromide, and by paper chromatography. The crude extract of murine sulfomucopolysaccharides, when extracted by the same procedure that was used to extract bovine Sulfomucopolysaccharides, was associated with nitrogen-rich material, unlike the comparable bovine preparation. The nitrogen-rich heparin-containing material, which was precipitable with 0.25 M NaCl and strongly adsorbed to Ecteola, was immobile upon paper chromatography. Examination of material prepared in the same way from bovine lung, guinea pig lung, a canine mastocytoma, and the lung and kidney of the rat, showed that only the tissues of the rat, like the murine mast cells, contained an immobile component. Purified murine sulfomucopolysaccharide showed a greater affinity for histamine and 5-hydroxytryptamine than did bovine sulfomucopolysaccharide. It is suggested that the relatively greater affinity of the murine sulfomucopolysaccharide for amino-containing compounds explains the high concentration of nitrogen in crude extracts of the murine sulfomucopolysaccharide.

Relation between the fixation of histamine by cancerigenic hydrocarbons and the solvent effect

A relationship is observed between the action of certain solvents on cancerogenesis and the affinity of histamine for cancerproducing substances. Tw-type solvents, which increase the tumoral incidence brought about by a chemical substance, intensify the reaction of histamine with this substance; while PEG-type solvents, which retard tumorogenesis, inhibit the reaction.

Binding of histamine in mammalian tissues.

MUCH of the histamine in mammalian tissues is contained in tissue mast cells1; but it is by no means certain how it is held at high concentration inside these cells. Evidence suggests that the mast cells do not produce the histamine but have a specific faculty of storing this compound. However, storage does not occur until metachromatically staining granules of heparin become visible in the cytoplasm of the cells. Experiments have been carried out, therefore, to study the affinity of histamine and heparin for one another.

Homosexuality and Prostitution

Previously, a novel series of 1<i>H</i>-4-substituted imidazole compounds were described as potent and selective histamine (HA) H₃ receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H₃ receptor affinity and central nervous system penetration by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H₃ receptor with the development of high affinity HA H₃ receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H₃receptor-binding affinities using [³H]N^α-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H₃ receptor affinity provided some of the most potent HA H₃ receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H₃ receptors with a <i>K</i>_i of 0.125 nM. In vivo, GT-2331 has a favorable central nervous system penetration profile with an ED₅₀ of 0.08 mg/kg (i.p.) in rats and a long duration of action (<i>T</i>_1/2 &gt; 4 h). In addition, GT-2331 was extremely selective for the HA H₃receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H₃ receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H₃ receptor.