Histamine inactivation

Applying the analysis in the left-hand column to the results of Figure 1.24, Furchgott estimated Ka to be 10 pM for the combination of histamine with its receptors. He used this figure, and the values of q obtained as just described, to construct the dashed curves in the illustration. These lie close to the experimental points, which is certainly in keeping with the predictions of the approach taken. Just as certainly, this does not provide decisive proof that either the experimental or the theoretical suppositions that underlie it are correct. An important assumption, and one that is difficult to test, is that the irreversible antagonist has had no action other than to inactivate the receptors under study. Were it, for example, to have interfered with one or more of the steps that link receptor activation to the observed response, the approach would be invalid. Furchgott later showed that this was not a complication under the conditions he used. 

HA turnover is rapid in the brain, with a half-life of about 30 min. This can change very quickly depending on neuronal activity. There is no high-affinity uptake system for HA once released, HA is inactivated by catabolism. In the brain, released HA is methylated almost exclusively by the enzyme histamine-N-methyltransferase (E.C. 2.1.1.8). The tele-methyl-HA is subsequently degraded by monoamine oxidase-B (MAO-B) and aldehyde dehydrogenase to produce tele-methylimidazoleacetic acid (Brown et ah, 2001). 

Barnes, W. G. and Hough, L. B. Membrane-bound histamine N-methyltransferase in mouse brain possible role in the synaptic inactivation of neuronal histamine. /. Neurochem. 82 1262-1271, 2002. 

Bk has been shown to stimulate histamine release from isolated peritoneal rat mast cells [30, 87] and this secretory response, like that elicited by other peptides, requires a source of metabolic energy and is prevented by depletion of cellular Ca [30, 87]. The subsequent treatment of such cellular Ca-depleted mast cells with Bk produces an inactivation or desensitization phenomenon to the subsequent addition of extracellular Ca (secretion declines as the time... 

Desensitization (inactivation) of mast cells to a particular peptide (for example, bradykinin) or to compound 48/80, desensitizes the mast cells to further stimulation by another peptide or by compound 48/80 but not to IgE-dependent stimulation [3,86a, 87]. This suggests that peptides (and 48/80) share a common mechanism of action in eliciting histamine secretion and that they compete for a common binding site. 

Histamine is synthesized from the amino acid histidine by an action of the enzyme histidine decarboxylase (Fig. 38.1). Following synthesis, histamine is either rapidly inactivated or stored in the secretory granules of mast cells and basophils as an inactive complex with proteases and heparin sulfate or chondroitin sulfate. 

The inactivation of histamine is achieved both by enzymatic metabolism of the amine and by transport processes that reduce the concentration of the compound in the region of its receptors. Histamine metabolism occurs primarily through two pathways (Fig. 38.1). The most important of these involves histamine N-methyltransferase, which catalyzes the transfer of a... 

It inactivates many of the neurotransmitters in the synaptic gap or in the synapse if the latter are not protected by synaptic vesicles. The metabolism of NE, DA, 5-HT, tyramine, and histamine is thus taken care of by MAO as well as by some other enzymes. 

Histamine is formed by decarboxylation of the amino acid l -histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged. The major metabolic pathways involve conversion to /V-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites. 

Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most commonly used muscle relaxants in clinical practice. Although cisatracurium resembles atracurium, it has less dependence on hepatic inactivation, produces less laudanosine, and is less likely to release histamine. From the clinical perspective, cisatracurium has all the advantages of atracurium with fewer side effects. Therefore, cisatracurium has largely replaced atracurium in clinical practice. 

Receptors for histamine, which probably acts as a neuromodulator,801 occur in the brain.802 Histamine is formed by decarboxylation of histidine (p. 745)803 and is inactivated by histidine N-methyltransferase. Histamine is best known for its presence in mast cells,804 components of the immune system that release histamine during inflammatory and allergic reactions (Chapter 31). However, histaminergic neurons of the hypothalamus extend throughout the whole forebrain,805 and specific receptors have been found both in the brain and in peripheral tissues.806 Several other amines that are formed by decarboxylation of amino acids are present in trace amounts but may have im-... 

Eosinophils are attracted by proteins released by T cells, mast cells and basophils [eosinophil chemotactic factor of anaphylaxis (ECF-A)]. They bind schistosomulae coated with IgG or IgE, degranulate and release major basic protein, which is toxic. Eosinophils also release histaminase and aryl sulfatase, which inactivates histamine and Slow reacting substance of anaphylaxis (SRS-A). This results in antiinflammatory effects and inhibits migration of granulocytes to the site of injury. 

Gold alters the morphology and functional capabilities of human macrophages—possibly its major mode of action. As a result, monocyte chemotactic factor-1, interleukin-8, interleukin-IB production, and vascular endothelial growth factor are all inhibited. Intramuscular gold compounds also alter lysosomal enzyme activity, reduce histamine release from mast cells, inactivate the first component of complement, and suppress the phagocytic activities of polymorphonuclear leukocytes. Auranofin also inhibits release of prostaglandin E2 and leukotriene B4. 

Synthesis Histamine is an amine formed by the decarboxylation of the amino acid histidine (Figure 40.3). This process occurs primarily in the mast cells, basophils, and in the lungs, skin, and gastrointestinal mucosa—the same tissues in which histamine is stored. In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the polysulfated anion, heparin, along with an anionic protein. If histamine is not stored, it is rapidly inactivated by amine oxidase enzymes. 

However, if histamine release is too fast for inactivation to be efficient, a full-blown anaphylactic reaction occurs. (See p. 221 for a more complete discussion of allergic reactions.)... 

Exchange of the nicotinamide moiety of NADP for nicotinic acid, forming NAADP. Early studies also showed that the enzyme can catalyze exchange of nicotinamide with a variety of other bases, including histamine. Formation of histamine adenine dinucleotide phosphate was thought to provide an alternative to amine oxidase for rapid inactivation of histamine. 

Luse and M(iLaren (1963) have reviewed published research on the photolysis products and quantum yields tor the destruction of amino acids and have attributed the photochemical inactivation of the enzymes chymo-trypsin, lysozyme, ribonuclease, and trypsin by UV light at 254 m i primarily to destruction of the cystyl and tryptophyl residues. The destruction of these residues in proteins was suggested to be a function of the product of the number of residues present, the molecular extinction coefficient, and the quantum yield for destruction of each residue. Cysteine and tryptamine were identified among the irradiation products from cystine and tryptophan, respectively. Tyrosine, histidine, and phenylalanine were also shown to be degraded by UV, histidine yielding histamine, urocanic acid, and other imidazole derivatives, and phenylalanine yielding tyrosine and dihydroxyphenylalanine. Destruction of these three amino acids was not considered to contribute appreciably to the enzyme inactivation. 

Metabolism. Histamine is formed from the amino acid histidine and is inactivated largely by deamination and by methylation. In common with other local hormones, this process is extremely rapid. 

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