Histamine synthesis and

In 1966, the name was proposed (5) for receptors blocked by the at that time known antihistamines. It was also speculated that the other actions of histamine were likely to be mediated by other histamine receptors. The existence of the H2 receptor was accepted in 1972 (6) and the receptor was recognized in rat brain in 1983 (7). receptors in the brain appear to be involved in the feedback control of both histamine synthesis and release, whereas release of various other neurotransmitters, eg, serotinin (5-HT), dopamine, noradrenaline, and acetylcholine, is also modulated (8) (see Neuroregulators). 

Figure 6.1 Histamine synthesis and metabolism in neurons. L-histidine is transported into neurons by the L-amino acid transporter. Once inside the neuron, L-histidine is converted into histamine by the specific enzyme histidine decarboxylase. Subsequently, histamine is taken up into vesicles by the vesicular monoamine transporter and stored there until released. In the absence of a high-affinity uptake mechanism in the brain, released histamine is rapidly degraded by histamine methyltransferase, which is located postsynaptically and in glia, to telemethylhistamine, a metabolite that does not show any histamine-like activity.

Specific enzymes control histamine synthesis and breakdown 253 Several forms of histidine decarboxylase may derive from a single gene 254... 

Specific enzymes control histamine synthesis and breakdown. Figure 14-3 summarizes the major mechanisms for the synthesis and metabolism of histamine. 

Schwartz, J.C.,Arrang, J. M., Garbarg, M., Gulat-Marnay, C. and Pollard, H. Modulation of histamine synthesis and release in brain via presynaptic autoreceptors and heteroreceptors. Ann. N.Y.Acad. Sci. 604 40-54,1990. 

Corbel, S., Schneider, E. and Lemoine, F. (1995) Dy, Murine hematopoietic progenitors are capable of both histamine synthesis and update. Blood, 86, 531-539. 

Suppression of lymphocyte proliferation Suppression of antibody production by B lymphocytes Relaxes stomach and gallbladder smooth muscle H3Modulation of histamine synthesis and release Inhibits vagally mediated bronchoconstriction Vasodilatation... 

The H3 receptor was initially detected as an autoreceptor controlling histamine synthesis and release in brain [22]. Thereafter it was shown to inhibit presynaptically the release of other monoamines in brain and peripheral tissues as well as of neuropeptides from unmyelinated C-fibers [23],... 

Figure 3. Effect of N -methylhistamine produced by Helicobacter pylori on acid secretion On the one hand, this compound may reduce acid secretion by inhibiting, via H3 receptor activation, histamine synthesis and release from ECL cells on the other hand, FI3 receptor activation on D cells, with consequent inhibition of somatostatin release, may increase acid secretion. Additionally, direct activation of H2 receptors on parietal cell by N -metylhistamine must also be considered (this mechanism is not shown in the scheme).

Blockade of histamine autoreceptors increases histamine synthesis and release and may support higher CNS functions such as arousal, cognition and learning. Peripheral histamine heteroreceptors on C liber and on postganglionic sympathetic fiber terminals diminish neuropeptide and noradrenaline release, respectively. Both inhibititory effects are beneficial in myocardial ischemia. The inhibition of neuropeptide release also explains the antimigraine effects of some agonists of presynaptic histamine receptors. 

Histamine is an endogenous substance that activates histamine H2, and H3 receptors, and its principal pharmacologic effects involve exocrine glands, extravascular smooth muscles, and the cardiovascular system. H, receptor stimulation increases inositol-1,4,5-triphosphate, which increases intracellular calcium, resulting in vasoconstriction. Activation of H2 receptors increases intracellular cAMP, which mediates gastric acid secretions and cardiovascular effects. H3 receptor stimulation may be involved in feedback inhibition of histamine synthesis and release. 

Histamine plays a central role in immunologic and anti-inflammatory responses, particularly in the immediate hypersensitivity response. Three subclasses of histamine receptors have been identified Hj, Hj, and Hj receptors. Hj receptors are involved in mediating increased vascular permeability, pruritus, coutraction of smooth muscle in the respiratory and gastrointestinal tracts, release of mediators of inflammation, and recruitment of inflammatory cells. Among other effects, Hj receptors mediate the negative feedback control of histamine synthesis and release and may play some defensive role against excess bronchoconstriction. H, and Hj receptors are both found primarily in bronchial smooth muscle in the human respiratory tract (40). 

Figure 5-9. Georg Kahlson s proposed scheme of histamine synthesis and mobilization in the rat gastric mucosa. (From Kahlson G, Rosengren E, Svann D, et al. Mobilization and formation of histamine in the gastric mucosa as related to acid secretion. I Physiol Lond 174 400-416, 1964.)...

Holland et al. (1978) suggested that a second enzyme may be required for histamine synthesis and/or stability (histidine decarboxylase was shown to be unstable). Histamine production can have a significant effect on the course of acne vulgaris. If the pH inside the follicle drops to 4.5, approaching the first pH-optimum, histamine production in vivo will increase, serving as a metabolic response to the bacterial environment since amines reduce the acidity, histamine production creates more favorable... 

A model of histamine synthesis and mobilization in the gastric mucosa, as described by G. Kahlson in 1964. He postulated a feedback control of the histamine-forming capacity (HFC) of the mucosa by the histamine content of the mucosa itself. Some 30 years later, the validity of this prescient suggestion appears substantiated by the identification of different histamine receptor subtypes on the enterochro-maffin-like cell and their ability to regulate histamine secretion. 

The synthesis and disposition of histamine is well described both in allergy textbooks (9,10) and in review articles (11). 

Although mast cells and basophils probably account for >90% of stored histamine in the body, histamine is also present in platelets, enterochromaffin-like cells, endothelial cells, and neurons. Histamine can act as a neurotransmitter in the brain. Histaminergic nerves have their cell bodies within a very small area of the brain (the magnocellular nuclei of the posterior hypothalamus) but have axons in most areas of the forebrain. There is also evidence for axons projecting into the spinal (Fig. 1) cord. Finally, there is evidence that histamine synthesis can be induced in tissues undergoing rapid tissue growth and repair. In certain neonatal tissues (e.g. liver), the rate of synthesis of this unstored diffusable histamine (termed nascent histamine) is profound and may point to a role for histamine is cell proliferation. 

The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

Figure 13.4 Histamine synthesis, metabolism and receptors. Current knowledge does not justify presentation of a schematic histaminergic synapse. (1) Histidine decarboxylase (2) histamine-A-methyltransferase (3) mono amine oxidase (MAOb)...

Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase 254 Histamine is stored within and released from neurons but a neuronal transporter for histamine has not been found 254 In the vertebrate brain, histamine metabolism occurs predominately by methylation 254... 

FIGURE 14-3 Synthesis and metabolism of histamine. Solid lines indicate the pathways for histamine formation and catabolism in brain. Dashed lines show additional pathways that can occur outside the nervous system. HDC, histidine decarboxylase HMT, histamine methyltransferase DAO, diamine oxidase MAO, monoamine oxidase. Aldehyde intermediates, shown in brackets, have been hypothesized but not isolated. 

Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase. Although histamine is present in plasma, it does not penetrate the blood-brain barrier, such that histamine concentrations in the brain must be maintained by synthesis. With a value of 0.1 mmol/1 for L-histidine under physiological conditions, HDC is not saturated by histidine concentrations in the brain, an observation that explains the effectiveness of large systemic doses of this amino acid in raising the concentrations of histamine in the brain. The essential amino acid L-histidine is transported into the brain by a saturable, energy-dependent mechanism [5]. Subcellular fractionation studies show HDC to be localized in cytoplasmic fractions of isolated nerve terminals, i.e. synaptosomes. 

Activation of brain H receptors also stimulates cGMP synthesis [19]. Outside the brain, histamine is known to relax vascular smooth muscle by activation of endothelial H receptors, thereby increasing endothelial Ca2+ concentrations and stimulating the synthesis and release of nitric oxide. The latter, a diffusible agent, then activates the smooth muscle guanylyl cyclase [30]. Although less is known about these mechanisms in the CNS, there is evidence that brain H receptor activation can produce effects that depend on guanylyl cyclase activity [19]. 

Gomez-Ramirez, J., Ortiz, J. and Blanco, I. Presynaptic H3 autoreceptors modulate histamine synthesis through cAMP pathway. Mol. Pharmacol. 61 239-245, 2002. 

Abe Y. Ogino S. Irifune M. Imamura I, Fukui H. Wada H. Matsunaga T Histamine content, synthesis and degradation in human nasal mucosa. Clin Exp Allergy 1993 23 132-136. 

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