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Histamine

Histamine is an endogenous transmitter involved in allergic manifestations, gastric secretion and vigilance regulation.

Metabolism

Biosynthesis

Histamine results from the decarboxylation of L-histidine catalyzed by L-histidine decarboxylase, an inducible enzyme whose activity is inhibited by tritoqualine. Histidine is involved in other biochemical pathways than that leading to histamine. H istidine intake has been reported to reduce appetite.

Distribution

Histamine is present in all tissues of mammals, the richest ones being lung, liver and skin. In tissues, histamine is found especially in mast cells (cells whose cytoplasm contains many basophilic granulations), bound to acid compounds like heparin. In mast cells its turn-over is slow and after depletion, it takes several weeks to return to the initial level. Brain, in particular hypothalamus, also contains histamine whose concentrations vary according to a circadian rhythm.

Histamine concentration in plasma is lower than 1 microgram per liter but it can be higher in asthmatic patients. Histamine level in blood is 10 to 100 micrograms / liter, localized primarily in basophils. Its concentration rises in patients with chronic myelogenous leukemia or gastroduodenal ulcers.

In gastric cells and the nervous system, renewal of histamine is fast because it is continuously released.

Release

  • In the periphery:
    Basophils and mast cells can release histamine during antigen-antibody reactions and in response to drugs and toxic products. Enterochromaffin cells in the stomach release histamine when they are stimulated by gastrin.
  • In the central nervous system:
    Regulation of histamine release in synapses of the central nervous system is not well known. Stimulation of presynaptic H1 receptors inhibits it.

Catabolism

Histamine released is inactivated by biochemical transformations, either oxidative deamination catalyzed by diamine oxidase, or N-methylation catalyzed by N-methyl transferase. Part of the histamine released in blood circulation binds to plasma globulins.

Effects and receptors

The best known histaminic receptors are H1 and H2. The role of H3 and H4 remains to be clarified.

H1 effects

Stimulation of H1 receptors, which are coupled to phospholipase C, induces:

  1. Capillary vasodilation and Increased capillary permeability. Vasodilation, resulting from nitric oxide release, can give flushing of the face and headache and tends to lower arterial pressure. In case of anaphylactic shock, there is an important release of histamine, inducing blood trapping in dilated vessels and collapse. Increased capillary permeability is responsible for edema resulting from leakage of protein and fluid from plasma into the extracellular spaces, by opening of precapillary sphincters and capillary dilation enhanced by contraction of efferent veins.
  2. Contraction of smooth muscles, in particular bronchial and digestive ones, via G proteins which activate phospholipase C, leading to an increase in intracellular Ca2+. An aerosol of histamine elicits a bronchoconstriction, but the pathophysiological role of histamine in asthma does not seem important.
  3. Increase in vigilance by a central effect: inhibition of this stimulant effect by H1-antihistamines, which cross blood-brain barrier, explains their sedating effect.

H2 effects

Stimulation of H2 receptors which act through cyclic AMP induces:

  1. increase of gastric secretion of hydrochloric acid, HCl, which can be regarded as the main H2 effect. Stimulation of HCl secretion by histamine involves a cascade of reactions: stimulation of H2 receptors, activation of adenylcyclase, increase in cyclic AMP which modulates the activity of proteins kinases, which themselves activate H+/K+-ATPASE, responsible of excretion of protons in gastric fluid.
  2. cardiac stimulation: positive inotropic and chronotropic effects.
  3. vasodilation: stimulation of H2 receptors induces vasodilation, but the H2 vasodilatator effect of slower onset and more durable than that of H1.
  4. small bronchodilatator effect.
  5. possible inhibition of prolactin release.

Effects of Histamine

 

H1 (by stimulation of phospholipase C)

H2 (by stimulation of adenyl cyclase)

Heart

Slowing of atrioventricular conduction

positive inotropic effect
positive chronotropic effect (sinus)

Vessels

Dilation (fast and fugacious by NO release)

Dilation (delayed and durable)

Extravascular smooth muscles, bronchial

Contraction

Relaxation

Gastric secretion

 

Increase of HCl secretion

Allergy

Increase in capillary permeability

Possible immunoregulator effect

SNC

Stimulation of vigilance
Decrease of appetite

Cellular hyperpolarisation

Main H1 and H2 effects of histamine, CNS = central nervous system

H3 and H4 Effects

  • Stimulation of presynaptic H3 receptors reduces histamine release in the central nervous system and in the periphery (autoreceptors) and also the release of other transmitters (heteroreceptors). But the role of H3 receptors remains unresolved. It seems that H3 antagonists could have applications in certain neuropsychiatric disorders but at present there is not any drug of this type.
  • H4 receptors appear to be involved in immune reactions but there is no clinical application.

Histaminomimetic agents

The only marketed histaminergic agonist today is betahistine which is a low H1 agonist used for its vasodilator properties in treatment of Menière syndrome (dizziness, tinnitus, deafness). Betahistine has also an antagonist effect on presynaptic H3 receptors which increases histamine release in histaminergic synapses of the central nervous system.

Betazole is a H2 agonist, used as pharmacological reagent but not as a drug.

A certain number of compounds, including drugs, (see further) can elicit histamine release and induce clinical symptoms: facial flushing, headache, tachycardia, arterial hypotension.

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