Histamine

Histamine is an endogenous compound synthesized, stored, and released primarily by mast cells and after release exerts profound effects on many tissues and organ.It is a cellular mediator of the immediate hypersensitivity reaction and acute inflammatory response and also a primary stimulant of gastric acid secretion.It has a central neurotransmitter role

Histamine importance in medicine and pharmacology lies in its pathophysiological actions and in the therapeutic usefulness of drugs that block the receptors that mediate its actions.

The actions of histamine are mediated by at least three distinct receptors: H1, H2, and H3. Of these, the H1 and H2 receptors are the best characterized and mediated well-defined response in humans that have been used as the basis for drug development.

Response such as bronchoconstriction are mediated by H1 receptors and are selectively antagonized by classic antihistamines such as diphenhydramine, mepyramine.

Responses such as facial cutaneous vasodilation and gastric acid secretion are mediated by H2 receptors and are antagonized by agents such as cimetidine and ranitidine.

The H3 receptors has been studied mainly in experimental animals. This receptor is found on the nerve endings and mediate the inhibition of neurotransmitter release.

This includes the inhibition of the release of histamine from the histaminergic neurons in the central nervous system ( CNS) and other transmitter in the CNS and of the release of transmitter from peripheral nerves in the autonomic nervous system and the myenteric plexus.Mechanism of actionAction of histamine

The mechanism of signal transduction by histamine at H1, H2, and H3 receptors differs.

The contractile actions on smooth muscle and neuronal actions mediated by H1 receptor result from stimulation of the breakdown of inositol phospholipids.The stimulus – response mechanism for the H1 receptor- mediated relaxation of vascular smooth muscle involves the synthesis and release of nitric oxide, an endothelium-derived relaxant factor.

The actions of histamine mediated by H2 receptors may stem from the activation of adenylate cyclase. This occurs in H2 receptor systems that mediate acid secretion, the relaxation of vascular smooth muscle, neuronal excitation, the inhibition of basophil degranulation, and increase in myocardial contractility.

The inhibition of transmitter release mediated by H3 receptors is thought to involve a modulation of Ca2+ entry into nerve endings

Synthesis and metabolism of histamineHistamine is synthesized in vivo by decarboxylation of the amino acid L- histidine, which is catalyzed by the L-histadine decarboxylase.

Two primary pathways exist for the catabolism of histamine:The first is the oxidative deamination pathway, which is catalyzed by diamine oxidase and leads to the formation of imidazole acetic acid.

The second pathway involves the methylation of the tele nitrogen in the imidazole ring, which is catalyzed by histamine –N- methyltransferase and results in the formation of T-N- methlhistamine

Storage and release of histamineHistamine is found in most tissues of the body but present in high concentrations in the lungs and the skin and in particularly high concentrations in the gastrointestinal tract.

At cellular level, it is found largely in mast cells and basophils, associated with heparin, but non-mast-cell histamine occurs in ‘histaminocytes’ in the stomach and in histaminergic neurons in the brain.

The basophil content of the tissues is negligible – except in certain parasitic infections and hypersensitivity reactions and basophils form only 0.5% of circulating white blood cells.

In mast cells and basophils, histamine is held in intracellular granules in complex with an acidic protein and heparin of high molecular weight, termed macroheparin.Together these comprise the matrix of the granules in which the basic molecule histamine is held by ionic forces, the histamine content being approximately 0.1 – 0.2 pmol per mast cell, and 0.01 pmol per basopil.

Histamine releaseHistamine is released from mast cells and basophils by two general processes of degranulation: noncytolytic and cytolytic.

Cytolytic release of histamine from mast cells occurs when the plasma membrane is damaged. This type of release is energy- independent, does not require intracellular Ca2+, and is accompanied by the leakage of cytoplasmic content.

Cytolytic release can be induced by variety of substances, including the phenothiazines, H1-antagonist, and some narcotics analgesics.

Noncytolytic release can be induced by variety of compounds, release of histamine through this process is suspected to be as a result of specific binding of a ligand to a receptor in the plasma membrane of the mast cell or basophilIn contrast to cytolytic release, noncytolytic release requires adenosine triphosphate for energy, depends on the changes in the concentration of intracellular Ca2+, and is not accompanied by the leakage of cytoplasmic content. Noncytolytic release is characterized by exocytosis.

Agents that increase cAMP formation (e.g. β- adrenoceptor agonists) inhibit histamine secretion. Replenishment of the histamine content of mast cell or basophil after secretion is a slow process, which may take days or weeksWhereas turnover of histamine in the gastric histaminocyte is very rapid.

Actions of histamine:Gastric secretion: Histamine stimulates the secretion of gastric acid by action on H2 – receptor. In clinical terms, this is the most important action of histamine, since it is implicated in the pathogenesis of peptic ulcer.

Smooth muscle effects: Histamine, acting through H1- receptors, causes contractions of the smooth muscle of the ileum, bronchi, and bronchioles, and the uterus. Histamine is one of the main mediators causing reduction of air flow in the phase of bronchial asthma. Uterine muscle in most species is contracted.

Cardiovascular effects: Histamine dilates blood vessels in humans by action on H1-receptors, the effect being partly endothelium – dependent in some vascular beds.It increases the rate and the output of the heart by action on cardiac H2 – receptors.

Injection intradermally, histamine causes a reddening of the skin and a wheal with a surrounding flare

The reddening results from vasodilation of the small arterioles and precapillary sphincters, and the wheal is caused by the increased permeability of the postcapillary venules. These effect is mainly mediated through the activation of H1- receptors.

The flare is an axon reflex that involves stimulation of sensory nerve fibers and the passage of antidromic impulses through neighboring branches of the same nerve with release of a vasodilator mediator.

Itching : itching occurs if histamine is injected into the skin or applied to a blister base; it is caused by stimulation of sensory nerve endings.

CNS effect: Histamine is present in the brain in much smaller amounts than in other tissues, such as skin, and lungs, undoubtedly serves as neurotransmitter. H1 receptors are mainly located in postsynaptically and cause excitation; H2 – and H3 – receptor are inhibitory, respectively post- and presynaptic, H3 – receptor being inhibitory autoreceptors on histamine – releasing neurons.