Histamine

Histamine was first discovered in 1910 by the British physiologist Sir Henry Hallett Dale as a contaminant of ergot, generated by bacterial action.¹¹ It was first synthesized before its physiological significance was known and due to its wide range of biological activity, it has become one of the most important biogenic amines in medicine and biology. The word 'histamine' comes from Greek, histos, which means tissue. Most of the early studies on the biological actions of histamine were carried out by Sir Henry Dale and his colleagues. Dale had shown that a local anaphylactic reaction was result of an antigen-antibody reaction in sensitized tissue. He subsequently demonstrated that histamine could largely mimic both in vitro and in vivo anaphylactic responses.¹¹

Histamine is an important chemical mediator and neurotransmitter on a broad range of physiological and pathophysiological conditions. Its specific effects are mediated by four different aminergic G-protein coupled receptor (GPCR) subtypes (H₁-H₄) in central and peripheral tissues.¹⁵ The biogenic amine is known to participate in allergic, inflammatory, gastric acid secretion, immunomodulation, and neurotransmission conditions.¹⁵

Histamine is used to maintain homeostasis (the body's natural balance of chemicals, temperature, metabolic rates). It is also a neurotransmitter and plays a role in our immune system by acting as a chemoattractant. Histamine imbalances in our body cause a variety of effects. Histamine shortage (Histapenia) causes effects ranging from heavy body hair growth and headaches to anaphylactic shock and paranoia. Histamine abundance (Histadelia) in the body also causes a variety of effects ranging from the mundane (such as phobias, symptoms of seasonal allergies - such as runny nose, inflammation, soreness, etc - and an increased metabolism) to the serious (like chronic depression).¹¹

1.6.1 Metabolism of histamine

The histamine N-methyltransferase (HNMT) plays an important role in metabolism of histamine within the human airways and gut. It is the only enzyme responsible for the termination of neurotransmitter actions.¹²The HNMT inactivates histamine by transferring a methyl group from S-adenosyl-L-methionine to the imidazole ring. Inactive N г-methylhistamine is excreted in urine or can be further oxidized by diamine oxidase (DAO) or

monoamine oxidase (MAO) into N^г-methyl-imidazole-aldehyde, which can be further oxidized into its corresponding acid (Fig. 8). The histamine metabolism pathway starting with DAO is only relevant in Peripheral Nervous System (PNS).¹³

N

Figure. 8 Metabolism of histamine 1

1.6.2 Synthesis and storage

Histamine is a basic amine, 2-(4-imidazolyl)-ethyl-amine and is synthesized in the body from histidine by the enzyme histidine decarboxylase (Figure 9). It is found in most tissues of the body and skin. On the other hand histamine is present in high concentrations in the lungs and in the gastrointestetinal tract. At the cellular level, it is found largely in mast cells and

N NH

NH₂

H CO₂H histidine decarboxylase L-histidine

N NH

NH₂

histamine

8 1

Figure. 9

1.6.3 Release

Histamine is released from mast cells by a secretory process during inflammatory or allergic reactions. The mast cell membrane has receptors both for a special class of antibody (IgE) and for complement components C3a and C5a. The cell can be activated to secrete mediators through these receptors and also by direct physical damage. The secretory process is intiated by a rise in intra-cellular calcium. This follows cross linking of receptors which intiates an increase in calcium permeability and a release of calcium from intracellular stores. Some neuropeptides release histamine, though the concentrations required are fairly high.⁴

Agents which increase cAMP formation (example β-adrenoreceptor agonists) inhibit histamine secretion, so it seems that, in these cells, cAMP dependent protein kinase is an intracellular ‘‘braking’’ mechanism. Replenishment of the histamine content of mast cell or basophil, after secretion, is a slow process which may take days or weeks, where as turnover of histamine in the gastric ‘histaminocyte’ is very rapid.⁴

Histamine is metabolized by diamine oxidase and by the methylating enzyme imidazole N-methyl-transferase. Sensitivity to the effects of histamine varies between tissues and species.

The guinea pig is very sensitive and mouse is very insensitive to this agent. Human sensitivity lies between these two extremes.⁴

1.6.4 Actions

1.6.5 Gastric secretion

Histamine stimulates the secretion of gastric acid via H₂-receptor. In clinical terms this is the most important action of histamine, since it is implicated in the pathogenesis of peptic ulcer.⁴

1.6.6 Smooth muscle effects

Histamine acting on H₁-receptors causes contractions of the smooth muscle of the ileum, the bronchi, bronchioles and the uterus. The effects on the ileum is not as marked in man as it is in the guinea pig.⁴ The response of guinea pig ileum to histamine is the basis of the standard bioassay for histamine. Bronchial construction by histamine is also more marked in guinea pigs than in man, though the histamine may be one of the many factors causing reduction of

air-flow in the first phase of bronchial asthma. Uterine muscle in most species is contracted and in human this is only significant if a massive release of histamine is produced by anaphylaxis during pregnancy, which may lead to abortion.⁴

1.6.7 Cardiovascular effects

Histamine expands blood vessels by an action on H1-receptors in man and by a combined action on H1 and H2-receptors in some experimental animals. The effect may be partly endothelium-dependent. It increases the rate and output of the heart by action on cardiac H2 -receptor. This is a direct effect which may be coupled to an indirect, reflex response if there is a fall in blood pressure.⁴

When injected intradermally, histamine causes a reddening of the skin and a wheal with a surrounding flare. This combination of effects was described by Sir Thamos Lewis over 60 years ago and was termed the ‘triple response’.⁴ The reddening is due to vasodilation of the small arterioles, precapillary sphincters and the wheal is due to increased permeability of postcapillary venules. These effects are mainly due to activation of H₁-receptor.⁴