Function of histamine | Role in inflammation, stomach & Body

Histamine is an autocoid, which means a self-healing substance.

It is found in plenty in the region of wounds and infection, indicating its role in healing.

Even the itch during wound healing also indicates histamine presence.

Histamine is present in many body cells and tissues. It is an essential chemical that controls body physiology.

It acts by two receptors, viz. H1, H2 while H3 is not prominent in health care.

Functions of histamine:

In the Whole body: Histamine is present in mast cells, so during an infection or wound, it is accumulated there. This histamine acts to attract leukocytes (white blood cells). It produces constriction in the lungs, intestine and lowers blood pressure.

Function of histamine
Credit: wikipedia.org

In other tissue like the brain, skin, stomach, it is also present without mast cells.

Role of histamine in gastric secretion and peptic ulcer formation

Histamine stimulates acid secretion in the stomach. Acetylcholine and gastrin act on mast cells in gastric mucosa, which results in the release of histamine. This histamine acts on H2 receptors on oxyntic cells and stimulates the release of acid. Thus increased histamine secretion cause acidity in the stomach, leading to the formation of peptic ulcers over time. Anti-histamines such as diphenhydramine (Benadryl) and hydroxyzine are used to treat peptic ulcers. Anti-histamines work by blocking the histamine receptor.

Histamine in the gastrointestinal tract (GIT)

Histamine influences three major functions of GIT. Through the H2 receptors, it increases the gastric acid secretion in the stomach, thus helping in protein digestion. Histamine also regulates the GI motility and can alter the mucosal ion secretion.

In inflammation

Histamine plays an important role in inflammation. During a bruise or blow, it shows accumulation in the region of the blow. It causes redness (rubor), swelling(tumor), dolor (pain) and heat (calor) in the region. It also causes itchiness. H4 receptor-mediated mast cell activation causes the release of several inflammatory mediators via an inflammatory cascade. These mediators stimulate the migration of different inflammatory cells into the inflammatory site.

In the brain (CNS)

Histamine acts as a neurotransmitter. It has excitatory effects via H1and H2 receptors while it is inhibitory via H3 receptors. Histaminergic neurons are located in the tuberomammillary nucleus of the posterior hypothalamus and project to many parts of the brain, thus exerting their effects on wakefulness, alertness, temperature control, arousal, the release of pituitary hormones and thirst. It influences higher brain functions like sleep-wake regulation, circadian and feeding rhythms, homeostasis, cognitive functions, etc. Neuronal histamine is also involved in pain perception. It has antinociceptive properties. Histamine plays a role in the repair of neuronal damage.

It triggers the release of the adrenaline hormone from the adrenal gland. Drugs that work to mitigate histamine include Anti-histamine drugs like cetirizine, promethazine, dimenhydrinate, etc. These drugs are used in times of common cold, allergy, vomiting during pregnancy, motion sickness, etc.

Distorted histamine signaling in the brain affects addictive behaviors and degenerative diseases such as Alzheimer’s, Parkinson’s disease and multiple sclerosis.

Histamine in narcolepsy

Narcolepsy is a chronic sleep disorder where the patient displays overwhelming daytime drowsiness and sudden attacks of sleep. Though histamine is a wakefulness-promoting substance, there is still a marked increase in the histaminergic system of neurons in the brain of narcoleptic patients. This is a compensatory mechanism to make up for the loss of orexin and hypocretin neurons in the hypothalamus. Normally orexin and hypocretin neuropeptides are mainly responsible for wakefulness.

Histamine in migraine

When excess histamine accumulates within the brain, it acts via H1 receptors to induce a migraine. This excess occurs when histamine is not properly metabolized due to the lack of the enzyme diamine oxidase (DAO).

Histamine on cognition

Histamine is one of the main neurotransmitters in the brain. It mediates its effects via H1, H2, H3 and H4 receptors, which are all G protein-coupled receptors. Its effect on cognition, learning and memory may be either facilitatory or inhibitory, depending on which receptor it acts.

Histamine’s effects on the immune response

Cells involved in immune response like macrophages, T and B lymphocytes, endothelial cells, etc., express histamine receptors and also secrete histamine. Histamine influences the recruitment of the major effector cells into tissue sites and affects their maturation, activation, polarization, and effector functions. Histamine regulates antigen-specific helper T cells(Th1 and Th2 cells). Histamine acting via H2 receptor modulates peripheral antigen tolerance induced by T regulatory cells in several pathways.  The differential expression of H4 receptors on immune cells and their varied intracellular signaling mechanisms lead to the diverse effects of histamine on immune responses.

Histamine in hypersensitivity reactions

Hypersensitivity reactions are an overreaction of the immune system to an antigen (may be endogenous or exogenous), which in normal conditions would not cause an immune response. In Type 1 hypersensitivity reaction (known as an immediate reaction), histamine is released from mast cells along with other mediators. The mast cells store histamine in the form of granules and release it when they get activated. In Type 1, the reaction they are activated when antibodies are released against the antigen via the action of IgE (immunoglobulin E)

In blood vessels

The vascular walls contain large amounts of histamine located in mast cell and non-mast cell stores. Mast cells present in postcapillary venules secrete histamine, which causes protein leakage and edema formation. Activation of vascular H1 and H2 receptors causes vasoconstriction and vasodilatation, respectively. In humans, the effect of vasodilation predominates.

H2 receptors are located on vascular smooth muscle cells and the vasodilator effects are mediated by cyclic Adenosine monophosphate (cAMP).H1 receptors are present on endothelial cells, and their stimulation leads to the formation of local vasodilator Nitric Oxide which diffuses from endothelial cells to vascular smooth muscle cells, increase the cGMP concentration which leads to relaxation of vascular smooth muscle.

Histamine’s effect on venules

Histamine release from mast cells (in allergic reactions) acts on endothelial cells of venules and highly increases vascular permeability. Endothelial cells form a single layer covering the inner surface of the blood vessel. The vascular permeability depends on blood flow and vascular endothelial barrier. The endothelial barrier is formed by intercellular adherens junctions consisting of vascular endothelial cadherin (VE-cadherin), catenins, and the cytoskeleton. Histamine acts by phosphorylating VE-cadherin, by increasing the intracellular calcium concentration in endothelial cells, etc.

Effect of histamine in hypertension

Histamine has hypertensive effects on the cardiac system. It increases blood pressure. In cases of excess histamine accumulation in the Body (histamine intolerance), which occurs due to lack/inhibition of enzyme diamine oxidase (DAO), which is responsible for breaking down histamine, the patient experiences high blood pressure.

In wound healing

Histamine has an accelerating effect on cutaneous wound healing. Histamine stimulates angiogenesis, the process of formation of new blood vessels, which increase the rate of healing. It also stimulates the exudation of molecules involved in wound healing from blood vessel to site. Histamine also helps in macrophage recruitment.

In phagocytosis

Histamine is released from stimulated basophils and mast cells. Histamine inhibits chemotaxis, which is the movement of phagocytic cells towards the direction of a higher concentration of pathogenic microbe. Histamine inhibits the formation of superoxide ions and other free radicals/. This inhibits the process of phagocytosis.

 On heart

Mast cells are present in the heart, mostly around vessels and between myocytes. Histamine is stored in cytoplasmatic granules of mast cells. On activation of mast cells, the histamine is released. It produces arrhythmogenic effects. The effects are mediated by H2-receptor. It stimulates heartbeat and causes tachyarrhythmias by increasing sinus rate and ventricular automaticity and in slowing atrioventricular conduction.  Histamine also influences sodium and potassium influx, thus affecting depolarization and repolarization.

Effect of histamine on respiratory system and asthma

Histamine acts on the smooth muscle cells of the respiratory airways and causes contraction, which leads to reflex bronchoconstriction. Histamine directly stimulates the H1 receptors present in the smooth wall, or histamine indirectly stimulates afferent vagal fibers. Both of these processes lead to bronchoconstriction.

In allergic asthma, the mast cells get activated. These mast cells secrete histamine. Histamine causes airway obstruction through 3 processes. It stimulates bronchoconstriction, increases secretion in airways and causes mucosal oedema. This narrows the airway passages and causes asthma. Thus anti-histamines are often given to treat allergic asthma.

Histamine and platelet aggregation

When histamine is added to a system, the platelets display increased levels of cAMP. Platelet aggregation is inhibited by histamine. When platelets are stimulated and begin to aggregate, there is also a release of histamine. This release precedes aggregation.

Histamine in allergic rhinitis

Histamine is a major mediator in the development of allergic rhinitis. It may be secreted by mast cells or basophils. Nasal administration of histamine causes sneezing, itching, rhinorrhea, and nasal congestion. Histamine acts via H1 receptors. Anti-histamines are used to treat rhinitis and reduce sneezing.

Histamine on sleep-wakefulness

The posterior hypothalamus contains a well-developed system of histaminergic neurons that project to most major areas in the brain. They act via H₁ and/or H₃ receptor and have a major role in the regulation of sleep-wakefulness. Histamine or H₁ receptor agonists cause wakefulness, while administration of H₁ receptor antagonists induce sleep. Histamine release in the hypothalamus is highest during the awake state. The histaminergic neurons show maximum activity during the state of high vigilance.  Their activity reduces during rapid eye movement (REM) sleep and non-REM sleep.

Histamine in depression

The state of wakefulness, the sleep-wake cycle, learning and memory, appetite, emotions, etc., are all controlled by the histaminergic system of neurons present in the CNS. The histamine receptor present in the brain is H1. Patients who are depressed show decreased binding of histamine to the H1 receptor. The more the severity of the depressive symptoms, the more is the decrease in binding affinity to H1 receptors.

Histamine in ocular allergy

Ocular allergy is the inflammatory reaction of the eye surface in response to allergens present in the environment. When mast cells in the eye are exposed to allergens, they release histamine, which mediates the inflammatory processes and causes the eye to become red, watery and itchy.

Histamine’s role in vomiting

During motion sickness, histamine is the neurotransmitter transmitting signals from the inner ear to the brain. This induces vomiting.

In food allergies, histamine is released from mast cells in the gastrointestinal tract when the mast cells are activated on exposure to an antigen. Histamine influences the chemoreceptor trigger zone in the medulla oblongata, which in turn releases chemicals like serotonin and dopamine. These chemicals act on the vomiting center and induce emesis/vomiting.

Histamine and vertigo

Vertigo is when a person suddenly starts feeling off-balance and feels a spinning sensation.  Histamine is used in the treatment of vertigo due to its vasodilating properties. It is also used to treat inner ear disturbances. Histamine regulates the vestibular function and cerebral circulation. Thus it is often used to treat vertigo.

Histamine and burns

In burn injury, the mast cells are activated and they release histamine. This histamine cause dilation of arteries and constriction of venules. This leads to more perfusion. It also increases vessel permeability in the capillaries. Thus edema forms in burn injuries.

Histamine and eczema

Eczema (atopic eczema) is a condition where the skin becomes inflamed, rough, itchy and cracked. Histamine is released from basophil leucocytes of such patients. Histamine aggravates eczema by causing an inflammatory reaction. Histamine, in this case, acts via the H1 receptor.

Histamine and pain

Histamine influences the processing of nociceptive information, acting in an antinociceptive manner in the CNS while it acts in a nociceptive manner in the PNS(peripheral nervous system). Histamine is released when there is tissue damage or injury and it causes pain hypersensitivity, like neuropathic pain after nerve damage where histamine is released from mast cells. The release of histamine causes the recruitment of macrophages and neutrophils.H3 receptor and H4 receptor are involved in the modulation of neuropathic pain.

Histamine, when applied to the skin, can also induce itching sensation and pruritis.

Histamine in anaphylaxis

Anaphylaxis is a highly severe allergic reaction, where the immune system(mast cells and basophils) releases histamine, basophils, mast cells, and other chemical substances in response to allergens. Histamine exerts its effects through the activation of histamine 1 (H1) and histamine 2 (H2) receptors and causes the symptoms of anaphylaxis to occur.

Vasodilation, hypotension, and flushing are caused due to histamine action on both H1 receptors and H1 receptors. Action on H1 receptors alone causes tachycardia, vascular permeability, coronary artery vasoconstriction, bronchospasm, pruritus and rhinorrhea.

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