Histamine, Serotonin, and their Antagonists

Histamine, Serotonin, and their Antagonists

Wolfgang Bäumer

The author thanks H.R. Adams for the original chapter upon which this is based.


Research on the effects of histamine (2-[4-imidazole]-ethylamine) began more than 100 years ago (Dale and Laidlaw, 1910) and is still not losing its attraction. Rather, histamine has been described as one of the most extensively researched molecules in the field of medicine (Akdis and Simmons, 2006). The first descriptions of histamine actions were contraction of smooth muscle and lowering of blood pressure. In these early publications, histamine was extracted from ergot extract contaminated with histamine-synthesizing bacteria. At the end of the 1920s, histamine was isolated from mammalian tissue and a direct connection to allergic-inflammatory reactions was discovered. Further characterization of histamine action was made possible by the discovery of specific histamine receptor antagonists. The early antagonists were mainly H1 receptor blockers but it became obvious that these antagonists could not block all histamine actions. This led to the discovery of further histamine receptors (H2 and H3 receptors) and in 2000 the latest of the histamine receptors, the H4 receptor, was cloned and characterized, breaking new ground in histamine research (Skidgel et al., 2011).

Mainly through H1 receptor (and partly through the H4 receptor), histamine is involved in anaphylaxis, inflammations and allergies, and certain types of adverse drug reactions. Using the second type of receptor (H2), it regulates gastric secretion (Morris, 1992). The H3 receptors modulate neurotransmitter release from neurons (Sander et al., 2008), whereas H4 receptors participate in inflammation involving modulation of chemotaxis and cytokine secretion of eosinophils, T cells, and antigen-presenting cells into the site of inflammation (Zampeli and Tiligada, 2009). Both, the histamine H1 and H4 receptors are involved in the mediation of pruritus (itch) induced by histamine (Rossbach et al., 2011; Kollmeier et al., 2014). Histamine itself is not used therapeutically, but histamine receptor blocking agents (acting as histamine receptor inverse agonists) are commonly used to inhibit effects of endogenous histamine (MacGlashan, 2003).

Sources, Synthesis, and Metabolism of Histamine

Histamine is formed by the decarboxylation of the amino acid L-histidine by the enzyme histidine decarboxylase. Thus, this enzyme is present in all cell types that contain or synthesize histamine.

Histamine is widely distributed throughout mammalian tissue, but concentrations vary considerably in different species; for example quantities of circulating histamine are relatively high in the goat and rabbit but low in the horse, dog, cat, and human. Most of the histamine stored within the body is derived locally from enzymatic decarboxylation of L-histidine. Two general stores of histamine can be identified in mammalian species: the mast cell pool made up of mast cells in tissue and basophils in the blood. The non–mast-cell pool is localized in the gastrointestinal (GI) tract, central nervous system (CNS), skin, and other organs. These two pools differ not only in cellular composition but also in responsiveness to physiological and pharmacological stimuli.

The mast cell pool of highly concentrated histamine is distributed in connective tissue throughout the body. Circulating basophils, free counterparts of fixed-tissue mast cells, also contain high concentrations of histamine and are grouped with mast cells because of basic similarities. Within these two cell types, histamine is synthesized rather slowly and stored tenaciously in secretory granules; hence, the turnover rate is low. Because of the slow turnover rate, mast cell stores are replenished slowly after exposure to a histamine-releasing agent. The mast cell pool represents the histamine that participates in inflammatory responses, allergic phenomena, shock, some adverse drug reactions, and other forms of cellular insult.

The precise cellular localizations and physiological functions of the non–mast-cell pool of histamine within the gastric mucosa, brain, and skin are still being identified. Histamine in the stomach mucosa – the source of stimulation of acid secretion on H2 receptors of the gastric parietal cells – is derived from the enterochromaffin-like cells. Histamine in these regions, in contrast to the mast cell pool, undergoes a rapid turnover rate; it is synthesized and released continuously rather than being stored. Portions of this newly synthesized or nascent histamine are present within neural elements, and histamine acts as a neurotransmitter in the CNS. In the gastric mucosa, a “local hormone” action of histamine controls acid secretion.

Histamine`s pharmacological actions are brief because of rapid metabolism and distribution into tissues. Biotransformation of histamine involves methylation and oxidation, as shown in Figure 19.1. For most tissues and species the more important is ring methylation to form N-methylhistamine catalyzed by the enzyme histamine-N-methyltransferase. Most of this metabolite is oxidized to methylimidazole acetic acid by the enzyme monoamine oxidase B. The second pathway is oxidative deamination catalyzed by the enzyme diamine oxidase (histaminase) to form imidazoleacetic acid, which is conjugated with ribose as riboside. Only a small percentage of the primary amine can be acetylated in the GI tract, absorbed, and excreted in urine. Trace amounts of free histamine is also excreted in urine.

Diagram shows histamine’s synthesis and metabolism having compounds like histidine, methyltransferase, diamine oxidase, aldehyde dehydrogenase, imidazoleacetic acid, et cetera.

Figure 19.1 Synthesis and metabolism of histamine. Histamine is synthesized from L-histidine by decarboxylation. There are two major metabolizing pathways for histamine. The N-methylation of the ring followed by oxidative deamination and the oxidative deamination followed by conjugation with ribose. There seems to be tissue and species specific differences in which pathway is more pivotal; generally the N-methylation occurs more often. MAO, monoamine oxidase.

Histamine Release

Histamine is highly concentrated in mast cell granules, where it is stored with a heparin–protein complex, proteolytic enzymes, and other autacoids. Release of histamine basically is a two-step process: sudden exocytotic extrusion of granules from the cell and release of histamine from the granules into the interstitial milieu. The latter occurs as an ionic exchange reaction between extracellular cations and molecules of granular histamine. Release can be initiated by a variety of stressful stimuli, including anaphylaxis-allergy, different drugs and chemicals, and physical injury.

Anaphylaxis and Allergy 

Hypersensitivity phenomena associated with antigen–antibody reactions evoke active release of histamine from the mast cell pool (type I or immediate hypersensitivity). Free histamine then plays an important role in mediating physiological manifestations of such reactions as vasodilation, itching, smooth muscle contraction, and edema. Other autacoids also participate in tissue responses to hypersensitivity reactions. Signs of histamine involvement in systemic anaphylaxis vary in different species. In carnivores, histamine and anaphylaxis produce pronounced hypotension and hepatomegaly. In rabbits, pulmonary arterioles constrict and the right heart dilates in response to either histamine injection or exposure of a sensitized individual to the appropriate antigen. In guinea pigs, dominant manifestations are bronchial constriction and death by asphyxiation. Humans seem to respond like guinea pigs and dogs in that severe hypotension, bronchial constriction, and laryngeal edema are principal signs of anaphylaxis.

The mast cell pool of histamine represents a major target for acute types of hypersensitivity-allergy reactions. As part of the allergic reaction to an antigen, IgE antibodies are generated which bind to the high affinity IgE receptor (FCϵR1) on mast cells. Upon reexposure of the antigen, a crosslinking of two or more IgE molecules induces a signaling cascade involving tyrosine kinases and phosphorylation of several protein substrates within seconds leading eventually to a mobilization of intracellular calcium, which triggers the exocytosis of contents of secretory granules. Recent findings implicate, that the degranulation and secretion of proinflammatory mediators (cytokines/chemokines and leukotrienes) can be regulated by the affinity of the antigen to the specific IgE antibodies bound to the FCϵR1 (Suzuki et al., 2014).

Release is an active process, requiring metabolic energy as well as Ca2+, and should be distinguished from simple release secondary to cell destruction and cytolysis.

The ubiquitous cyclic adenosine 3′,5′-monophosphate (cAMP) system is involved in histamine release evoked by antigen–antibody interactions. An increase in cAMP concentration suppresses histamine release (Lichtenstein and Margolis, 1968). Agents that activate adenylyl cyclase (e.g., catecholamines), inhibit phosphodiesterase (e.g., methylxanthines), or activate β2-adrenergic receptors on mast cells can be anticipated to inhibit the release of histamine. The beneficial effects of drugs widely used in treating allergic disorders, such as the catecholamines, β2-agonists, and theophylline, may therefore involve inhibition of histamine release in addition to their well-known and more important physiological antagonism of histamine actions on target cells.

Drugs and Chemicals 

Many drugs and chemicals produce direct degranulation of mast cells with release of histamine independently from development of allergy (anaphylactoid reaction). This characteristic action represents an untoward side effect associated either with intravenous (IV) administration of a relatively large dose or direct intradermal injection. Certain chemicals have as their dominant property the ability to release histamine from the mast cell pool.

The curare alkaloids are used clinically as neuromuscular blocking agents (Chapter 10), but they also are notorious for releasing histamine as an adverse side effect; in some species, IV injection of these agents can be followed by histamine-induced bronchospasm and hypotension. Other clinically used drugs that may release histamine include morphine (Guedes et al., 2007), codeine, doxorubicin, vancomycin, and polypeptide antibiotics (polymyxin). However, other opiates such as oxymorphone and hydromorphone are not associated with as much histamine release (Guedes et al., 2006, 2007).

Certain chemicals have been classified simply as histamine-releasing agents because this particular activity supersedes their other pharmacological properties. The best known and most active is the polybasic substance called compound 48/80, a condensation product of p-methoxyphenylethylmethylamine with formaldehyde (Goth and Johnson, 1975). Injection of compound 48/80 or other similar agents evokes classic pharmacological signs of histamine release that are susceptible to blockade by antihistaminic drugs. Tachyphylaxis to repeated injections is characteristic of these chemicals, presumably because of decreased availability of releasable stores of histamine. Endogenous substances that provoke histamine release and may be involved in physiological release mechanisms include bradykinin and stronger histamine releasing substances like kallidin and substance P. Cellular reactions to many venoms (e.g., wasp venom) and toxins also involve histamine release.

Physical Injury 

When the skin is scratched or pricked, the characteristic redness and urtication that result are due to histamine. This response is quite pronounced in humans. Dermal reactions to severe cold or heat stress likewise depend on histamine liberated by local mast cells. Physical injury of virtually any type sufficiently intense to damage the cells will evoke release of histamine.

Histamine Receptors

The four histamine receptors are named in the order of their discovery: histamine H1 receptor (H1R) to H4 receptor (H4R) (Table 19.1). Classic pharmacology studies led to the discovery of H1R, H2R, and H3R (Akdis and Simmons, 2006). Decades later their genetic structure was decoded and they were identified as belonging to membrane-bound G-protein coupled receptors. The most recently discovered, H4R, was described in parallel to the cloning of the DNA sequence in 2000 (Oda et al., 2000).

Table 19.1 Characterization of histamine receptors in terms of tissue distribution, signal transduction, and physiological and pathophysiological function. Source: Adapted from Baumer and Rossbach, 2010. Reproduced with permission of John Wiley & Sons.

Receptor H1R H2R H3R H4R
Expression tissue Smooth muscle in respiratory, gastrointestinal, uregenital tracts and vessels, nerve cells, hepatocytes, endothelial and epithelial cells, neutrophils, eosinophils, monocytes, dendritic cells, T and B cells Parietal cells in gastric mucosa, nerve cells, smooth muscle in respiratory tract and vessels, hepatocytes, endothelial and epithelial cells, neutrophils, eosinophils, monocytes, dendritic cells, T and B cells Histaminergic neurons, eosinophils, monocytes Mast cells, basophils, eosinophils, monocytes, dendritic cell, T cells, sensory nerve cells, fibroblasts and keratinocytes, endocrine cells in gastrointestinal tract
Intracellulular signal cascade Ca2+↑, phospholipase C, NFκB cAMP ↑, adenylate cyclase, c-Fos, c-Jun, PKC cAMP ↓, Ca2+ ↑, MAP kinase cAMP↓, Ca2+ ↑, AP-1↑
G-protein Gq/11 Gαs Gi/o Gi/o
Physiological function Contraction of smooth muscle, increase of capillary permeability, mediation of itch, sleep–wake cycle Glandular secretion, relaxation of smooth muscle Regulation of sleep and food intake, cognition Chemotaxis/ cytokine/ chemokine secretion by immune cells, mediation of itch
Pathological relevance Immediate hypersensitivity Acid-induced gastritis, gastrointestinal ulcers Cognitive disorders, obesity Inflammation, pruritus
Selective agonists N-methylhistaprodifen Amthamine, impromidine Immethridine ST 1006
Selective aantagonists (+)-Chlorpheniramine Cimetidine, Ranitidine Pitolisant JNJ7777120

H1R couples to Gq/11 and activates the PLC-IP3-Ca2+ pathway. Receptor expression is found in the smooth muscles of the respiratory, gastrointestinal, and urogenital tracts. It has also been identified in neuronal tissue including brain, spinal ganglia, and spinal cord (Akdis and Simmons, 2006). Additionally, H1R is found on immune cells like T lymphocytes, dendritic cells, and endothelial cells. Activation of H1R causes contraction of smooth muscle, vasodilation of arterioles and capillaries, increased vessel permeability, and stimulation of afferent nerve endings. The effects, reddening of the skin, edema, and pruritus, are the classic symptoms of an allergic reaction. In addition to these peripheral effects, H1R plays a pivotal role in the regulation of neuronal processes like food ingestion, the sleep–wake cycle, and triggering vomiting.

H2R, comparably to H1R, is widely distributed in peripheral tissues as well as in the central nervous system. The receptor is linked to Gs leading to activation of the adenylyl cyclase. One of the first actions discovered was the gastric acid production from parietal cells, which is largely mediated by H2R (Black et al., 1972). However, beyond this effect, histamine acts via H2R to relax smooth muscle, as has been shown in the respiratory tract, uterus, and vascular muscle. Stimulation of H2R in the heart causes positive chronotropic and inotropic effects. Immunomodulatory action of histamine is also mediated via H2R. Activation of H2R influences the production of diverse cytokines in various types of cells such as monocytes, dendritic cells, and T cells, mainly to an antiinflammatory stage (Baumer and Rossbach, 2010).

H3R couples to Gi/o to inhibit adenylyl cyclase leading to decreased cyclic AMP. H3R is pivotally expressed in the central nervous system (Lovenberg et al., 1999), where it is predominantly found in areas of the brain that are responsible for cognitive abilities. On the one hand, H3R acts as an autoreceptor, regulating the synthesis and release of histamine from histaminergic neurons. On the other hand, this histamine receptor also regulates the release of various other neurotransmitters such as dopamine, serotonin, and acetylcholine from nonhistaminergic neurons (Sander et al., 2008). The wide distribution of H3R in the central nervous system indicates a large list of possible indications for H3R antagonists, including cognitive disorders, sleep disorders, obesity, Alzheimer’s disease, and schizophrenia (Sander et al., 2008). The role of H3R in inflammatory processes and in pruritus is also under investigation; an intradermal injection of a selective H3R antagonist in mice can induce pruritus (Rossbach et al., 2011).

H4R has the highest sequence homology to the H3R. The H4R is expressed on several cells of the immune system. Comparable to H3R, it is coupled to Gi/o, reducing, for example, forskolin-induced cAMP in cells. But activation of H4R also induced Ca2+ influx in immune cells and sensory neurons. H4R-expression occurs on numerous hematopoietic cells such as mast cells, basophils, eosinophils, different T cells, monocytes, macrophages, and dendritic cells (Thurmond et al., 2008). Expression of H4R has also been shown on nerve cells of the dorsal root ganglia and in the spinal cord (Strakhova et al., 2009; Rossbach et al., 2011). H4R seems to have a central function in modulating the immune response. H4R influences cell activation, cell migration, and cytokine and chemokine production of various immune cells (Hofstra et al., 2003; Zampeli and Tiligada, 2009; Baumer and Rossbach, 2010). These findings have been corroborated by in vivo studies in which blockade of H4R led to reduction of inflammation and pruritus (Thurmond et al., 2004, 2008; Cowden et al., 2010) and clinical trials with H4R antagonists in humans for allergic-inflammatory diseases are currently under way (Kollmeier et al., 2014).

Pharmacological Effects

Histamine administered orally has essentially no effect because it is destroyed rapidly by the GI tract and liver. Intravenous histamine produces a spectrum of characteristic effects including smooth muscle contraction, hypotension, increased gastric secretion, and dermal reactions.

Difficulties are encountered when attempts are made to designate H1– or H2-receptor responsibility for each action of histamine. In some tissues, H1 and H2 receptors are complementary and subserve similar tissue responses. In contrast, distinct and even opposing functions of the two receptor types have been identified in some tissues. Species differences are formidable and in most cases await further study for classification. In the following paragraphs, only the more representative examples of H1– or H2-receptor involvement, when known, are discussed.

Cardiovascular System 

The principal circulatory effects of histamine are dilation of terminal arterioles and other vessels of the microcirculation, edema formation caused by increased capillary permeability, and contraction of large arteries and veins. Relative dominance of the actions varies in different species so that net circulatory response to histamine changes as the zoological scale is ascended; for example, arterioles are contracted strongly by histamine in rodents, less so in cats, and actually are dilated in dogs, nonhuman primates, and humans.

In rabbits, histamine is a pressor agent as a result of pronounced constriction of large blood vessels. This constrictor activity is feeble in carnivores where vasodilation of the microcirculation dominates instead. Thus the blood pressure response to histamine in cats, dogs, and primates is hypotension caused by a sharp fall in peripheral vascular resistance. The fall in blood pressure is dose dependent but is usually short lived because of compensatory reflexes and inactivation of histamine.

The striking effects of histamine on the microcirculation can be demonstrated quite convincingly in the human subject. When this agent is administered intradermally, a characteristic triple response is produced, which includes: localized redness at the injection site, developing within a few seconds and attaining maximal hue within a minute; localized edema fluid, forming a wheal in about 90 seconds; and diffuse redness or “flare,” extending about 1 cm from the original red spot. The central redness and edema are from the dilation and increased permeability of local microcirculatory vessels (terminal arterioles, capillaries, and venules). The surrounding flush, which is accompanied by itching and perhaps pain, is due to dilation of neighboring arterioles brought about by a poorly understood axonal reflex mechanism. The triple response of human skin may be similar to manifestations of urticaria in animals. Intradermal injection of histamine leads to a consistent wheal and flare reaction also in dogs. As therapeutically relevant concentrations of cetirizine reduce wheal and erythema by more than 80%, it is likely that these reactions are mainly mediated by activation of H1 receptor (Bizikova et al., 2008).

Cardiac effects of histamine are minimal when compared to vascular actions. In the intact animal, slight tachycardia is a common finding. This response is mainly secondary to baroreceptor reflexes activated by the depressor effect. In isolated heart muscle, histamine can elicit positive inotropic and chronotropic effects that are produced partly by release of norepinephrine from nerve endings and also to direct activation of H2 receptors in the heart muscle. There is some evidence that in vivo cardiac responses to histamine injection may partially reflect activation of cardiac H2 receptors.

Nonvascular Smooth Muscle 

Histamine contracts bronchial smooth muscle via H1 receptors in numerous mammals including the guinea pig, cat, rabbit, dog, goat, calf, pig, horse, and human (Chand and Eyre, 1975; Mohammed et al., 1993; Vietmeier et al., 2007). Guinea pigs are exceptionally sensitive, and even minute doses of histamine can evoke bronchoconstriction leading to death. Humans with bronchial asthma likewise demonstrate increased sensitivity to bronchial effects of histamine and other bronchial smooth muscle stimulants. In contrast, histamine can mediate relaxation of respiratory smooth muscle in some species. Histamine-induced tracheal relaxation in cats involves both H1 and H2 receptors, while bronchial relaxation in sheep seems to be mediated by H2 receptors (Hirschowitz, 1979).

Relaxation of the rat uterus by histamine is mediated by H2 receptors, but uterine muscle of other species is generally contracted by histamine. Responses of intestinal muscle also vary with species and region, but the classic effect is a contractile response caused by H1 receptors.

Peripheral Nerve Endings

In humans, nonhuman primates, and mice, intradermal injection of histamine induces itch by stimulation C-type nerve fibers (Johanek et al., 2007). Interestingly, dogs show low and very inconsistent itch behavior after intradermal injection of histamine (Carr et al., 2009). In mice and humans it has been shown that both H1 and H4 receptor antagonists reduce histamine induced itch, indicating also a central role for H4R in histamine-dependent pruritus (Kollmeier et al., 2014).

Exocrine Glands 

The following exocrine glands are listed in descending order of response to histamine: gastric, salivary, pancreatic, bronchial, and lacrimal. Gastric secretion of hydrochloric acid and, to a lesser degree, pepsinogen is unquestionably the most important; this response is mediated by H2 receptors.

Medical Use 

There is no direct medical use of histamine. It is used as a diagnostic agent to assess bronchial hypersensitivity in humans patients and it is serves as a positive control in humans and dogs during allergy skin testing.


Although the pharmacological effects of histamine can be antagonized by several types of drugs, the term antihistamine is restricted to agents that act on histamine receptors.

Agents such as catecholamines and xanthines exhibit pharmacological activities that are, among other things, antagonistic to actions of histamine. However, these opposing actions are mediated by different receptors and cellular pathways; they represent physiological antagonism.


Bovet and Staub (1937), of the Pasteur Institute in Paris, first demonstrated that two phenolic esters possessed antihistaminic activity. One of these compounds, 929F (thymoxyethyldiethylamine), protected guinea pigs against several lethal doses of histamine. Although the original drugs were too toxic for therapeutic use, their discovery led to development of many modern antihistamines. Such compounds are now referred to as H1 and H2 antihistamines, based on the previously described differentiation of histamine receptors into H1 and H2 subtypes (Ash and Schild, 1966; Black et al., 1972). Currently, there are also H3 and H4 antihistamines in clinical trials but no substance is close to marketing and only very few data exist for species relevant to veterinary science.

H1 Receptor Antagonists

H1 receptor antagonists are classified as inverse agonists, rather than histamine antagonists (Simons, 2004), as they reduce constitutive activity of the receptor and compete with histamine. The binding of the natural ligand histamine induces a fully active conformation, whereas antihistamine binding yields an inactive conformation. However, the term histamine antagonists is still often used in veterinary literature.

The H1

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Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Histamine, Serotonin, and their Antagonists

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