History. The history of histamine (β-aminoethylimidazole) parallels that of acetylcholine (ACh). Both were chemically synthesized before their biological significance was recognized; they were first detected as uterine stimulants in, and isolated from, extracts of ergot, where they proved to be contaminants derived from bacterial action (Dale, 1953).
Dale and Laidlaw subjected histamine to intensive pharmacological study (Dale, 1953), discovering that it stimulated a host of smooth muscles and had an intense vasodepressor action. Importantly, they observed that when a sensitized animal was injected with a normally inert protein, the immediate responses closely resembled those of poisoning by histamine. These observations anticipated by many years the finding that endogenous histamine contributes to immediate hypersensitivity reactions and to responses to cellular injury. Best and colleagues (1927) isolated histamine from fresh samples of liver and lung, thereby establishing it as a natural constituent of mammalian tissues, hence the name histamine after the Greek word for tissue, histos. The presence of histamine in tissue extracts delayed the acceptance of the discovery of some peptide and protein hormones (e.g., gastrin) until the technology for separating the naturally occurring substances was sufficiently advanced (Grossman, 1966).
Lewis and colleagues (Lewis, 1927) proposed that a substance with the properties of histamine ("H substance") was liberated from the cells of the skin by injurious stimuli, including the reaction of antigen with antibody. We now know that endogenous histamine plays a role in the immediate allergic response and is an important regulator of gastric acid secretion. More recently, a role for histamine as a modulator of neurotransmitter release in the central and peripheral nervous systems has emerged.
Early suspicions that histamine acts through more than one receptor have been borne out by the elucidation of four classes of receptors, designated H1 (Ash and Schild, 1966), H2 (Black et al., 1972), H3 (Arrang et al., 1987), and H4 (Leurs et al., 2009). H1 receptors are blocked selectively by the classical "antihistamines." Second-generation H1 antagonists are collectively referred to as nonsedating antihistamines. The term third generation has been applied to some recently developed antihistamines, such as active metabolites of first- or second-generation antihistamines that are not further metabolized (e.g., cetirizine derived from hydroxyzine or fexofenadine from terfenadine) or to antihistamines that have additional therapeutic effects. However, the Consensus Group on New-Generation Antihistamines concluded that none of the currently available antihistamines can be classified as true third-generation drugs, defined as lacking in cardiotoxicity, drug-drug interactions, and CNS effects or with possible additional beneficial effects (e.g., anti-inflammatory) (Holgate et al., 2003). The discovery of H2 antagonists and their ability to inhibit gastric secretion has contributed greatly to the resurgence of interest in histamine in biology and clinical medicine (Chapter 45). H3 receptors were discovered as presynaptic autoreceptors on histamine-containing neurons that mediate feedback inhibition of the release and synthesis of histamine. The development of selective H3 receptor agonists and antagonists has led to an increased understanding of the importance of H3 receptors in histaminergic neurons in vivo. None of these H3 agonists or antagonists has yet emerged as a therapeutic agent (Sander et al., 2008). The H4 receptor is most similar to the H3 receptor but is expressed in cells of hematopoietic lineage; the availability of H4-specific antagonists with anti-inflammatory properties should help to define the biological roles of the H4 receptor (Thurmond et al., 2008).
Chemistry. Histamine is a hydrophilic molecule consisting of an imidazole ring and an amino group connected by two methylene groups. The pharmacologically active form is the monocationic Nγ–H tautomer, which is the charged form of the species depicted in Figure 32–1 (Ganellin and Parsons, 1982). H3 and H4 receptors have a much higher affinity for histamine than H1 and H2 receptors, and the four histamine receptors can be activated differently by analogs of histamine (Venable and Thurmond, 2006) (Figure 32–1 and Table 32–1). The specificities of histamine analogs were re-evaluated after the discovery of the H4 receptor. Thus, 4-methylhistamine and dimaprit, originally classified as H2 receptors (Black et al., 1972), are full H4 agonists with a ∼100-fold higher affinity for the H4 receptor. A number of H3 agonists also are weaker agonists of the H4 receptor (Lim et al., 2005; Venable and Thurmond, 2006).
Table 32-1Characteristics of Histamine Receptors ||Download (.pdf) Table 32-1 Characteristics of Histamine Receptors
| ||H1 ||H2 ||H3* ||H4 |
|Size (amino acids) ||487 ||359 ||329-445 ||390 |
|G protein coupling (second messengers) ||Gq/11 (↑ Ca2+; ↑ NO and ↑ cGMP) ||Gs (↑ cAMP) ||Gi/o (↓ cAMP; ↑ MAP kinase) ||Gi/o (↓ cAMP; ↑ Ca2+) |
|Distribution ||Smooth muscle, endothelial cells, CNS ||Gastric parietal cells, cardiac muscle, mast cells, CNS ||CNS: presynaptic ||Cells of hematopoietic origin |
|Representative agonist ||2-CH3-histamine ||Amthamine ||(R)-α-CH3-histamine ||4-CH3-histamine |
|Representative antagonist ||Chlorpheniramine ||Ranitidine ||Tiprolisant ||JNJ7777120 |
Structure of histamine and some H1, H2, H3, and H4 agonists- Dimaprit and 4-methylhistamine, originally identified as specific H2 agonists, have a much higher affinity for the H4 receptor; 4-methylhistamine is the most specific available H4 agonist, with ∼10-fold higher affinity than dimaprit, a partial H4 agonist. Impromidine is among the most potent H2 agonists but also is an antagonist at H1 and H3 receptors and a partial agonist at H4 receptors. (R)-α-Methylhistamine and imetit are high-affinity agonists of H3 receptors and lower-affinity full agonists at H4 receptors.
Distribution and Biosynthesis of Histamine
Distribution. Histamine is widely, if unevenly, distributed throughout the animal kingdom and is present in many venoms, bacteria, and plants. Almost all mammalian tissues contain histamine in amounts ranging from <1 to >100 μg/g. Concentrations in plasma and other body fluids generally are very low, but human cerebrospinal fluid (CSF) contains significant amounts. The mast cell is the predominant storage site for histamine in most tissues; the concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial mucosa, and intestinal mucosa.
Synthesis, Storage, and Metabolism. Histamine is formed by the decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase (Figure 32–2), found in every mammalian tissue that contains histamine. The chief site of histamine storage in most tissues is the mast cell; in the blood, it is the basophil. These cells synthesize histamine and store it in secretory granules.
Pathways of histamine synthesis and metabolism in humans. Histamine is synthesized from histidine by decarboxylation. Histamine is metabolized via two pathways, predominantly by methylation of the ring followed by oxidative deamination (left side of figure), and secondarily by oxidative deamination and then conjugation with ribose.
At the secretory granule pH of ∼5.5, histamine is positively charged and ionically complexed with negatively charged acidic groups on other granule constituents, primarily proteases and heparin or chondroitin sulfate proteoglycans. The turnover rate of histamine in secretory granules is slow, and when tissues rich in mast cells are depleted of their histamine stores, it may take weeks before concentrations return to normal levels. Non–mast cell sites of histamine formation include the epidermis, the gastric mucosa, neurons within the CNS, and cells in regenerating or rapidly growing tissues. Turnover is rapid at these non–mast cell sites because the histamine is released continuously rather than stored. Non–mast cell sites of histamine production contribute significantly to the daily excretion of histamine metabolites in the urine. Because L-histidine decarboxylase is an inducible enzyme, the histamine-forming capacity at such sites is subject to regulation. Histamine that is ingested or formed by bacteria in the gastrointestinal (GI) tract does not contribute to the body's stores; rather, it is rapidly metabolized, and the metabolites are eliminated in the urine.
There are two major paths of histamine metabolism in humans (Figure 32–2). The more important is ring methylation to form N-methylhistamine, catalyzed by histamine-N-methyltransferase, which is distributed widely. Most of the N-methylhistamine formed is then converted to N-methylimidazole acetic acid by monoamine oxidase (MAO), and this reaction can be blocked by MAO inhibitors (Chapters 8, 15, and 22). Alternatively, histamine may undergo oxidative deamination catalyzed mainly by the nonspecific enzyme diamine oxidase, yielding imidazole acetic acid, which is then converted to imidazole acetic acid riboside. These metabolites have little or no activity and are excreted in the urine. Measurement of N-methylhistamine in urine affords a more reliable index of histamine production than assessment of histamine itself. Artifactually elevated levels of histamine in urine arise from genitourinary tract bacteria that can decarboxylate histidine. In addition, the metabolism of histamine appears to be altered in patients with mastocytosis such that determination of histamine metabolites is a more sensitive diagnostic indicator of the disease than histamine.
Release and Functionsof Endogenous Histamine
Histamine has important physiological roles. After its release from storage granules as a result of the interaction of antigen with immunoglobulin E (IgE) antibodies on the mast cell surface, histamine plays a central role in immediate hypersensitivity and allergic responses. The actions of histamine on bronchial smooth muscle and blood vessels account for many of the symptoms of the allergic response. In addition, some drugs act directly on mast cells to release histamine, causing untoward effects. Histamine has a major role in regulating gastric acid secretion and also modulates neurotransmitter release.
Role in Allergic Responses. The principal target cells of immediate hypersensitivity reactions are mast cells and basophils (Schwartz, 1994). As part of the allergic response to an antigen, IgE antibodies are generated and bind to the surfaces of mast cells and basophils via specific high-affinity Fc receptors. This receptor, Fc∊RI, consists of α, β, and two γ chains (Chapter 35). Atopic individuals develop IgE antibodies to commonly inhaled antigens. This is a heritable trait, conferring a predilection to rhinitis, asthma, and atopic dermatitis.
Antigen bridges the IgE molecules and via Fc∊RI activates signaling pathways in mast cells or basophils involving tyrosine kinases and subsequent phosphorylation of multiple protein substrates within 5-15 seconds of contact with antigen. Protein kinases implicated include the Src-related kinases Lyn and Syk. Prominent among the phosphorylated proteins are the β and γ subunits of Fc∊RI, itself, and phospholipase C (PLC)γ1 and PLCγ2, with consequent production of inositol trisphosphate (IP3) and mobilization of intracellular Ca2+ (Chapter 3). These events trigger the exocytosis of the contents of secretory granules.
Release of Other Autacoids. The release of histamine only partially explains the biological effects that ensue from immediate hypersensitivity reactions because a broad spectrum of other inflammatory mediators is released on mast cell activation.
Stimulation of IgE receptors also activates phospholipase A2 (PLA2), leading to the production of a host of mediators, including platelet-activating factor (PAF) and metabolites of arachidonic acid such as leukotrienes C4 and D4, which contract the smooth muscles of the bronchial tree (Chapters 33 and 36). Kinins also are generated during some allergic responses. Thus, the mast cell secretes a variety of inflammatory mediators in addition to histamine, each contributing to the major symptoms of the allergic response (see below).
Regulation of Mediator Release. The wide variety of mediators released during the allergic response can explain the ineffectiveness of drug therapy focused on a single mediator. Agents that act at muscarinic or α-adrenergic receptors increase the release of mediators, an effect of little clinical significance. Epinephrine and related drugs that act through β2 adrenergic receptors increase cellular cyclic AMP and thereby inhibit the secretory activities of mast cells. However, the beneficial effects of β adrenergic agonists in allergic states such as asthma are due mainly to relaxing bronchial smooth muscle (Chapters 12 and 36).
Histamine Release by Drugs, Peptides, Venoms, and Other Agents. Many compounds, including a large number of therapeutic agents, stimulate the release of histamine from mast cells directly and without prior sensitization. Responses of this sort are most likely to occur following intravenous injections of certain categories of substances, particularly organic bases such as amides, amidines, quaternary ammonium compounds, pyridinium compounds, piperidines, and alkaloids (Rothschild, 1966). Tubocurarine, succinylcholine, morphine, some antibiotics, radiocontrast media, and certain carbohydrate plasma expanders also may elicit the response. The phenomenon is one of clinical concern, and may account for unexpected anaphylactoid reactions. For example, vancomycin-induced red-man syndrome, involving hypotension and flushing in the upper body and face, may be mediated through histamine release.
In addition to therapeutic agents, certain experimental compounds stimulate the release of histamine as their dominant pharmacological characteristic. The archetype is the polybasic substance known as compound 48/80. This is a mixture of low-molecular-weight polymers of p-methoxy-N-methylphenethylamine, of which the hexamer is most active.
Basic polypeptides often are effective histamine releasers, and over a limited range, their potency generally increases with the number of basic groups. For example, bradykinin is a poor histamine releaser, whereas kallidin (Lys-bradykinin) and substance P, with more positively charged amino acids, are more active. Some venoms, such as that of the wasp, contain potent histamine-releasing peptides (Johnson and Erdös, 1973). Polymyxin B also is very active. Basic polypeptides released upon tissue injury constitute pathophysiological stimuli to secretion for mast cells and basophils.
Within seconds of the intravenous injection of a histamine liberator, human subjects experience a burning, itching sensation. This effect, most marked in the palms of the hand and in the face, scalp, and ears, is soon followed by a feeling of intense warmth. The skin reddens, and the color rapidly spreads over the trunk. Blood pressure falls, the heart rate accelerates, and the subject usually complains of headache. After a few minutes, blood pressure recovers, and crops of hives usually appear on the skin. Colic, nausea, hypersecretion of acid, and moderate bronchospasm also frequently occur. The effect becomes less intense with successive injections as the mast cell stores of histamine are depleted. Histamine liberators do not deplete tissues of non–mast cell histamine.
Mechanism of Histamine-Releasing Agents. Histaminereleasing substances activate the secretory responses of mast cells and basophils by causing a rise in intracellular Ca2+. Some are ionophores and directly facilitate the entry of Ca2+ into the cell; others, such as neurotensin, act on specific G protein–coupled receptors (GPCRs). In contrast, the precise mechanism by which basic secretagogues (e.g., substance P, mastoparan, kallidin, compound 48/80, and polymyxin B) release histamine still is unclear. These agents can directly activate Gi proteins after being taken up by the cell (Ferry et al., 2002), but more recent evidence indicates the involvement of a cell-surface GPCR in the Mas-related gene family or integrin-associated protein CD47 coupled to Gi (Sick et al., 2009). The downstream effectors appear to be βγ subunits released from Gαi, which activate the PLCβ–IP3–Ca2+ pathway. Antigen–IgE complexes lead to mobilization of stored Ca2+ and activation of isoforms of PLCγ, as described in "Role in Allergic Responses."
Histamine Release by Other Means. Clinical conditions related to histamine release include cold, cholinergic, and solar urticaria. Some of these involve specific secretory responses of the mast cells and cell-fixed IgE. However, nonspecific cellular damage from any cause can release histamine. The redness and urticaria that follow scratching of the skin is a familiar example.
Increased Proliferation of Mast Cells and Basophils and Gastric Carcinoid Tumors. In urticaria pigmentosa (cutaneous mastocytosis), mast cells aggregate in the upper corium and give rise to pigmented cutaneous lesions that sting when stroked. In systemic mastocytosis, overproliferation of mast cells also is found in other organs. Patients with these syndromes suffer a constellation of signs and symptoms attributable to excessive histamine release, including urticaria, dermographism, pruritus, headache, weakness, hypotension, flushing of the face, and a variety of GI effects, such as diarrhea or peptic ulceration. Episodes of mast cell activation with attendant systemic histamine release are precipitated by a variety of stimuli, including exertion, insect stings, exposure to heat, and exposure to drugs that release histamine directly or to which patients are allergic. In myelogenous leukemia, excessive numbers of basophils are present in the blood, raising its histamine content to high levels that may contribute to chronic pruritus. Gastric carcinoid tumors secrete histamine, which is responsible for episodes of vasodilation as part of the patchy "geographical" flush.
Gastric Acid Secretion. Histamine acting at H2 receptors is a powerful gastric secretagogue, evoking a copious secretion of acid from parietal cells (see Figure 45–1); it also increases the output of pepsin and intrinsic factor. The secretion of gastric acid from parietal cells also is caused by stimulation of the vagus nerve and by the enteric hormone gastrin. However, histamine undoubtedly is the dominant physiological mediator of acid secretion; blockade of H2 receptors not only antagonizes acid secretion in response to histamine but also inhibits responses to gastrin and vagal stimulation. (For regulation of gastric acid secretion and the clinical utility of H2 antagonists, see Chapter 45.)
Central Nervous System. There is substantial evidence that histamine functions as a neurotransmitter in the CNS. Histamine-containing neurons control both homeostatic and higher brain functions, including regulation of the sleep-wake cycle, circadian and feeding rhythms, immunity, learning, memory, drinking, and body temperature (see Haas et al., 2008). However, knockout animals lacking histamine or its receptors exhibit only subtle defects unless challenged, and no human disease has yet been directly linked to dysfunction of the brain histamine system. Histamine, histidine decarboxylase, enzymes that metabolize histamine, and H1, H2, and H3 receptors are distributed widely but non-uniformly in the CNS (see Haas et al., 2008). H1 receptors are associated with both neuronal and non-neuronal elements (e.g., glia, blood cells, vessels) and are concentrated in regions that control neuroendocrine function, behavior, and nutritional state. Distribution of H2 receptors is more consistent with histaminergic projections than H1 receptors, suggesting that they mediate many of the postsynaptic actions of histamine. H3 receptors also are heterogeneously concentrated in areas known to receive histaminergic projections, consistent with their function as presynaptic autoreceptors. Histamine inhibits appetite and increases wakefulness via H1 receptors, explaining sedation by classical antihistamines (Haas et al., 2008).
Receptor–Effector Coupling and Mechanisms of Action. Histamine receptors are GPCRs (Leurs et al., 2009; Haas et al., 2008; Thurmond et al., 2008) (Table 32–1). H1 receptors couple to Gq/11 and activate the PLC–IP3–Ca2+ pathway and its many possible sequelae, including activation of PKC, Ca2+–calmodulin–dependent enzymes (eNOS and various protein kinases), and PLA2. H2 receptors link to Gs to activate the adenylyl cyclase–cyclic AMP–PKA pathway, whereas H3 and H4 receptors couple to Gi/o to inhibit adenylyl cyclase and decrease cellular cyclic AMP. Activation of H3 receptors also can activate MAP kinase and inhibit the Na+/H+ exchanger, and activation of H4 receptors mobilizes stored Ca2+ in some cells (Leurs et al., 2009; Haas et al., 2008; Thurmond et al., 2008; Esbenshade et al., 2008). Armed with this information, knowledge of the cellular expression of H receptor subtypes, and an understanding of the differentiated functions of a particular cell type, one can predict a cell's response to histamine. Of course, in a physiological setting, a cell is exposed to a myriad of hormones simultaneously, and significant interactions may occur between signaling pathways, such as the Gq → Gs cross-talk described in a number of systems (Meszaros et al., 2000). Furthermore, the differential expression of H receptor subtypes on neighboring cells and the unequal sensitivities of H receptor–effector response pathways can cause parallel and opposing cellular responses to occur together, complicating interpretation of the overall response of a tissue. For example, activation of H1 receptors on vascular endothelium stimulates the Ca2+ - mobilizing pathway (Gq–PLC–IP3) and activates eNOS to produce nitric oxide (NO), which diffuses to nearby smooth muscle cells to increase cyclic GMP and cause relaxation. Stimulation of H1 receptors on smooth muscle also will mobilize Ca2+ but cause contraction, whereas activation of H2 receptors on the same smooth muscle cell will link via Gs to enhanced cyclic AMP accumulation, activation of PKA, and thence to relaxation.
The existence of multiple histamine receptors was predicted by the studies of Ash and Schild (1966) and Black and colleagues (1972) a generation before the cloning of histamine receptors. Similarly, heterogeneity of H3 receptors, predicted by kinetic and radioligand-binding studies, has been confirmed by cloning, which revealed H3 isoforms differing in the third intracellular loop, transmembrane helices 6 and 7, and C-terminal tail, and in their capacity to couple Gi, inhibit adenylyl cyclase, and activate MAP kinase. Molecular cloning studies also identified the H4 receptor.
As Figure 32–1 and Table 32–1 indicate, the pharmacological definition of H1, H2, and H3 receptors is clear because relatively specific agonists and antagonists are available. However, the H4 receptor exhibits 35-40% homology to isoforms of the H3 receptor, and the two were harder to distinguish pharmacologically because many high-affinity H3 ligands also interact with H4 receptors. Several non-imidazole compounds that are more selective H3 antagonists have been developed (Sander et al., 2008), and there are now several selective H4 antagonists (Leurs et al., 2009; Venable and Thurmond, 2006). 4-Methylhistamine and dimaprit, previously identified as specific H2 agonists (Black et al., 1972), are actually more potent H4 agonists (Venable and Thurmond, 2006).
H1 and H2 Receptors. H1 and H2 receptors are distributed widely in the periphery and in the CNS. Histamine can exert local or widespread effects on smooth muscles and glands. It causes itching and stimulates secretion from nasal mucosa. It contracts many smooth muscles, such as those of the bronchi and gut, but markedly relaxes others, including those in small blood vessels. Histamine also is a potent stimulus of gastric acid secretion (see "Gastric Acid Secretion"). Other, less prominent effects include formation of edema and stimulation of sensory nerve endings. Bronchoconstriction and contraction of the gut are mediated by H1 receptors. Gastric secretion results from the activation of H2 receptors and, accordingly, can be inhibited by H2 receptor antagonists. Some responses, such as vascular dilation, are mediated by both H1 and H2 receptor stimulation.
H3 and H4 Receptors. H3 receptors are expressed mainly in the CNS (Arrang et al., 1987), especially in the basal ganglia, hippocampus, and cortex. H3 receptors function as autoreceptors on histaminergic neurons, much like presynaptic α2 receptors, inhibiting histamine release and modulating the release of other neurotransmitters. Because H3 receptors have high constitutive activity, histamine release is tonically inhibited, and inverse agonists will thus reduce receptor activation and increase histamine release from histaminergic neurons. H3 agonists promote sleep; thus, H3 antagonists promote wakefulness. H4 receptors primarily are found in cells of hematopoietic origin such as eosinophils, dendritic cells, mast cells, monocytes, basophils, and T cells but has also been detected in the GI tract, dermal fibroblasts, CNS, and primary sensory afferent neurons (Leurs et al., 2009). Activation of H4 receptors in some of these cell types has been associated with induction of cellular shape change, chemotaxis, secretion of cytokines and upregulation of adhesion molecules, suggesting that H4 antagonists may be useful inhibitors of allergic and inflammatory responses (Thurmond et al., 2008.
Effects on Histamine Release. H2 receptor stimulation increases cyclic AMP and leads to feedback inhibition of histamine release from mast cells and basophils, whereas activation of H3 and H4 receptors has the opposite effect by decreasing cellular cyclic AMP (Oda et al., 2000). Activation of presynaptic H3 receptors also inhibits histamine release from histaminergic neurons.
Histamine Toxicity from Ingestion. Histamine is the toxin in food poisoning from spoiled scombroid fish such as tuna (Morrow et al., 1991). The high histidine content combines with a large bacterial capacity to decarboxylate histidine, generating a lot of histamine. Ingestion of the fish causes severe nausea, vomiting, headache, flushing, and sweating. Histamine toxicity, manifested by headache and other symptoms, also can follow red wine consumption in persons with a diminished ability to degrade histamine. The symptoms of histamine poisoning can be suppressed by H1 antagonists.
Cardiovascular System. Histamine characteristically dilates resistance vessels, increases capillary permeability, and lowers systemic blood pressure. In some vascular beds, histamine constricts veins, contributing to the extravasation of fluid and edema formation upstream in capillaries and postcapillary venules.
Vasodilation. This is the most important vascular effect of histamine in humans. Vasodilation involves both H1 and H2 receptors distributed throughout the resistance vessels in most vascular beds; however, quantitative differences are apparent in the degree of dilation that occurs in various beds. Activation of either the H1 or H2 receptor can elicit maximal vasodilation, but the responses differ. H1 receptors have a higher affinity for histamine and cause Ca2+-dependent activation of eNOS in endothelial cells; NO diffuses to vascular smooth muscle, increasing cyclic GMP (Table 32–1) and causing relaxation that results in a relatively rapid and short-lived vasodilation. By contrast, activation of H2 receptors on vascular smooth muscle stimulates the cyclic AMP–PKA pathway, causing dilation that develops more slowly and is more sustained. As a result, H1 antagonists effectively counter small dilator responses to low concentrations of histamine but only blunt the initial phase of larger responses to higher concentrations of the amine. In addition, there is a variable distribution of H1 receptors on vascular smooth muscle, resulting in direct vasoconstrictor responses in vein, skin, and skeletal muscle and in larger coronary arteries.
Increased "Capillary" Permeability. Histamine's effect on small vessels results in efflux of plasma protein and fluid into the extracellular spaces and an increase lymph flow, causing edema. H1 receptors on endothelial cells are the major mediators of this response; the role of H2 receptors is uncertain.
Increased permeability results from histamine activation of H1 receptors on postcapillary venules. This contracts the endothelial cells, disrupts interendothelial junctions, and exposes the basement membrane, which is freely permeable to plasma proteins and fluid. The gaps between endothelial cells also may permit passage of circulating cells recruited to tissues during the mast cell response. Recruitment of circulating leukocytes is enhanced by H1 receptor–mediated expression of adhesion molecules (e.g., P-selectin) on endothelial cells (Thurmond et al., 2008).
Triple Response of Lewis. If histamine is injected intradermally, it elicits a characteristic phenomenon known as the triple response (Lewis, 1927). This consists of:
a localized red spot extending for a few millimeters around the site of injection that appears within a few seconds and reaches a maximum in ∼1 minute
a brighter red flush, or "flare," extending ∼1 cm beyond the original red spot and developing more slowly
a wheal that is discernible in 1-2 minutes and occupies the same area as the original small red spot at the injection site.
The initial red spot results from the direct vasodilating effect of histamine (H1 receptor–mediated NO production), the flare is due to histamine-induced stimulation of axon reflexes that cause vasodilation indirectly, and the wheal reflects histamine's capacity to increase capillary permeability (edema formation).
Constriction of Larger Vessels. Histamine tends to constrict larger blood vessels, in some species more than in others. In rodents, the effect extends to the arterioles and may overshadow dilation of the finer blood vessels, leading to an elevation in blood pressure. As noted earlier, H1 receptor–mediated constriction may occur in some veins and in conduit coronary arteries.
Heart. Histamine affects both cardiac contractility and electrical events directly. It increases the force of contraction of both atrial and ventricular muscle by promoting the influx of Ca2+, and it speeds heart rate by hastening diastolic depolarization in the sinoatrial (SA) node. It also directly slows atrioventricular (AV) conduction to increase automaticity and, in high doses, can elicit arrhythmias. The slowed AV conduction involves mainly H1 receptors, while the other effects are largely attributable to H2 receptors and cyclic AMP accumulation. The direct cardiac effects of histamine given intravenously are overshadowed by baroreceptor reflexes due to reduced blood pressure.
Histamine Shock. Histamine given in large doses or released during systemic anaphylaxis causes a profound and progressive fall in blood pressure. As the small blood vessels dilate, they trap large amounts of blood, their permeability increases, and plasma escapes from the circulation. Resembling surgical or traumatic shock, these effects diminish effective blood volume, reduce venous return, and greatly lower cardiac output.
Extravascular Smooth Muscle. Histamine directly contracts or, more rarely, relaxes various extravascular smooth muscles. Contraction is due to activation of H1 receptors on smooth muscle to increase intracellular Ca2+ (in contrast to intact vessels, where endothelium-derived NO causes vasodilation; see "Vasodilation"), and relaxation is mainly due to activation of H2 receptors. Responses vary widely among species and even among humans. Bronchial smooth muscle of guinea pigs is exquisitely sensitive. Minute doses of histamine also will evoke intense bronchoconstriction in patients with bronchial asthma and certain other pulmonary diseases, but in normal humans, the effect is much less. Although the spasmogenic influence of H1 receptors is dominant in human bronchial muscle, H2 receptors with dilator function also are present. Thus, histamine-induced bronchospasm in vitro is potentiated slightly by H2 blockade. In asthmatic subjects in particular, histamine-induced bronchospasm may involve an additional reflex component that arises from irritation of afferent vagal nerve endings (Nadel and Barnes, 1984).
The uterus of some species is contracted by histamine; in the human uterus, gravid or not, the response is negligible. Responses of intestinal muscle also vary with species and region, but the classical effect is contraction. Bladder, ureter, gallbladder, iris, and many other smooth muscle preparations are affected little or inconsistently by histamine.
Peripheral Nerve Endings: Pain, Itch, and Indirect Effects. Histamine stimulates various nerve endings and sensory effects. In the epidermis, it causes itch; in the dermis, it evokes pain, sometimes accompanied by itching. Stimulant actions on nerve endings, including autonomic afferents and efferents, contribute to the "flare" component of the triple response and to indirect effects of histamine on the bronchi and other organs. In the periphery, neuronal receptors for histamine are generally of the H1 type (see Rocha e Silva, 1978; Ganellin and Parsons, 1982).
The practical application of histamine is limited to use as a diagnostic agent, such as to assess nonspecific bronchial hyperreactivity in asthmatics or as a positive control injection during allergy skin testing.