Gastric Acid Secretion

Acting at H2 receptors, histamine is a powerful gastric secretagogue and evokes a copious secretion of acid from parietal cells (see Figure 36-1); it also increases the output of pepsin and intrinsic factor. Although the secretion of gastric acid also is evoked by stimulation of the vagus nerve and by the enteric hormone gastrin, presumably by activation of M3 and CCK2 receptors on the parietal cell, acetylcholine and gastrin also stimulate histamine release from the ente-rochromaffin-like cell. There is no doubt that histamine is the dominant physiological mediator of acid secretion: blockade of H2 receptors not only eliminates acid secretion in response to histamine but also causes nearly complete inhibition of responses to gastrin and vagal stimulation. The regulation of gastric acid secretion and the clinical utility of H2 antagonists are discussed in Chapter 36.

404 SECTION IV Autacoids: Drug Therapy of Inflammation CENTRAL NERVOUS SYSTEM

There is substantial evidence that histamine functions as a neurotransmitter in the CNS. Hista-mine, histidine decarboxylase, and enzymes that catalyze the degradation of histamine are distributed nonuniformly in the CNS and are concentrated in synaptosomal fractions of brain homogenates. H1 receptors are found throughout the CNS and are densely concentrated in the hypothalamus. Histamine increases wakefulness via H1 receptors, explaining the potential for sedation by classical antihistamines. Histamine acting through H1 receptors inhibits appetite. His-tamine-containing neurons may participate in the regulation of drinking, body temperature, and the secretion of vasopressin (antidiuretic hormone), as well as in the control of blood pressure and the perception of pain.

Pharmacological Effects

RECEPTOR-EFFECTOR COUPLING AND MECHANISMS OF ACTION Histamine receptors are G protein-coupled receptors (GPCRs) and details of their pharmacodynamic actions and agonist and antagonist ligands are presented in Table 24-1. The pharmacologic definition of Hj, H2, and H3 receptors generally is clear: relatively specific agonists and antagonists are available. However, the H4 receptor exhibits 35-40% homology to the H3 receptor, and the two are harder to distinguish pharmacologically. High-affinity H3 agonists interact with H4 receptors as well, albeit with reduced potency, as do the H3 antagonists burimamide and clobenpropit. Several nonimidazole compounds are selective H3 antagonists. The atypical antipsychotic agent clozapine is an effective Hj-receptor antagonist, a weak H3-receptor antagonist, but a putative H4-receptor agonist. Many neuroleptics are H1- and H2-receptor antagonists, but it is unclear whether interactions with H receptors play a role in the effects of antipsychotic agents. The finding of high constitutive activity of the human H3 receptor has sparked a reexamination of the potential role of inverse agonists (see Chapter 1) of H3 receptors as therapeutic modulators of H3-receptor-mediated inhibition of hista-mine release from histaminergic neurons. H1 receptors also are reported to express intrinsic or constitutive activity; thus, many H1 antagonists may function as inverse agonists. H2-receptor stimulation increases cyclic AMP and leads to feedback inhibition of histamine release from mast cells and basophils. Activation of H3 and H4 receptors decreases cellular cyclic AMP; H3 receptors also may function as presynaptic autoinhibitory receptors on histaminergic neurons.

Hj AND H2 RECEPTORS Once released, histamine can exert local or widespread effects on smooth muscles and glands. 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 above). 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 (see Chapter 36).

H3AND H4 RECEPTORS H3 receptors are expressed mainly in the CNS, especially in the basal ganglia, hippocampus, and cortex. H3 receptors function as autoreceptors on histaminergic neurons. H3 antagonists promote wakefulness; conversely, H3 agonists promote sleep. H4 receptors are on immune active cells such as eosinophils and neutrophils, as well as in the GI tract and CNS. Activation of H4 receptors on eosinophils induces a cellular shape change, chemotaxis, and up-regulation of adhesion molecules such as CD11b/CD18 and ICAM-1 suggesting that the histamine released from mast cells acts at H4 receptors to recruit eosinophils. H4 antagonists may be useful inhibitors of allergic and inflammatory responses.

CARDIOVASCULAR SYSTEM Histamine characteristically causes dilation of resistance vessels, an increase in capillary permeability, and an overall fall in systemic blood pressure. In some vascular beds, histamine will constrict veins, contributing to the extravasation of fluid and edema formation upstream of the capillaries and postcapillary venules.

Vasodilation Vasodilation, the most important vascular effect of histamine, involves both Hj and H2 receptors distributed throughout the resistance vessels in most vascular 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 mediate an endothelium-NO-dependent dilation that is relatively rapid in onset and short-lived. By contrast, activation of H2 receptors (stimulating the cyclic AMP-PKA pathway in smooth muscle) causes dilation that develops more slowly and is more sustained.

Increased "Capillary" Permeability This effect of histamine on small vessels results in outward passage of plasma protein and fluid into the extracellular spaces, an increase in the flow of lymph and its protein content, and edema formation. H1 receptors on endothelial cells are the major mediators of this response.

Increased permeability results mainly from actions of histamine on postcapillary venules, where histamine causes the endothelial cells to contract and separate at their boundaries and thus to expose the basement membrane, which is freely permeable to plasma protein and fluid. The gaps between endothelial cells also may permit passage of circulating cells that are recruited to the tissues during the mast cell response. Recruitment of circulating leukocytes is promoted by H1-receptor-mediated up-regulation of leukocyte adhesion. This process involves histamine-induced expression of the adhesion molecule P-selectin on the endothelial cells.

Triple Response of Lewis

Intradermal histamine injection elicits a characteristic phenomenon known as the triple response. This consists of (1) 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 about a minute; (2) a brighter red flush, or "flare," extending about 1 cm or so beyond the original red spot and developing more slowly; and (3) 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 (H-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).

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 speeds heart rate by hastening diastolic depolarization in the sinoatrial (SA) node. It also acts directly to slow atrioventricular (AV) conduction, to increase automaticity, and in high doses especially, to elicit arrhythmias. With the exception of slowed AV conduction, which involves mainly H1 receptors, all these effects are largely attributable to H2 receptors and cyclic AMP accumulation. If histamine is given intravenously, direct cardiac effects of histamine are overshadowed by baroreceptor reflexes elicited by the reduced blood pressure. 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, and as their permeability increases, 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 stimulates or, more rarely, relaxes various extravascular smooth muscles. Contraction is due to activation of H1 receptors (linked to Gq and Ca2+ mobilization); relaxation (for the most part) is due to activation of H2 receptors. Minute doses of histamine will evoke intense bronchoconstriction in patients with bronchial asthma and certain other pulmonary diseases. Although the spasmogenic influence of H1 receptors is dominant in bronchial muscle, H2 receptors with dilator function also are present. Thus, histamine-induced bronchospasm is potentiated slightly by H2 blockade.


STRUCTURE-ACTIVITY RELATIONSHIP All the available H1-receptor antagonists are reversible competitive inhibitors of the interaction of histamine with H1 receptors. Like histamine, many H1 antagonists contain a substituted ethylamine moiety. Unlike histamine, which has a primary amino group and a single aromatic ring, most H1 antagonists have a tertiary amino group linked by a two- or three-atom chain to two aromatic substituents (e.g., diphenhydramine).


DIPHENHYDRAMINE (an ethanolamlne)

DIPHENHYDRAMINE (an ethanolamlne)

Pharmacological Properties

Most Hj antagonists have similar pharmacological actions and therapeutic applications. Their effects are largely predictable from knowledge of the consequences of the activation of Hj receptors by histamine.

SMOOTH MUSCLE Within the vascular tree, the Hj antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by activation of Hj receptors on endothelial cells (synthesis/release of NO and other mediators).

CAPILLARY PERMEABILITY Hj antagonists strongly block the increased capillary permeability and formation of edema and wheal brought about by histamine.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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