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The biogenic amine, histamine, is a major mediator of inflammation, anaphylaxis, and gastric acid secretion; in addition, histamine plays a role in neurotransmission. Our understanding of the physiological and pathophysiological roles of histamine has been enhanced by the development of subtype-specific receptor antagonists and by the cloning of four receptors for histamine. Competitive antagonists of H1 receptors have diverse actions and are used therapeutically in treating allergies, urticaria, anaphylactic reactions, nausea, motion sickness, insomnia, and some symptoms of asthma. Antagonists of the H2 receptor are effective in reducing gastric acid secretion. The peptide, bradykinin, has cardiovascular effects similar to those of histamine and plays prominent roles in inflammation and nociception.

This chapter presents the physiology and pathophysiology of histamine and kinins and the pharmacology of the antagonists that inhibit responses to these mediators.


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...

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