Chapter 39: Histamine, Bradykinin, and Their Antagonists

INTRODUCTION

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. The cloning of four receptors for histamine and the development of subtype-specific receptor antagonists have enhanced our understanding of the physiological and pathophysiological roles of histamine. Competitive antagonists of H₁ receptors are used therapeutically in treating allergies, urticaria, anaphylactic reactions, nausea, motion sickness, and insomnia. Antagonists of the H₂ receptor are effective in reducing gastric acid secretion.

The peptides bradykinin and kallidin, released after activation of the kallikrein-kinin system, have cardiovascular effects similar to those of histamine and play prominent roles in inflammation and nociception. Icatibant, a competitive antagonist of the bradykinin B₂ receptor, and ecallantide, a specific plasma kallikrein inhibitor, are approved for the treatment of acute episodes of edema in patients with hereditary angioedema.

ABBREVIATIONS

HISTAMINE

Histamine is a hydrophilic molecule consisting of an imidazole ring and an amino group connected by an ethylene group; histamine is biosynthesized from histidine by decarboxylation (Figure 39–1). Histamine acts through four classes of receptors, designated H₁ through H₄. The four histamine receptors, all GPCRs, can be differentially activated by analogues of ­histamine (Figure 39–2) and inhibited by specific antagonists (Table 39–1).