RECEPTORS FOR BRADYKININ AND RELATED KININS - A CRITICAL ANALYSIS

Kinins exert a variety of biological actions and have been implicated in the pathogenesis of inflammation, pain, asthma, and other diseases. Kinins act through specific receptors that are widespread and belong to two major categories, B-1 and B-2. B-2 has been cloned and shown to be of the rhodopsin type, consisting of seven hydrophobic membrane do mains connected by extracellular and intracellular loops. Recent pharm acological findings from various laboratories suggest the existence of new receptor types, which have been named B-3, B-4, and B-5. These fi ndings are analysed critically, especially with respect to the criteri a that have been used for affirming the existence of new receptor enti ties. The analysis is restricted to data obtained in isolated organs, almost exclusively smooth muscle preparations. Criteria for receptor c haracterization and classification are the order of potency of agonist s and the apparent affinities of antagonists. The analysis reveals tha t receptors for bradykinin and related kinins are of two types, B-1 an d B-2. B-1 mediates the rapid acute response (smooth muscle contractio n or relaxation) as well as some effects occurring more slowly (e.g., collagen synthesis). B-1 receptor functions have been shown to be modu lated by interleukins. B-2 receptors are responsible for most of the k inins' biological effects, including arterial vasodilatation, plasma e xtravasation, venoconstriction, activation of sensory fibers (e.g., fi bers for pain), and stimulation of the release of prostaglandins, endo thelium-dependent relaxing factor (from endothelia), noradrenaline (fr om nerve terminals and adrenals), and other endogenous agents. The pha rmacological characteristics of the receptor sites (B-2) mediating thi s array of biological effects show differences between species, and tw o B-2 receptor subtypes are proposed, namely B-2A (rabbit, dog, and po ssibly man) and B-2B (guinea pig, hamster, rat). B-2A and B-2B recepto r subtypes have been characterized by using fairly selective agonists and competitive antagonists (e.g., D-Arg[Hyp(3),D-Phe(7),Leu(8)]BK). N oncompetitive antagonists (nonequilibrium), such as HOE 140, do not di scriminate between B-2A and B-2B subtypes. Species differences cannot account for the multiplicity of receptors that have been proposed for rat vas deferens, pre- and post-junctional sites, and rat uterus, guin ea pig ileum, and rat blood pressure. The existence of hypothetical ne w receptor sites was based on data obtained with partial agonists and have not been substantiated by data obtained with potent pure antagoni sts. The B-3 receptor, proposed to explain the unusual behaviour of th e guinea pig tracheal response to kinins, has to be carefully reconsid ered after the finding that HOE 140 acts as a pure antagonist on this tissue and shows a fairly high affinity for the tracheal site. B-3, B- 4, and B-5 receptors described in the esophagus of the opossum have no t been sufficiently characterized either with agonists or with antagon ists to be considered as new functional sites.