Bradykinin receptors.

1. The last decade has witnessed a phenomenal increase in our understanding of the pharmacology of bradykinin receptors, and has led to an appreciation of a key role for the peptide kinins as proinflammatory mediators. This short review summarises the major changes that have taken place in the expanding area of bradykinin receptor pharmacology, and highlights important advances that we hope to anticipate in the future. 2. Bradykinin receptors are cell surface, G-protein coupled receptors of the seven-transmembrane domained family. The existence of two subtypes of bradykinin receptor, B1 and B2, has been confirmed through the use of high affinity peptide and nonpeptide receptor antagonists, radioligand binding studies and, recently, receptor cloning and expression studies. 3. Differences in the affinities of B2 receptor antagonists, including those of the [D-Phe7]-bradykinin series, D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (Hoe140, Icatibant) and the non-peptide, WIN64338, have led to proposals of the possible existence of further subtypes of bradykinin receptor (including a tracheal B3 receptor), and/or of species homologues of the B2 receptor. 4. Molecular cloning techniques have identified the gene encoding B1 receptors in the rabbit, human and mouse, and B2 receptors in the rat, human and mouse. B1 and B2 receptor show little (36%) overall sequence homology. Cloning studies reveal the potential for the existence of species homologues of receptors. 5. The use of bradykinin receptor antagonists in vivo has led to an appreciation of the involvement of bradykinin receptors in inflammation. Evidence suggests a role for B2 receptors in more classical acute inflammatory events, such as oedema and inflammatory pain, whereas B1 receptors appear to be involved in chronic inflammatory responses, including certain forms of persistent hyperalgesia. 6. The continuing advances in our knowledge of the characteristics of bradykinin receptors through the further development of selective receptor antagonists and molecular biology techniques will aid in the rational design of drugs effective in the therapeutic manipulation of inflammatory processes and in the control of inflammatory disease.