McLean, Perretti & Ahluwalia Kinin B 1 receptors as novel anti-inflammatory targets Anti-inflammatory Kinin B 1 receptors as novel anti-inflammatory targets Peter G McLean 1,2 , Mauro Perretti 2 & Amrita Ahluwalia 1 1 Centre for Clinical Pharmacology, Dept. of Medicine, University College London, WC1E 6JJ, UK 2 Dept. of Biochemical Pharmacology, William Harvey Research Institute, St. Bartholomew’s Medical College, London, EC1M 6BQ, UK The kinin peptides exert their pro-inflammatory effects by the selective activation of two distinct G-protein coupled receptors, termed B 1 and B 2 . The principle kinin peptides involved in the acute inflammatory response are bradykinin (BK) and Lys-BK, which produce their effects via the selective activation of constitutively expressed B 2 receptors. The B 1 receptor in contrast is not normally expressed, but is induced selectively by certain inflammatory stimuli. Additionally, the B 1 receptor is selectively activated by the des-Arg 9 kinin metabolites, namely des-Arg 9 BK and Lys-des-Arg 9 BK, the synthesis of which are also increased during inflamma- tion. Recent investigations into the molecular mechanisms of B 1 receptor induction and their distribution and function have shown that, following an inflammatory stimulus, the B 1 receptor is induced and may play an important role in the progression of an acute inflammatory response to a more sustained chronic inflammatory state characterised by leukocyte recruitment. This review summarises recent studies on B 1 receptor expres- sion and function, and discusses the role of these receptors in regulation of inflammation and their potential as therapeutic targets. Keywords: adhesion, inflammation, kinin B 1 receptor, leukocyte, plasma extravasation, sensory C-fibre Emerging Therapeutic Targets (2000) 4(2):127-141 1. Introduction Inflammation is a highly complex process involving interaction between multiple factors at humoral, cellular and neuronal levels. One particularly important family of inflammatory peptides playing integral roles at all of these individual levels is the kinin family. The endogenous kinin peptides, BK, Lys-BK (also known as kallidin) and their biologically active des-Arg 9 metabolites, are the functional components of the kallikrein-kinin system. The acute physiological actions of this system are produced by BK and Lys-BK, formed by proteolytic cleavage of high and low molecular weight kininogens (HMWK and LMWK) by plasma or tissue kallikrein (PK or TK), respectively. BK and Lys-BK are then metabolised and deactivated by kininase I or kininase II (also known as angiotensin-converting enzyme [ACE]). The activity of kininase I is of particular relevance to this review in that it produces kinin metabolites without the C-terminal arginine residue, des-Arg 9 BK (DABK) and Lys-des-Arg 9 BK (Lys-DABK) from BK and Lys-BK, respectively. Whilst these des-Arg 9 kinin metabolites are largely inactive in 127 2000 © Ashley Publications Ltd. ISSN 1460-0412 Review 1. Introduction 2. The kinin B 1 receptor: an inducible GPCR 2.1 Kinin receptor antagonists 3. B 1 receptor regulation: relevance to the inflammatory response 4. B 1 receptor-mediated inflammation 4.1 Plasma protein extravasation 4.2 Inflammatory pain 4.3 Leukocyte recruitment 5. Role played by B 1 receptors in human inflammatory disease 5.1 Sepsis and the kallikrein-kinin system 5.2 Ischaemia-reperfusion injury 5.3 Atheromatous disease 5.4 Angioplasty 5.5 Asthma 5.6 Urology 5.7 Other diseases 6. Conclusions Bibliography http://www.ashley-pub.com Emerging Therapeutic Targets