THE ROLE OF BRADYKININ B-1 RECEPTORS IN THE MAINTENANCE OF INTRAARTICULAR PLASMA EXTRAVASATION IN CHRONIC ANTIGEN-INDUCED ARTHRITIS

1 The role of bradykinin B-1 and B-2 receptors in bradykinin- and des- Arg(9)-bradykinin-induced plasma extravasation in normal and inflamed rat knee joints was investigated by use of an antigen-induced model of chronic arthritis. A modification of an Evans blue extraction techniq ue allowed the unstimulated (basal) plasma extravasation to be assesse d in this model. The contributions of bradykinin B-1 and B-2 receptors towards basal synovial plasma extravasation were determined. 2 In nor mal knees, intra-articular injection of bradykinin (BK) induced plasma extravasation in a potent, dose-dependent manner with a threshold of 0.01 nmol and an ED(50) of 0.1 nmol. In day 5 arthritic knees. basal p lasma extravasation was substantially enhanced. Lower doses of BK had no demonstrable effect and increases above basal extravasation were fi rst observed at 0.1 nmol. Thereafter the dose-response mirrored the re sponse in normal knees and the maximal response was unaltered. 3 The B -1 agonist, des-Arg(9)-BK, induced slight but significant plasma extra vasation in normal knees but was less potent than bradykinin. This res ponse was inhibited by the B-1 receptor antagonist, des-Arg(9), [Leu(8 )]-BK. Lower doses of des-Arg(9)-BK bradykinin did not significantly i ncrease basal extravasation in day 5 arthritic knees but, in contrast to BK, the maximal response was significantly enhanced. 4 The B-2 anta gonist, Hoe 140, inhibited BK-induced plasma extravasation in normal j oints over a dose-range of 0.0-1.0 nmol but was relatively inactive in day 5 inflamed knees. The B-1 receptor antagonist, des-Arg(9), [Leu(8 )]-BK, was relatively inactive in normal joints but showed increased p otency against BK-induced plasma extravasation in day 5 arthritic join ts. 5 Hoe 140 and des-Arg(9),[Leu(8)]-BK both inhibited basal extravas ation in arthritic joints on days 1 and 5 post-challenge in a dose-dep endent fashion. Whilst Hoe 140 was the more potent inhibitor on day 1, it was less potent than des-Arg(9),[Leu(8)]-BK on day 5. 6 Although t he majority of responses to BK in normal tissue are mediated via B-2 r eceptors, a small population of B-1 receptors may exist in normal join t tissues. The data presented in this study suggest an evolving role f or B-1 receptors in the mediation of plasma extravasation in inflamed joint tissues. A role for BK antagonists in the treatment of arthritis is also suggested.