The Role of Bradykinin B1 Receptors in the Maintenance of Intra-articular Plasma Extravasation in Chronic Antigen-induced Arthritis

1. The role of bradykinin B1 and B2 receptors in bradykinin- and des-Arg9-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 technique allowed the unstimulated (basal) plasma extravasation to be assessed in this model. The contributions of bradykinin B1 and B2 receptors towards basal synovial plasma extravasation were determined. 2. In normal 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 ED50 of 0.1 nmol. In day 5 arthritic knees, basal plasma extravasation was substantially enhanced. Lower doses of BK had no demonstrable effect and increases above basal extravasation were first observed at 0.1 nmol. Thereafter the dose-response mirrored the response in normal knees and the maximal response was unaltered. 3. The B1 agonist, des-Arg9-BK, induced slight but significant plasma extravasation in normal knees but was less potent than bradykinin. This response was inhibited by the B1 receptor antagonist, des-Arg9, [Leu8]-BK. Lower doses of des-Arg9-BK bradykinin did not significantly increase basal extravasation in day 5 arthritic knees but, in contrast to BK, the maximal response was significantly enhanced. 4. The B2 antagonist, Hoe 140, inhibited BK-induced plasma extravasation in normal joints over a dose-range of 0.1-1.0 nmol but was relatively inactive in day 5 inflamed knees. The B1 receptor antagonist, des-Arg9, [Leu8]-BK, was relatively inactive in normal joints but showed increased potency against BK-induced plasma extravasation in day 5 arthritic joints.5. Hoe 140 and des-Arg9,[Leu8]-BK both inhibited basal extravasation in arthritic joints on days 1 and 5 post-challenge in a dose-dependent fashion. Whilst Hoe 140 was the more potent inhibitor on day 1, it was less potent than des-Arg9,[Leu8]-BK on day 5.6. Although the majority of responses to BK in normal tissue are mediated via B2 receptors, a small population of B1 receptors may exist in normal joint tissues. The data presented in this study suggest an evolving role for B1 receptors in the mediation of plasma extravasation in inflamed joint tissues. A role for BK antagonists in the treatment of arthritis is also suggested.