Pharmacological and biochemical characterization of bradykinin B2 receptors in the mouse colon:: Influence of the TNBS-induced colitis

This study analyzed bradykinin (BK)-evoked contractile responses in the mouse colon under normal and inflammatory conditions. BK and the preferential B-1 receptor agonists Hyp(3)-BK, Lys-BK, Met-Lys-BK and Tyr(8)-BK produced a marked and concentration-related contraction of the normal mouse colon, whereas the selective B-2 receptor agonist des-Arg(9)-BK had no effect. BK-induced contraction was concentration-dependently antagonized (in a non-competitive manner) by both B-2 receptor antagonists Hoe 140 and FR173657, but not the B-2 receptor antagonist des-Arg(9)-[Leu(8)]-BK. Analysis of the possible mechanisms implicated in the contractile responses of BK in the mouse colon revealed the involvement of the neural release of acetylcholine, the activation of L- and N-type voltage-gated calcium channels, and the release of neuropeptides, prostanoids and leukotrienes. The contraction induced by BK was markedly increased in preparations obtained from TNBS-treated mice. The up-regulation of B-2 receptors following the induction of colitis was confirmed with binding studies using [H-3]-BK, which revealed a marked increase in B-2 receptor densities, without alterations of affinity. We provide convincing evidence on the relevance of B-2 receptors in the mouse colon under normal conditions, as well as under an inflammatory profile of colitis. Selective B-2 receptor antagonists might well represent rational therapeutic options for treating inflammatory bowel diseases. (C) 2007 Elsevier B.V. All rights reserved.