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 B2 receptor agonists Hyp3-BK, Lys-BK, Met-Lys-BK and Tyr8-BK produced a marked and concentration-related contraction of the normal mouse colon, whereas the selective B1 receptor agonist des-Arg9-BK had no effect. BK-induced contraction was concentration-dependently antagonized (in a non-competitive manner) by both B2 receptor antagonists Hoe 140 and FR173657, but not the B1 receptor antagonist des-Arg9-[Leu8]-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 B2 receptors following the induction of colitis was confirmed with binding studies using [3H]-BK, which revealed a marked increase in B2 receptor densities, without alterations of affinity. We provide convincing evidence on the relevance of B2 receptors in the mouse colon under normal conditions, as well as under an inflammatory profile of colitis. Selective B2 receptor antagonists might well represent rational therapeutic options for treating inflammatory bowel diseases.