The relevance of kinin B(1) receptor upregulation in a mouse model of colitis

Background and purpose: Kinins are implicated in many pathophysiological conditions, and recent evidence has suggested their involvement in colitis. This study assessed the role of the kinin B(1) receptors in a mouse model of colitis.Experimental approach: Colitis was induced in mice by 2,4,6-trinitrobenzene sulphonic acid (TNBS), and tissue damage and myeloperoxidase activity were assessed. B(1) receptor induction was analysed by organ bath studies, binding assay and reverse transcription PCR.Key results: TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of colon B(1) receptor-mediated contraction, with the maximal response observed at 72 h. the upregulation of the B(1) receptor at this time point was also confirmed by means of binding studies. B(1) receptor mRNA levels were elevated as early as 6 h after colitis induction and remained high for up to 48 h. TNBS-evoked tissue damage and neutrophil influx were reduced by the selective B(1) receptor antagonist SSR240612, and in B(1) receptor knockout mice. in vivo treatment with inhibitors of protein synthesis, nuclear factor-kappa B activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor alpha (TNF alpha) significantly reduced B(1) receptor agonist-induced contraction. Similar results were observed in iNOS and TNF receptor 1-knockout mice.Conclusions and implications: These results provide convincing evidence on the role of B1 receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B1 receptors might represent a new therapeutic option for treating inflammatory bowel diseases.Univ Fed Santa Catarina, Dept Pharmacol, Ctr Biol Sci, BR-88049900 Florianopolis, SC, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilPontificia Univ Catolica Rio Grande do Sul, Dept Surg, Fac Dent, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilWeb of Scienc