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The relevance of kinin B 1 receptor upregulation in a mouse model of colitis
Author(s) -
Hara D B,
Leite D F P,
Fernandes E S,
Passos G F,
Guimarães A O,
Pesquero J B,
Campos M M,
Calixto J B
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.212
Subject(s) - colitis , receptor , kinin , downregulation and upregulation , agonist , tumor necrosis factor alpha , receptor antagonist , endocrinology , inflammatory bowel disease , knockout mouse , immunology , medicine , chemistry , pharmacology , biology , antagonist , biochemistry , bradykinin , disease , gene
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‐κB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor α (TNFα) 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 B 1 receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B 1 receptors might represent a new therapeutic option for treating inflammatory bowel diseases. British Journal of Pharmacology (2008) 154 , 1276–1286; doi: fn1 ; published online 9 June 2008