Role of the bradykinin B-2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury
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2003-05-01
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1 Bradykinin (BK) appears to play an important role in the development and maintenance of inflammation. Here, we assessed the role of the BK B-2 receptor for the injuries that occur after ischemia and reperfusion (I/R) of the territory irrigated by the superior mesenteric artery.2 Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein, Phenylacetyl-Phe-Ser-Arg-N-(2,3-dinitrophenyl)-ethylenediamine (TKI, 0.001 - 10 mg ml(-1)), inhibited kallikrein activity in a concentration-dependent manner in vitro. in vivo, pretreatment with TKI (30 mg kg(-1)) prevented the extravasation of plasma and the recruitment of neutrophils.3 Similarly, the bradykinin B-2 receptor antagonists, HOE 140 (0.01-1.0 mg kg(-1)) or FR173657 (10.0 mg kg(-1)), inhibited reperfusion-induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs.4 in a model of more severe I/R injury, HOE 140 (1.0mg kg(-1)) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited the elevations of TNF-alpha in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL-10 in tissue and serum.5 Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B-2 receptors. B-2 receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury.
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British Journal of Pharmacology. London: Nature Publishing Group, v. 139, n. 1, p. 129-139, 2003.