Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury.
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 (1.0 mg 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.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Danielle G
DG
Souza
Vanessa
V
Pinho
Jorge L
JL
Pesquero
Eliane S
ES
Lomez
Steve
S
Poole
Luiz
L
Juliano
Ary
A
Correa
M Salete
MS
de A Castro
Mauro M
MM
Teixeira
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D017538:Mesenteric Artery, Superior; D020556:Neutrophil Infiltration / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2 / Q000819:agonists / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications / Q000401:mortality / Q000473:pathology*; D020840:Tissue Kallikreins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065094:Bradykinin B2 Receptor Antagonists; D007378:Interleukins; D009842:Oligopeptides; D043782:Receptor, Bradykinin B2; D014409:Tumor Necrosis Factor-alpha; C414353:phenylacetyl-Phe-Ser-Arg-N-(2,4-dinitrophenyl)ethylenediamine; C065679:icatibant; D020840:Tissue Kallikreins; D001920:Bradykinin