Differential bradykinin B1 and B2 receptor regulation in cell death induced by hepatic ischaemia/reperfusion injury.
The biological and pharmacological effects of BK (bradykinin) are mediated by two receptors: the constitutive B2R (B2 receptor) and the inducible B1R (B1 receptor). BK plays a role in the hepatic microcirculation by inducing the PHR (portal hypertensive response) via B2R, whereas DABK (des-Arg9-BK), a B1R agonist, does not elicit the response. During IRI (ischaemia/reperfusion injury), important changes occur in the microcirculation, and cell death by necrosis and apoptosis is involved in poor graft function. The aim of the present study was to analyse the role of B1R and B2R in liver cell death induced by IRI. Livers from Wistar rats were submitted to ischaemia (4°C) for 4 or 24 h. After this period, livers were reperfused ex vivo with Krebs-Henseleit solution (37°C). BK or DABK was then injected as a bolus during reperfusion in the absence or presence of HOE-140 (a B2R antagonist) or DALBK (des-Arg(9)-Leu(8)-BK) (a B1R antagonist) respectively. Liver viability was analysed by glucose release and bile secretion. The PHR to kinins did not change. Cell death was higher in the DABK group and its antagonist significantly decreased cell death. Interestingly, the B1R antagonist did not alter the number of necrotic cells, but it decreased the number of apoptotic cells. On the other hand, the B2R antagonist decreased the number of necrotic cells, but did not alter the number of apoptotic cells. Therefore B1R may participate in apoptotic cell death signalling, and B2R may be involved in necrotic cell death.
*Department of Medicine, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Mayra A
MA
Paio
†Department of Biochemistry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Maria
M
Kouyoumdjian
*Department of Medicine, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Durval R
DR
Borges
‡Department of Biosciences, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Marcia R
MR
Nagaoka
D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D016923:Cell Death; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*
D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2