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-Arg⁹-Leu⁸-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.