THE BRADYKININ B-2 RECEPTOR ANTAGONIST ICATIBANT (HOE-140) CORRECTS AVID NA-INDUCED LIVER-CIRRHOSIS - POSSIBLE ROLE OF ENHANCED MICROVASCULAR LEAKAGE( RETENTION IN RATS WITH CCL4)

Avid Na+ retention is a hallmark of liver cirrhosis. The aim of this s tudy was to investigate whether and how bradykinin is involved in Naretention in rats with CCl4-induced liver cirrhosis. To this end the b radykinin B-2 receptor antagonist Icatibant (HOE 140) was used. On one hand, bradykinin has a renal natriuretic action. On the other hand, b radykinin is a potent mediator of both vasodilation and microvascular leakage. Both vascular mechanisms, which are reported for cirrhosis, c ould cause vascular underfilling and Na+ retention by activating the r enin-angiotensin-aldosterone system. Icatibant normalised Na+ retentio n and reduced the hyperactivity of the renin-angiotensin-aldosterone s ystem, suggesting a bradykinin-induced vascular disturbance. Icatibant had no significant effect on the mild hypotension which developed wit h CCl4 treatment. However, there was indirect evidence for enhanced mi crovascular leakage that was strongly inhibited by Icatibant. Our expe rimental results demonstrate that bradykinin is a key mediator of Naretention in liver cirrhosis and suggest that a bradykinin-induced inc rease in microvascular leakage is mainly responsible. (C) 1997 Elsevie r Science B.V.