Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-Mr ('high-molecular-weight') kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-Mr kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-Mr kininogen, activated factor XII and plasmin- antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3 fmol/ml (range 0.2-29.0 fmol/ml), and the median bradykinin-(1-5) concentration was 210 fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091 fmol/ml (range 58-7825 fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084 fmol/ml)] (P = 0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0 ng·h-1·ml-1 (7.9-80.0 ng·h-1·m-1)] than in patients with responsive ascites [6.9 ng·h-1·ml-1 (0.9-29.4 ng·h-1·ml-1)] (P = 0.002). In ascitic fluid, 48% (19-68%) of high-Mr kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P = 0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinino(1-9) and bradykinin-(1-5) are present, with cleavage of high-Mr kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.
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