Bradykinin in the ascitic fluid of patients with liver cirrhosis.
Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-M(r) ('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-M(r) 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-M(r) 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 x h(-1) x ml(-1) (7.9-80.0 ng.h(-1).ml(-1))] than in patients with responsive ascites [6.9 ng x h(-1) x ml(-1) (0.9-29.4 ng x h(-1) x ml(-1))] (P=0.002). In ascitic fluid, 48% (19-68%) of high-M(r) 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 bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-M(r) 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.
Cugno
M
M
Department of Internal Medicine, University of Milan, Maggiore Hospital IRCCS, Via Pace 15, 20122 Milan, Italy. massimo.cugno@unimi.it
Salerno
F
F
Nussberger
J
J
Bottasso
B
B
Lorenzano
E
E
Agostoni
A
A
D000328:Adult; D000368:Aged; D001202:Ascitic Fluid / Q000737:chemistry*; D001920:Bradykinin / Q000032:analysis*; D004591:Electrophoresis, Polyacrylamide Gel; D015956:Factor XIIa / Q000032:analysis; D005260:Female; D005341:Fibrinolysin / Q000032:analysis; D006801:Humans; D015151:Immunoblotting; D007704:Kininogens / Q000032:analysis; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis; D012083:Renin / Q000097:blood; D012709:Serum Albumin / Q000032:analysis; D000979:alpha-2-Antiplasmin / Q000032:analysis
D007704:Kininogens; D010446:Peptide Fragments; D012709:Serum Albumin; D000979:alpha-2-Antiplasmin; C079000:bradykinin (1-5); D015956:Factor XIIa; D005341:Fibrinolysin; D012083:Renin; D001920:Bradykinin