EFFECT OF THE SERINE-PROTEASE INHIBITOR, APROTININ, ON SYSTEMIC HEMODYNAMICS AND RENAL-FUNCTION IN PATIENTS WITH HEPATIC CIRRHOSIS AND ASCITES

1. Previous studies have documented activation of protease enzymes, su ch as the plasma kallikrein-kinin system, in hepatic cirrhosis. Increa sed plasma kinin generation could contribute to pathological systemic vasodilatation in cirrhosis, and reduced systemic vascular resistance has been suggested as a trigger to renal sodium retention in this dise ase. We investigated the effect of aprotinin, a protease inhibitor whi ch binds to plasma kallikrein, on systemic haemodynamics and renal fun ction in patients with hepatic cirrhosis and ascites. 2. Aprotinin was infused intravenously in high dosage (2 x 10(6) kallikrein inhibitory units loading, 1 x 10(6) kallikrein inhibitory units/h). 3. Of 13 pat ients, 10 had a low systemic vascular resistance (< 1200 dyn s cm(-5)) at baseline. In this group, eight showed an increase in systemic vasc ular resistance during aprotinin infusion. Overall, the increase in sy stemic vascular resistance was significant, and there was a small but significant increase in mean arterial pressure. In all patients, there were increases in renal plasma flow, glomerular filtration rate, and absolute and fractional urinary sodium excretion during aprotinin infu sion. 4. Plasma renin activity, plasma angiotensin II and plasma aldos terone fell significantly during aprotinin infusion. Plasma prekallikr ein, plasma noradrenaline and plasma atrial natriuretic peptide did no t change. Plasma aprotinin concentration was 209 +/- 11 kallikrein inh ibitory units/ml at the end of the infusion. 5. Before and during the infusion, there was a significant negative correlation between systemi c vascular resistance and plasma renin activity. There was a positive correlation between the change in systemic vascular resistance and the change in renal plasma flow during aprotinin infusion. 6. In patients with hepatic cirrhosis and ascites, treatment with aprotinin appears beneficial in relation to systemic and renal haemodynamics, sodium exc retion and hormonal stimulation, with no evidence of adverse effects. The results are compatible with an association between plasma kallikre in-kinin activation, systemic vasodilatation, renin-angiotensin activa tion, and renal vasoconstriction and sodium retention in this conditio n.