A. Macgilchrist et al., EFFECT OF THE SERINE-PROTEASE INHIBITOR, APROTININ, ON SYSTEMIC HEMODYNAMICS AND RENAL-FUNCTION IN PATIENTS WITH HEPATIC CIRRHOSIS AND ASCITES, Clinical science, 87(3), 1994, pp. 329-335
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.