Amiloride reduces portal hypertension in rat liver cirrhosis

Objective This study aimed to investigate the effect of amiloride
on portal hypertension. Amiloride is known to inhibit Na(+)/H(+)
exchangers on activated hepatic stellate cells. Methods Liver
cirrhosis in rats was induced by bile duct ligation (BDL) or
thioacetamide (TAA) administration. The effects of zymosan for
Kupffer cell (KC) activation or a thromboxane (TX) analogue
(U46619) were tested in isolated perfused livers of cirrhotic rats
and in vivo. Downstream mechanisms were investigated using Rho
kinase inhibitor (Y-27632) or amiloride. Acute and chronic effects
of amiloride and canrenoate on portal pressure were compared in
perfused livers and in vivo. TXB(2) efflux was measured by ELISA.
The phosphorylation state of moesin (p-moesin) as an indicator of
Rho kinase activity and expression of the thromboxane synthase were
assessed by western blot analyses. The activity of hepatic stellate
cells was analysed by western blot and staining for alpha-smooth
muscle actin (alpha-SMA). Results In BDL rats, KC activation via
zymosan increased portal pressure. This was attenuated by the Rho
kinase inhibitor Y-27632. Increased thromboxane efflux following
zymosan infusion remained unaltered by Y-27632. The infusion of
amiloride attenuated zymosan- and U46619-induced increases in
portal perfusion pressure. In vivo, direct administration of
amiloride, but not of canrenoate, lowered portal pressure. In TAA
and BDL rats, treatment with amiloride for 3 days reduced basal
portal pressure and KC-induced increases in portal pressure whereas
canrenoate had no effect. In livers of amiloride-treated animals,
the phosphorylation state of moesin and the number of alpha-SMA
positive cells were reduced. Conclusions Amiloride lowers portal
pressure in rat liver cirrhosis by inhibition of intrahepatic
vasocontraction. Therefore, patients with cirrhosis and portal
hypertension may benefit from amiloride therapy.