Amiloride reduces portal hypertension in rat liver cirrhosis

Abstract

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 a-smooth muscle actin (a-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 zymosanand 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 a-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.

Salvianolic acid B lowers portal pressure in cirrhotic rats and attenuates contraction of rat hepatic stellate cells by inhibiting RhoA signaling pathway

“…17 Laparotomy was performed and a PE tube (23 G) was inserted into the ileocolic vein and advanced to the confluence of the portal vein and splenic vein. This cannula was used to monitor portal pressure by a transducer system.…”

Infection as a Trigger for Portal Hypertension

“…5-HPETE is degraded to leukotriene (LT) A 4 and consecutively to B 4 or the cysteinyl (Cys)-LT C 4 , D 4 and E 4 . In the cirrhotic liver the vasoconstrictor TXA 2 and Cys-LT C 4 and D 4 have been identified as the most relevant [7,8,9,10,11,12,13,14,15,16,17]. …”

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

“…Thioacetamide (TAA), a potent selective hepatotoxin, is well known to induce both acute and chronic hepatic failure (Steib et al, 2010;Zaldivar et al, 2010;Ishikawa et al, 2011). Prolonged exposure to TAA always results in bile duct proliferation and liver cirrhosis histologically similar to that in human viral hepatitis infection (Hunter et al, 1977;Ledda-Columbano et al, 1991;Yeh et al, 2004).…”