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

Of rodents and humans: a light microscopic and ultrastructural study on cardiomyocytes in pulmonary veins

Cardiomyocytes in pulmonary veins (PVs) have been reported in rodents and humans. In humans they were related to atrial arrhythmias, including atrial fibrillation (AF). To investigate histological similarities and differences in PV cardiomyocyte localization and distribution, we performed comparative light and electron microscopic studies on humans, rats and mice, and generated a transgenic mouse strain. Results on mice (C57BL/6 and BALBc) and rats (Wistar) revealed that cardiomyocytes regularly extend from the hilus along venous vessels into the lung tissue surrounding individual intrapulmonary veins of varying diameters (70-250&#181;m). The cardiomyocytes showed the ultrastructure of a normal working myocardium with intact intercalated discs and tightly packed contractile filaments. In both lung and hilus cardiomyocytes were localized either close to the basal lamina of the endothelium or separated from it by smooth muscle cells and/or collagen fibres. In humans (autopsies, n=20) extrapericardiac cardiomyocytes were only found in 23 out of 78 veins and showed an incomplete sleeve at the lung hilus. In addition, cardiomyocytes occurred significantly more often in right than in left veins, however, never in intrapulmonary veins. We discuss the hypothesis that the variance in distribution of PV cardiomyocytes in humans and rodents might reflect the difference in pathogenesis and development of AF.</p