Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction

Abstract

Background: Focal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis. In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical model of hepatic outflow obstruction after extended liver resection by administration of 5 different drugs in comparison to an operative intervention, splenectomy. Methods: Male inbred Lewis rats (Lew/Crl) were subjected to right median hepatic vein ligation+70% partial hepatectomy. Treatment consisted of a splenectomy or the application of saline, carvedilol or isosorbide-5-mononitrate (ISMN) (5mg·kg-1 respectively 7,2mg·kg-1 per gavage 12h-1). The splenectomy was performed during operation. The effect of the treatments on hepatic hemodynamics were measured in non-operated animals, immediately after operation (n=4/group) and 24h after operation (n=5/group). Assessment of hepatic damage (liver enzymes, histology) and liver cell proliferation (BrdU-immunohistochemistry) was performed 24h after operation. Furthermore sildenafil (10μg·kg-1 i.p. 12h-1), terlipressin (0.05mg·kg-1 i.v. 12h-1) and octreotide (10μg·kg-1 s.c. 12h-1) were investigated regarding their effect on hepatic hemodynamics and hepatic damage 24h after operation (n=4/group). Results: Carvedilol and ISMN significantly decreased the portal pressure in normal non-operated rats from 11,1±1,1mmHg (normal rats) to 8,4±0,3mmHg (carvedilol) respectively 7,4±1,8mmHg (ISMN). ISMN substantially reduced surgery-induced portal hypertension from 15,4±4,4mmHg to 9,6±2,3mmHg. Only splenectomy reduced the portal flow immediately after operation by approximately 25%. No treatment had an immediate effect on the hepatic arterial perfusion. In all treatment groups, portal flow increased by approximately 3-fold within 24h after operation, whereas hepatic arterial flow decreased substantially. Neither treatment reduced hepatic damage as assessed 24h after operation. The distribution of proliferating cells appeared very similar in all drug treated groups and the splenectomy group. Conclusion: Transient relative reduction of portal pressure did not result in a reduction of hepatic damage. This might be explained by the development of portal hyperperfusion which was accompanied by arterial hypoperfusion.