Portal Hypertensive Rats Research Articles

Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension

Splenomegaly is a frequent hallmark of portal hypertension that, in some cases, can be very prominent and cause symptoms like abdominal pain, splenic infarction, and cytopenia. This study characterizes the pathogenetic mechanisms leading to spleen enlargement in portal hypertensive rats and focuses on mTOR pathway as a potential modulator of splenomegaly in portal hypertension. Characterization of splenomegaly was performed by histological, hematological, immunohistochemical and Western blot analyses in rats with portal hypertension induced by portal vein ligation, and compared with sham-operated animals. The contribution of the mTOR signaling pathway to splenomegaly was determined in rats with fully developed portal hypertension and control rats by treatment with rapamycin or vehicle. Our results illustrate that splenomegaly in portal hypertensive rats arises as a consequence of the interplay of several factors, including not only spleen congestion, as traditionally thought, but also enlargement and hyperactivation of the splenic lymphoid tissue, as well as increased angiogenesis and fibrogenesis. Since mTOR signaling plays a central role in immunological processes, angiogenesis and fibrogenesis, we next determined the involvement of mTOR in splenomegaly. Interestingly, mTOR signaling was overactivated in the spleen of portal hypertensive rats, and mTOR blockade by rapamycin profoundly ameliorated splenomegaly, causing a 44% decrease in spleen size. This effect was most likely accounted for the inhibitory action of rapamycin on lymphocyte proliferation, neovascularization and fibrosis. These findings shed light on the pathogenesis of splenomegaly in portal hypertension, and identify mTOR signaling as a potential target for therapeutic intervention in this disease.

Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilation in rat portal hypertension

Portal hypertension is associated with downregulation of mRNA and proteins involved in adrenergic transmission in the superior mesenteric artery (SMA) in portal vein-ligated (PVL) and cirrhotic rats. We aimed to investigate whether SMA adrenergic dysfunction was accompanied by sympathetic nerve structural changes and whether it was extensive to resistance mesenteric arteries. We also attempted to localize the origin of mRNA of specific adrenergic genes. In situ hybridization showed tyrosine hydroxylase (Th) mRNA expression in neuronal bodies of superior mesenteric ganglia and inside axonal fibres surrounding proximal SMA sections. Comparison of SMA by Th immunohistochemistry, both in PVL and bile duct-ligated (BDL) rats, demonstrated a significant decrease in the number of nervous structures (69% PVL; 62% BDL), total nervous area (70% PVL; 52% BDL) and Th-stained nervous area (89% PVL; 64% BDL) compared with sham rats. A strong correlation was detected between the Th-stained nervous area and the haemodynamic parameters, mainly with SMA resistance (r=0.9, P<0.001 for PVL and r=0.75, P=0.018 for BDL). Western blot analysis of Th, dopamine beta-hydroxylase and synaptosome-associated protein of 25 kDa indicated a significant inhibition in protein expression (35-58%) in mesenteric resistance arteries from both portal hypertension models compared with sham. By contrast, nervous structure analysis and protein expression in renal arteries showed no differences between sham and PVL rats. Portal hypertension is associated with sympathetic nerve atrophy/regression in the mesenteric arterial vasculature that could contribute to the splanchnic vasodilation associated with portal hypertension.

Determination of isoguanosine in Semen Crotonis Tiglii by high-performance liquid chromatography

To develop a high-performance liquid chromatographic method for the determination of isoguanosine in Semen Crotonis Tiglii. The determination was done by using reverse-phase high-performance liquid chromatography with a Hedera ODS-2 column (4.6 mm x 250 mm, 5 microm). Elution was employed with the mobile phase of acetonitrile-methanol-water (1:4:95) at flow rate of 1.0 mL/min. The detection wavelength was set at 292 nm and the column temperature was 25 degrees centigrade. Injection volume was 10 microL. The linear range of isoguanosine was from 0.161 to 0.967 mg. The correlation coefficient of the calibration curves was 0.999 8. The average recovery rate was 98.78% with relative standard deviation of 0.02%. The results show that the method is simple, accurate, and repeatable, and it is suitable for quality control of Semen Crotonis Tiglii.

EVOLUTION OF PORTAL-SYSTEMIC COLLATERAL VASOPRESSIN RESPONSE IN ENDOTOXEMIC PORTAL HYPERTENSIVE RATS

Cirrhotic patients with portal hypertension and variceal hemorrhage are vulnerable to endotoxemia. However, the direct influence of endotoxemia on portal-systemic collateral vasculature remains unexplored. In this study, portal hypertension was induced in Sprague-Dawley rats by partial portal vein ligation. On the 7th day after portal vein ligation, at 0.5, 1.5, and 5 h post endotoxin (LPS; Escherichia coli serotype O111:B4, 3 mg/kg, i.p., E0.5, E1.5 and E5, respectively) or saline (control, C0.5, C1.5, and C5, respectively) injection, hemodynamic measurements and concentration-response relationships to arginine vasopressin (AVP; 10(-10)-10(-7) mol/L) in collateral vascular bed were obtained. In another six parallel groups, reverse-transcriptase-polymerase chain reaction of iNOS, eNOS, and endothelin 1 (ET-1) mRNA expressions for splenorenal shunt, the most prominent intra-abdominal collateral vessel, was performed. The results showed that E0.5 had lower perfusion pressure changes to AVP and higher splenorenal shunt eNOS expression than C0.5 group (P < 0.05). Compared with C1.5, tachycardia, higher perfusion pressure changes and enhanced splenorenal shunt iNOS and ET-1 expression were observed in E1.5 group (P < 0.05). In E5, systemic and portal hypotension with markedly enhanced collateral AVP responsiveness and splenorenal shunt iNOS and ET-1 expressions were noted (P < 0.05). In conclusion, vasoactive substances counterregulation participates, at least in part, the time-dependent changes of collateral AVP responsiveness in endotoxemic portal hypertensive rats.

Bacterial Translocation to Mesenteric Lymph Nodes Increases in Chronic Portal Hypertensive Rats

Bacterial translocation is a frequent complication in portal hypertension related to cirrhosis in the human clinical area. The aim of this study was to verify the existence of intestinal bacterial translocation to mesenteric lymph nodes in male Wistar rats with triple partial portal vein ligation during short- (48 h) and long-term (1 month) postoperative evolution. At 48 h, ileal total aerobes bacteria (p < 0.001) and Lactobacillus decrease in sham-operated (SO) and portal hypertensive (PH) rats. At 1 month, ileal Enterococci and Streptococcus sp. show a statistically significant decrease in SO- and PH-rats. Lactobacillus decreases in the colon in SO- (p < 0.01) and in PH-rats (p < 0.001). At 1 month, colonic Enterococci decreases compared to control (p < 0.001) and SO-rats (p < 0.01). These intestinal microfloral changes are associated with bacterial translocation to mesenteric lymph nodes at 48 h (50%; p = 0.004) and 1 month (100%; p < 0.001) of postoperative evolution in PH-rats. The enlargement of the stenosed portal tract related to triple partial portal vein ligation in the rat, since it increases the resistance to the portal blood flow, may be a key factor involved in one of the pathological consequences of portal hypertension, as is bacterial translocation to mesenteric lymph nodes.

Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats

Portal hypertension (PHT) gastropathy is a frequent complication of liver cirrhosis and one of the leading causes of death from cirrhosis. Apoptosis is widely considered to be an active energy-dependent mode of cell death and a distinct entity from necrotic cell death. It is unclear whether gastric mucosal apoptosis is involved in PHT gastropathy. Prostaglandins (PGs) produced through cyclooxygenase (COX) are thought to play a key role in protection of the gastrointestinal mucosa from injury and apoptosis. However, the role of COX in PHT gastropathy is still not clearly understood. The aims of this study were to investigate whether (1) gastric mucosal apoptosis is involved in PHT gastropathy and (2) downregulation of COX contributes to this apoptosis. In this study, we show that gastric mucosal apoptosis was remarkably increased while mucosal proliferation was inhibited in PHT rats. Gastric mucosal COX-1 was significantly suppressed at both the mRNA and protein levels, and PGE(2) was reduced in PHT rats. Further, PGE(2) treatment suppressed gastric mucosal apoptosis in PHT rats. However, gastric mucosal COX-2 levels did not differ between sham-operated rats and PHT rats. Gastric mucosal levels of tumor necrosis factor-alpha (TNF-alpha) and Fas ligand, but not TNF-related apoptosis-inducing ligand, were increased, and activated caspase-8 and caspase-3 levels were upregulated in PHT rats. The release of cytochrome c from the mitochondria to the cytosol was not observed in PHT rats. Our data indicate that downregulation of COX-1 is involved in gastric mucosal apoptosis via death signaling-mediated type-I cell death in PHT rats.

Increased heat‐shock protein 90 expression contributes to impaired adaptive cytoprotection in the gastric mucosa of portal hypertensive rats

Portal hypertensive (PHT) gastropathy results in an increased susceptibility to damage. Adaptive cytoprotection against ethanol-induced damage is impaired in the gastric mucosa of rats with portal hypertension. Excessive nitric oxide (NO) production occurs in portal hypertension and is mediated in part via heat-shock protein (Hsp)90 production. The aim of this study was to investigate the relation between adaptive cytoprotection after exposure to ethanol and gastric expression of Hsp90 in PHT rats. Portal hypertension was induced in rats by staged portal vein occlusion. Adaptive cytoprotection to 70% ethanol was evaluated by assessing the injury index of the gastric mucosa with or without pretreatment with 10% ethanol. Expression of Hsp90 mRNA was evaluated by real-time polymerase chain reaction, and expression of Hsp90 protein was evaluated by western blotting. The effect of Hsp90 inhibition in PHT rats was evaluated by administration of geldanamycin. Gastric Hsp90 mRNA expression in PHT rats was significantly less than that in sham-operated (SO) controls. However, after 10% ethanol pretreatment, Hsp90 mRNA expression was significantly greater in PHT rats than in SO controls. In PHT rats, gastric Hsp90 protein expression after 10% ethanol pretreatment was significantly greater than that without the pretreatment. However, the pretreatment had no effect on the injury index compared to SO rats. Administration of geldanamycin prior to 10% ethanol pretreatment significantly decreased the injury index in response to 70% ethanol in the PHT rats. These results show that 10% ethanol pretreatment markedly increases gastric Hsp90 expression in PHT rats. Excessive production of Hsp90 may contribute impaired adaptive cytoprotection.

Combined use of propranolol and nifedipine offers better effects on portal vein nonuniform remodeling in carbon tetrachloride (CCl 4)-induced portal hypertensive rats

Portal hypertension is a hemodynamic syndrome due to pathological increase in portal flow and portal pressure. These pathological changes in external flow loads will inevitably cause vascular remodeling in the portal vein, which is usually measured by an opening angle. The present study showed that carbon tetrachloride (CCl 4)-induced portal hypertension fully developed at 8 weeks and the opening angle of portal vein increased progressively in the pathogenesis of intrahepatic portal hypertension which was significantly augmented at 10 weeks. Although portal pressure and portal flow were reduced, treatment with either propranolol or nifedipine alone for 3 weeks did not decrease the augmented opening angle of the portal vein, while combined treatment with propranolol and nifedipine markedly reduced the increased opening angle of the portal vein and endothelial nitric oxide synthase (eNOS) mRNA expression but not inducible nitric oxide synthase (iNOS) mRNA expression. The decreasing effect of propranolol plus nifedipine on the elevated opening angle was significantly weakened by L-arginine and markedly reinforced by N-nitro- l-arginine-mythel-ester (L-NAME). These results indicate that combined use of propranolol and nifedipine ameliorates portal vein remodeling in portal hypertension at least by the nitric oxide-dependent way.

Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis

Extrahepatic vasodilation and increased intrahepatic vascular resistance represent attractive targets for the medical treatment of portal hypertension in liver cirrhosis. In both dysfunctions, dysregulation of the contraction-mediating Rho kinase plays an important role as it contributes to altered vasoconstrictor responsiveness. However, the mechanisms of vascular Rho kinase dysregulation in cirrhosis are insufficiently understood. They possibly involve mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-dependent mechanisms in extrahepatic vessels. As the multikinase inhibitor sorafenib inhibits ERK, we tested the effect of sorafenib on haemodynamics and dysregulated vascular Rho kinase in rats with secondary biliary cirrhosis. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Sorafenib was given orally for 1 week (60 mg.kg(-1).d(-1)). Messenger RNA levels were determined by quantitative real time polymerase chain reaction, protein expressions and protein phosphorylation by Western blot analysis. Aortic contractility was studied by myographic measurements, and intrahepatic vasoregulation by using livers perfused in situ. In vivo, haemodynamic parameters were assessed invasively in combination with coloured microspheres. In BDL rats, treatment with sorafenib decreased portal pressure, paralleled by decreases in hepatic Rho kinase expression and Rho kinase-mediated intrahepatic vascular resistance. In aortas from BDL rats, sorafenib caused up-regulation of Rho kinase and an improvement of aortic contractility. By contrast, mesenteric Rho kinase remained unaffected by sorafenib. Intrahepatic dysregulation of vascular Rho kinase expression is controlled by sorafenib-sensitive mechanisms in rats with secondary biliary cirrhosis. Thus, sorafenib reduced portal pressure without affecting systemic blood pressure.

Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

To study glutamine synthetase (GS) activity and glutamate uptake in the hippocampus and frontal cortex (FC) from rats with prehepatic portal vein hypertension. Male Wistar rats were divided into sham-operated group and a portal hypertension (PH) group with a regulated stricture of the portal vein. Animals were sacrificed by decapitation 14 d after portal vein stricture. GS activity was determined in the hippocampus and FC. Specific uptake of radiolabeled L-glutamate was studied using synaptosome-enriched fractions that were freshly prepared from both brain areas. We observed that the activity of GS increased in the hippocampus of PH rats, as compared to control animals, and decreased in the FC. A significant decrease in glutamate uptake was found in both brain areas, and was more marked in the hippocampus. The decrease in glutamate uptake might have been caused by a deficient transport function, significantly and persistent increase in this excitatory neurotransmitter activity. The presence of moderate ammonia blood levels may add to the toxicity of excitotoxic glutamate in the brain, which causes alterations in brain function. Portal vein stricture that causes portal hypertension modifies the normal function in some brain regions.

Effect of early propranolol administration on portal hypertensive gastropathy in cirrhotic rats.

To investigate any protective effect of early propranolol administration in the development of portal hypertensive gastropathy in cirrhotic rats. For the development of liver cirrhosis and portal hypertensive gastropathy, 60 rats underwent ligation of the left adrenal vein and complete devascularization of the left renal vein, followed by phenobarbital and carbon tetrachloride (CCl(4)) administration. After two weeks of CCl(4) administration, the rats were randomly separated into two groups. In group A, propranolol was continuously administered intragastrically throughout the study, whereas in group B normal saline (placebo) was administered instead. Hemodynamic studies and vascular morphometric analysis of gastric sections were performed after complete induction of cirrhosis. Vascular morphometric studies showed higher numbers of vessels in all mucosal layers in the control group. Statistical analysis revealed a significantly higher total vascular surface in the control group compared to the propranolol group, but with no statistically significant difference between the mean vascular surfaces between the groups. Our study clearly shows that the increased mucosal blood flow is manifested by a marked increase of vessel count. Early propranolol's administration in portal hypertensive cirrhotic rats seems to prevent intense gastric vascular congestion that characterizes portal hypertensive gastropathy.

Stability of a rat model of prehepatic portal hypertension caused by partial ligation of the portal vein

To study the stability of portal hypertension (PHT) caused by partial ligation of the portal vein ligation (PVL) in a rat model. Thirty male adult Wistar rats were divided into two groups: 10 in Group I received a sham operation; and 20 in Group II received partial PVL. Portal vein pressure (PVP) was measured at four time periods: before ligation, 2 wk, 6 wk and 10 wk post-surgery. Portal venography, blood sampling and liver and spleen pathological examinations were conducted at 10 wk after surgery. The PVP was 9.15 +/- 0.58 cmH(2)O before ligation, and increased to 17.32 +/- 0.63 cmH(2)O 2 wk after PVL. By repeat measurement of the PVP in each rat, it was shown to remain elevated for 10 wk. There were no significant differences in the pressure measurements at 2 wk, 6 wk and 10 wk. Varices were found mainly in the mesenteric vein 2 wk after PVL, which were more obvious later, while these manifestations were similar at week 6 and week 10. Portal venography demonstrated the varices and collaterals. There was no significant change in liver pathology. The volume of the spleen was enlarged 2-fold after ligation, and the sinus of the spleen was enlarged due to congestion. Significant sinus endothelial cell proliferation was observed, but no evidence of hypersplenia was found on hemogram and biochemical examination. These findings suggest that a satisfactory prehepatic PHT rat model can be obtained by partial ligation of the portal vein, and this PHT rat model was stable for at least 10 wk.

Splanchnic-Brain Crosstalk Mediated By Chemokines In Portal Hypertensive Rats

In experimental portal hypertension, the inflammatory cerebral-splanchnic axis alterations could be mediated by chemokines. In Wistar rats with partial portal vein ligation, RANTES, CXCR4/SDF-1alpha and CX3CR1/Fractalkine were measured in several brain and gastrointestinal areas. Nestine and Bcl-2 were assayed in the hippocampus, and TNF-﷿a in the liver, ileum and mesenteric lymph nodes. In the CNS of portal hypertensive-rats, SDF-1alpha increased in the hippocampus (p<0.05), and cerebellum (p<0.05), and RANTES (p<0.05) decreased in the striatum. TNF-alpha and CXCR4 increased in the hippocampus and TNF-alpha in the ileum and in mesenteric lymphatic nodes. CX3CR1 increased in the ileum (p<0.05), whereas Fractalkine increased (p<0.05) in the mesenteric lymph nodes. Splanchnic CX3CR1 and fractalkine overexpression may suggest the development of anti-inflammatory and repair mechanisms to balance pro-inflammatory mechanisms. SDF1-alpha upregulation in the CNS could suggest its involvement in neuronal remodeling. The existence of a communication mechanism chemokinedependent through the splanchnic-brain axis in portal hypertension could be hypothesized.

Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension

Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension. Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed. Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels. This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.

Changes of hydrogen sulfide and its impact on nitric oxide/ nitric oxide synthase system in portal hypertensive rats

Objective To explore the changes of hydrogen sulfide and its impact on nitric oxide/ nitric oxide synthase system in portal hypertension rats.Methods Thirty SD rats were randomly divided into the normal group(n=5),sham-operated group(n=5),PPVL group (n=10) and PPVL+NaHS group (n=10).In PPVL group and PPVL+NaHS group,portal hypertension was established through the operation of partly portal vein ligation (PPVL).Two weeks later,portal vein pressure (PVP) and systemic arterial pressure (MAP) were measured.The immunohistochemical method was used for detection of expression of CSE and NOS in liver,and RT-PCR for that of CSEmRNA and NOSmRNA.Results After 14 days,there were no significant differences in the indexes between the sham-operated group and the normal group.Compared with normal group,PVP was increased significantly in PPVL group (P＜0.01 ),but MAP was decreased (P＜0.05).Compared with PPVL group,PVP was also increased in PPVL+ NariS group (P＜0.05),and MAP was decreased too (P＜0.05).Both CSE and NOS3 and the mRNA of them were expressed in the liver of rats.Compared with normal group or sham-operated group,the expression of CSE and the mRNA expression of it were increased in PPVL group (P＜0.05).Compared with PPVL group,the expression of CSE was increased too in PPVL+NaHS group (P＜0.05).NOS2 did not expressed in liver in normal group and sham-operated group.However,it was found after the operation of PPVL.Compared withPPVL group,the expression of NOS2 was decreased in PPVL+NaHS group.On the other hand,the expression of NOS3 protein and mRNA was of no significant difference among different groups.Conclusion Endogenous H2S is involved in the formation and development of portal hypertension.Exogenous application of H2S can aggravate the portal hypertension for the high level of endogenous H2S can inhibit the generation of NOS. Key words: Hypertension portal; Hydrogen sulfide; Sodium hydrosulfide; Cystathionine-γ-lyase; Nitric oxide; Liver

Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats #

Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.

Cordyceps mycelia extract decreases portal hypertension in rats with dimethylnitrosamine-induced liver cirrhosis: a study on its histological basis

Cordyceps mycelia extract decreases portal hypertension in rats with dimethylnitrosamine-induced liver cirrhosis: a study on its histological basis

Oxidative stress and hippocampus in a low‐grade hepatic encephalopathy model: protective effects of curcumin

The present study was performed on prehepatic portal hypertensive rats, a model of low-grade hepatic encephalopathy, designed to evaluate whether oxidative stress was a possible pathway implicated in hippocampal damage and if so, the effect of an anti-oxidant to prevent it. Prehepatic portal hypertension was induced by a regulated portal vein stricture. Oxidative stress was investigated by assessing related biochemical parameters in rat hippocampus. The effect of the anti-oxidant curcumin, administered in a single i.p. dose of 100 mg/kg on the seventh, ninth and eleventh days after surgery, was evaluated. Oxidative stress in the rat hippocampal area was documented. Curcumin significantly decreased tissue malondialdehyde levels and significantly increased glutathione peroxidase, catalase and superoxide dismutase activities in the hippocampal tissue of portal hypertensive rats. Oxidative stress was found to be implicated in the hippocampal damage and curcumin protected against this oxidative stress in low-grade hepatic encephalopathic rats. These protective effects may be attributed to its anti-oxidant properties.

Bacterial translocation increases phagocytic activity of polymorphonuclear leucocytes in portal hypertension: priming independent of liver cirrhosis

Bacterial translocation (BT) to mesenteric lymph nodes (MLN) in cirrhosis has been linked to impaired host defence. Phagocytosis by polymorphonuclear leucocytes (PMNLs) is the primary event in the killing of bacteria but has not been investigated in relation to the presence of BT. Mesenteric lymph nodes were harvested sterile and assessed for BT by culture techniques. Study groups included ascitic cirrhotic rats (LC), healthy controls (Con) as well as portal-vein-ligated (PVL) rats 2 days (acute PVL with and without norfloxacin) or 3 weeks after surgery (chronic PVL). PMNLs were isolated from systemic blood and the capacity to phagocytose opsonized Escherichia coli was evaluated by FACS analysis. No BT was observed in Con and chronic PVL animals but 11/20 LC (55%) and six out of six acute PVL (100%) presented with BT. In the presence of BT, PMNL from PVL as well as LC rats showed significantly increased phagocytic activity as compared with controls. In contrast, PMNL from animals without BT, whether PVL or LC, exhibited phagocytic activity similar to those from control rats. The number of PMNLs involved in the phagocytic process was significantly increased only in portal-hypertensive rats with but not without BT as compared with controls. Norfloxacin did prevent BT in acute PVL animals, thereby correcting the increase in phagocytic capacity in PMNL. Cirrhosis per se is not associated with alterations of the phagocytic capacity of PMNL. The occurrence of BT, however, increases the phagocytic capacity of PMNL, being observed likewise in prehepatic portal hypertension, indicating an in vivo'priming' of PMNL by BT independent of cirrhosis.

Vascular actions of the prostacyclin receptor antagonist BAY 73-1449 in the portal hypertensive rat

We have investigated the actions of the postacyclin receptor antagonist BAY 73-1449 on shunt vessel development and shunt flow in the portal vein ligated portal hypertensive Wistar rat in vivo. BAY 73-1449 (0.1–1 mg/kg), given intravenously, did not significantly reduce mesenteric inflow, but significantly reduced splenic shunt vessel outflow, compared to the effects of vehicle, in anaesthetized portal vein ligated rats as measured by shunt vessel conductance. There were no differences between portal vein ligated animals treated, beginning just before portal vein ligation, with vehicle for 7 days and animals treated for 7 days with BAY 73-1449 (1–5 mg/kg, s.c.) in the degree of porto-systemic shunting, as measured by the radioactive microsphere technique in anaesthetized rats. Portal pressure was similar in animals treated with vehicle or BAY 73-1449. It is concluded that the prostacyclin receptor antagonist BAY 73-1449 can acutely reduce shunt vessel blood flow in portal hypertensive rats.