Rat Model Of Portal Hypertension Research Articles

Relationship Between Spleen Pathologic Changes and Spleen Stiffness in Portal Hypertension Rat Model

The aim of the study described here was to explore the influence of splenic pathology and hemodynamic parameters on spleen stiffness in portal hypertension (PH). A Sprague‒Dawley rat model of PH (n=34) induced by CCl4 was established, and 9 normal rats were used as controls. All animals underwent a routine ultrasound examination, spleen stiffness measurement (SSM), liver stiffness measurement (LSM), portal vein pressure (PVP) measurement and histopathologic assessment. The diagnostic performance of SSM and LSM in PH was evaluated. SSMs were compared among the groups at different pathologic and hemodynamic levels. Multiple linear regression was used to analyze the factors affecting SSM. SSM had excellent diagnostic efficacy for PH (area under the receiver operating characteristic curve [AUC]=0.900) and was superior to LSM (AUC=0.794). In a rat model of PH, pathologic changes such as splenic sinus widening, thickening of the splenic capsule and an increase in collagen fibers were observed in the spleen. There were significant differences in SSM at different splenic capsule thicknesses and splenic sinus widths (all p values <0.05), but there were no significant differences in the SSM at different levels of the splenic collagen fiber area and red pulp area (all p values >0.05). In addition, there were significant differences in SSM at different levels of portal vein diameter, blood flow and congestion index (all p values <0.05). Multiple linear regression analysis revealed that PVP, portal vein congestion index and splenic capsule thickness were significantly associated with SSM. SSM is a good non-invasive way to assess PH. PVP, splenic capsule thickness and portal vein congestion index are responsible for spleen stiffness but not the proliferation of splenic fibrous tissue.

OCE-205, a Selective V1a Partial Agonist, Reduces Portal Pressure in Rat Models of Portal Hypertension.

Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists. We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT). For both models, OCE-205 was administered as a subcutaneous bolus injection. Thirty male Wistar rats were fed a methionine/choline-deficient (MCD) diet to model PHT. Animals received OCE-205 (10, 25, 100, or 500µg/kg) or intra-arterial terlipressin (100µg/kg). In a more severe model of PHT, 11 male Sprague Dawley rats had the common bile duct surgically ligated (BDL) and received OCE-205. Portal pressure (PP) and mean arterial pressure (MAP) were measured. For PP in the MCD model, MAP increased while PP decreased in rats treated with OCE-205 or terlipressin; the peak changes to MAP were 14.7 and 33.5 mmHg, respectively. Changes in MAP began to plateau after 10min in the OCE-205 groups, whereas in the terlipressin group, MAP rapidly increased and peaked after 20min. Across all treatment groups in the BDL model, a dose-related decrease from baseline in PP was observed following OCE-205, plateauing as the dose increased. In all treatment groups, PP change remained negative throughout the 30-min testing period. In both PHT rat models, a reduction in PP was coupled to an increase in MAP, with both plateauing in dose-response curves. Data support OCE-205 as a promising candidate for further development. Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee on July 13, 2011, under protocol FRI-07-0002.

Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model.

Portal hypertension (PT) commonly occurs in cirrhosis. Nitric oxide (NO) imbalance contributes to PT via reduced soluble guanylyl cyclase (sGC) activation and cGMP production, resulting in vasoconstriction, endothelial cell dysfunction, and fibrosis. We assessed the effects of BI 685509, an NO-independent sGC activator, on fibrosis and extrahepatic complications in a thioacetamide (TAA)-induced cirrhosis and PT model. Male Sprague-Dawley rats received TAA twice-weekly for 15 weeks (300-150 mg/kg i.p.). BI 685509 was administered daily for the last 12 weeks (0.3, 1, and 3 mg/kg p.o.; n = 8-11 per group) or the final week only (Acute, 3 mg/kg p.o.; n = 6). Rats were anesthetized to measure portal venous pressure. Pharmacokinetics and hepatic cGMP (target engagement) were measured by mass spectrometry. Hepatic Sirius Red morphometry (SRM) and alpha-smooth muscle actin (αSMA) were measured by immunohistochemistry; portosystemic shunting was measured using colored microspheres. BI 685509 dose-dependently increased hepatic cGMP at 1 and 3 mg/kg (3.92 ± 0.34 and 5.14 ± 0.44 versus 2.50 ± 0.19 nM in TAA alone; P < 0.05). TAA increased hepatic SRM, αSMA, PT, and portosystemic shunting. Compared with TAA, 3 mg/kg BI 685509 reduced SRM by 38%, αSMA area by 55%, portal venous pressure by 26%, and portosystemic shunting by 10% (P < 0.05). Acute BI 685509 reduced SRM and PT by 45% and 21%, respectively (P < 0.05). BI 685509 improved hepatic and extrahepatic cirrhosis pathophysiology in TAA-induced cirrhosis. These data support the clinical investigation of BI 685509 for PT in patients with cirrhosis. SIGNIFICANCE STATEMENT: BI 685509 is an NO-independent sGC activator that was tested in a preclinical rat model of TAA-induced nodular, liver fibrosis, portal hypertension, and portal systemic shunting. BI 685509 reduced liver fibrosis, portal hypertension, and portal-systemic shunting in a dose-dependent manner, supporting its clinical assessment to treat portal hypertension in patients with cirrhosis.

A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo.

The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression.

Electroacupuncture attenuates vascular hyporeactivity in a rat model of portal hypertension induced by bile duct ligation.

A hyperdynamic circulation and impaired vascular responsiveness to vasoconstrictors are observed in portal hypertension (PHT) rats. Inflammation is a major contributor to the hyperdynamic circulation state in murine models of PHT. Electroacupuncture (EA) may ameliorate the inflammatory response and limit arterial vasodilatation and portal pressure. This study investigated the possible mechanisms underlying putative hemodynamics effects of EA in normal and PHT rats. PHT was induced by bile duct ligation (BDL) surgery over 4 weeks in rats. Sham-operated and BDL rats were treated with low-frequency EA (2 Hz) at ST36 10 min three times weekly for one or two consecutive weeks (for a total of 3 or 7 treatments, respectively). Serum tumor necrosis factor-α (TNF-α), nitrite/nitrate (NOx) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were analyzed, and hemodynamic variation and contractile responses to phorbol-12,13-dibutyrate and phenylephrine in aortic and superior mesenteric arterial rings were recorded. Inducible (i) and endothelial (3) nitric oxide synthase (NOS), cyclooxygenase-1 (COX-1), and protein kinase C-α (PKC-α) levels were determined by Western blotting. EA significantly reduced portal pressure and serum TNF-α, NOx and 6-keto-PGF1α levels compared to the untreated BDL group, enhanced maximum contractile responses in the aorta, up-regulated PKC-α, and down-regulated iNOS and COX-1 levels. In addition, EA decreased the aortic angiogenesis signaling cascade, reflected by down-regulation of vascular endothelial growth factor (VEGF) abundance and transforming growth factor β receptor (TGFβR)I/II expression, as assessed by immunostaining. EA attenuates TNF-α, NO and 6-keto-PGF1α overproduction, modulates the vascular levels of constitutive NOS and PKC-α, blunts the development of the angiogenesis cascade, and enhances vascular contractile force in PHT rats.

Influence of miR-26b on hepatic cirrhosis and portal pressure in rats with cirrhotic portal hypertension by targeting hENT1 depending on RhoA/ROCK-1 pathway.

To explore the regulatory effect of micro ribonucleic acid-26b (miR-26b) on rat models of cirrhotic portal hypertension and the underlying mechanism of action. Common bile duct ligation (BDL) was applied to establish rat models. A total of 30 male Wistar rats were randomly divided into sham operation group (Sham group), operation group (BDL group) and miR-26b intervention group (miR-26b mimic group). Hematoxylin-eosin (HE) staining assay was performed to detect pathological characteristics of rat liver tissues in each group. The portal venous pressure in each group was then determined. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in rat serum were measured via serological test. Kits were used to detect serum levels of hyaluronic acid (HA), procollagen III peptide (PCIII) and laminin (LN) in rats. Western blotting was utilized to detect the protein levels of human equilibrative nucleoside transporter 1 (hENT1), ras homolog gene family, member A (RhoA) and Rho-associated coiled-coil-containing kinase protein-1 (Rock-1). In comparison with Sham group, BDL group had significantly increased portal venous pressure and protein levels of hENT1, RhoA and ROCK-1, and elevated levels of AST, ALT, HA, PCIII and LN in rats. Compared with those in BDL group, the portal venous pressure and protein levels of hENT1, RhoA and ROCK-1 were overtly reduced, while the levels of AST, ALT, HA, PCIII and LN declined in miR-26b mimic group. MiR-26b mimics played a role in the treatment of rats with cirrhotic portal hypertension by targeting hENT1 to inhibit the RhoA/ROCK-1 signaling pathway.

Characterization and evolution of intestine injury at the anhepatic phase in portal hypertensive rats.

The aim of the present study was to investigate the characteristics and progression of intestinal injury at the anhepatic phase in portal hypertensive rats. A total of 120 healthy male Wistar rats were purchased, with 15 rats in the normal control group and 105 rats were assigned to establish a prehepatic portal hypertension model. The 105 model rats were further divided into seven treatment groups following ischemia-reperfusion. Meanwhile, portal vein pressure, the area of lower esophageal mucosal vein, endotoxin levels in portal vein blood and the level of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Morphology changes of the intestine were observed using optical microscopy and transmission electron microscopy. A portal hypertension rat model was successfully established. Furthermore, endotoxin, MDA and SOD level reached a peak at 12-24 h following reperfusion and then decreased gradually to normal levels at 1 week following reperfusion. However, cytological damage did not recover to preoperative level within 1 week. These findings suggest that intestinal injury was most severe within 12-24 h following ischemia-reperfusion and most indicators recovered to almost normal levels. Therefore, further study on the intestinal mucosal damage is required, with the aim to reduce the production of intestinal endotoxin.

Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats.

This is a detailed protocol describing invasive hemodynamic measurements in cirrhotic rats for the characterization of portal hypertensive syndrome. Portal hypertension (PHT) due to cirrhosis is responsible for the most severe complications in patients with liver disease. The full picture of the portal hypertensive syndrome is characterized by increased portal pressure (PP) due to the increased intrahepatic vascular resistance (IHVR), hyperdynamic circulation, and increased splanchnic blood flow. Progressive splanchnic arterial vasodilation and increased cardiac output with elevated heart rate (HR) but low arterial pressure characterizes the portal hypertensive syndrome. Novel therapies are currently being developed that aim to decrease PP by either targeting IHVR or increased splanchnic blood flow - but side effects on systemic hemodynamics may occur. Thus, a detailed characterization of portal venous, splanchnic, and systemic hemodynamic parameters, including measurement of PP, portal venous blood flow (PVBF), mesenteric arterial blood flow, mean arterial pressure (MAP), and HR is needed for preclinical evaluation of the efficacy of novel treatments for PHT. Our video article provides the reader with a structured protocol for performing invasive hemodynamic measurements in cirrhotic rats. In particular, we describe the catheterization of the femoral artery and the portal vein via an ileocolic vein and the measurement of portal venous and splanchnic blood flow via perivascular Doppler-ultrasound flow probes. Representative results of different rat models of PHT are shown.

Influences of cirrhotic portal hypertension on rats' cognitive function and N-methyl-D-aspartic acid receptor 2B expression level

Objective Research on the influences of cirrhotic portal hypertension on rats' hcongnitive function and N-methyl-D-aspartic acid receptor 2B(NR2B) expression level. Methods Thirty seven male SD rats were randomly divided into 2 groups. In the cirrhotic portal hypertension group (group A), 25 rats were inducted into portal hypertension rat model using carbon tetrachloride-peanut oil solution. The remaining 12 rats served as control group (group B). Step-down method and Y-maze method were used in both groups prior to modeling and 1, 3, 5, 7 d after modeling respectively to study their behavior. All rats were killed after testing and hippocampi were collected. RT-PCR was used to detect NR2B mRNA level in the hippocampi, and Western blot was used to detect NR2B protein expression level. Immuno-histochemical method was used to detect NR2B protein distribution changes. ELISA was used to detect the level of ALT and AST, superoxide dismutase (SOD), malondialdehyde (MDA), TNF-α, IL-1 and IL-6. Results The level of AST, ALT, TNF-α, IL-1, IL-6 and MDA in group A were (261±7), (178±7) U/L, (206±18), (0.46±0.11), (298±41) μg/L, (19.7± 2.5) μmol/L, which were much higher than in group B(P<0.01), while SOD level[(96.0±7.0) U/ml] was lower than in group B (P<0.01). The step-down latent time of group A was longer and the number of error in Y-maze was more than B group (P<0.01). NR2B mRNA level and NR2B protein expression in the hippocampi of group A rats were evidently lower than that in group B(P<0.01). NR2B immunohistochemical level was lower in the CA1 area of the hippocampi of group A rats than that of the group B (P<0.01). Conclusions Cognitive function were decreased in cirrhotic portal hypertension rats, with decreasing NR2B mRNA and protein expression level in the hippocampus as well. Key words: Cirrhotic of liver; Portal hypertension; Cognitive function; N-methyl-D-aspartic acid receptor 2B; Rat

Pulmonary injury at the anhepatic phase without veno-venous bypass in portal hypertensive rats

ABSTRACTObjective: In order to understand the characterization and evolution of pulmonary injury, a portal hypertension rat model was used to imitate the anhepatic phase during standard orthotopic liver transplantation without veno-venous bypass. Methods: In this study, 135 healthy male Wistar rats were selected; in which 15 rats were assigned in the normal control (NC) group and the remaining 120 rats were used to establish a recoverable prehepatic portal hypertension model, which were further evenly divided into eight groups after ischemia-reperfusion: portal hypertensive control group (PHTC), R0h, R6h, R12h, R24h, R48h, R72h, and R7d groups. Meanwhile, arterial blood pressure, dry-to-wet weight ratios of the lung, alanine aminotransferase (ALT) level in serum, arterial oxygen pressure (PaO2), and myeloperoxidase (MPO) activity in lung tissue were measured. Morphology changes of the lung were observed using an optical microscope and a transmission electron microscope. Results: The portal hypertension rat model was successfully established three weeks after the first operation. These portal hypertensive rats could withstand 1 hour at the anhepatic phase. Pulmonary injury severity increased to the most at 12–24 hours, and decreased to normal at seven days after reperfusion. Conclusion: Ischemia-reperfusion injury is an important mechanism that results in pulmonary injury after liver transplantation. It is safe for portal hypertensive rats to tolerate 1 hour at the anhepatic phase. Pulmonary injury was the most severe within 12–24 hours after ischemia-reperfusion.

Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway.

BackgroundSpleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease.MethodsSpleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly.ResultsWe found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure.ConclusionsThis study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly.

Experimental study of the relationship between the angiopoietin-1/tyrosine kinase receptors-2 system and the neoangiogenesis in lower esophagus of rats with portal hypertension

Objective To establish a rat model of portal hypertension and explore the relationship between the angiopoietin-1(Ang-1)/tyrosine kinase receptors 2(Tie-2) system and the neoangiogenesis in lower esophagus of rats with portal hypertension. Methods Fifty SD rats were randomly divided into two groups:experimental group(thirty rats, partial portal vein and left suprarenal vein were ligatured to make portal hypertension model) and control group(twenty rats, the portal vein and left suprarenal vein were separated but not ligatured). The lower esophageal tissue was obtained two weeks after the operation.The immunohistochemical streptavidin-perosidase(SP) technique was used to detect the expression of Ang-1, Tie-2 and CD34.The microvessel density (MVD) was determined by CD34 staining.The relationship between Ang-1, Tie-2 and the neoangiogenesis in lower esophagus was analyzed after that. Results The models of portal hypertension were set up successfully in 37 rats(17 in experimental group and 20 in control group).Compared with those of control group, the differences in the expression of Ang-1, Tie-2 and MVD were statistically significant(P 0. 05), but the expression of Tie-2 was positively correlated with MVD(r= 0. 71, P< 0. 05). Conclusion The expression of Ang-1, Tie-2 and MVD is obviously higher in lower esophagus of rats in experimental group than that in the control group.The Ang-1/Tie-2 system is possibly related to the neoangiogenesis in lower esophagus of rats with portal hypertension. Key words: Portal hypertension; Angiopoietin-1; Tyrosine kinase receptors 2; Microvessel density

Effect of fluid shear stress on portal vein remodeling in a rat model of portal hypertension.

Aims. To explore the effects and mechanisms of fluid shear stress on portal vein remodeling in a rat model of portal hypertension. Methods. Subcutaneous injections of CCl4 were given to establish a rat model of liver cirrhosis and portal hypertension. Biomechanical technology was adopted to determine the dynamic changes of haemodynamic indices and fluid shear stress. Nitric oxide (NO), synthase (NOS), and endothelin-1 (ET-1) of the portal vein blood were measured. Changes in geometric structure and ultrastructure of the portal vein were observed using optical and electron microscopy. Results. After the CC14 injections, rat haemodynamics were notably altered. From week 4 onwards, PVP, PVF, and PVR gradually and significantly increased (P < 0.05 versus baseline). The fluid shear stress declined from week 4 onwards (P < 0.01 versus control group). NO, NOS, and ET-1 increased after repeated CCI4 injections. Hematoxylin and eosin staining showed thickened portal vein walls, with increased inside and outside diameters. Electron microscopy revealed different degrees of endothelial cell degeneration, destruction of basement membrane integrity, proliferating, and hypertrophic smooth muscle cells. Conclusions. Fluid shear stress not only influenced the biomechanical environment of the portal vein but also participated in vascular remodeling.

Lipopolysaccharide enhanced renal vascular response to endothelin-1 through ETA overexpression in portal hypertensive rats.

Hypo-perfusion resulting from intense renal vasoconstriction is traditionally contributed to renal dysfunction in advanced liver disease, although cumulative studies demonstrated renal vasodilatation with impaired vascular contractility to endogenous vasoconstrictors in portal hypertension and compensated liver cirrhosis. The pathophysiology of altered renal hemodynamics remains unclear. This study, using a rat model of portal hypertension with superimposed endotoxemia, was designed to delineate the evolution of renal vascular reactivity and vaso-regulatory gene expression during liver disease progression. Rats were randomized into sham surgery (SHAM) or partial portal vein ligation (PVL). Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS) on the seventh day following surgery. Isolated kidney perfusion was performed at 0.5 h or 5 h after LPS to evaluate renal vascular response to endothelin-1. In contrast to impaired vascular contractility of SHAM rats, PVL rats displayed enhanced renal vascular reactivity to endothelin-1 at 5 h following endotoxemia. There were extensive upregulations of inducible nitric oxide synthase in kidney tissues of endotoxemic rats. The changes of renal endothelin receptor type A (ETA ) level paralleled with the changes of renal vascular reactivity in LPS-treated rats. Compared with SHAM rats, PVL rats showed increased renal ETA and phosphorylated extracellular-signal-regulated kinases 1/2 (p-ERK1/2) at 5 h after LPS. LPS-induced systemic hypotension induces a paradoxical change of renal vascular response to endothelin-1 between SHAM and PVL rats. LPS-induced renal vascular hyperreactivity in PVL rats was associated with upregulation of renal ETA and subsequent activation of ERK1/2 signaling.

Endothelial progenitor cells in rat model of portal hypertension with esophagogastric varices

Objective To investigate the involvement of endothelial progenitor cells (EPCs) in collateral angiogenesis in portal hypertension.Methods A rat model of portal hypertension with esophagogastric varices was established (n =15) as model group,and the rats were subjected to sham operations as control group (n =5).The counts of EPCs in the portal veins in the two groups and the relationship between the EPCs and vessel density in esophageal tissue in the model group were analyzed.The expression of CD133 in the esophageal veins of rats with esophagogastric varices was detected by the immunohistochemical method.Results Significantly more EPCs colonies were observed in the model group than in the control group (P ＜ 0.01),and this finding was closely correlated with the vascular density of the esophageal tissue (P ＜ 0.01).CD133-positive endothelial cells were visible in the esophageal submucosal vessels of model group but not in control group.Conclusion EPCs may be involved in the angiogenesis of esophageal veins in rats with portal hypertension. Key words: Endothelial progenitor cells; Portal hypertension; Esophagogastric varices

Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats

ObjectiveTo observe the protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats. MethodsAll rats were randomly divided into normal control group, cirrhosis and treatment group. Thioacetamide was used to establish rat model of cirrhotic portal hypertension. The necrotic tissue of gastric mucosa ulcer focus, degree of neutrophils infiltration at the ulcer margin, portal pressure, portal venous flow, abdominal aortic pressure, abdominal aortic blood flow at front end, gastric mucosal blood flow (GMBF), glycoprotein (GP) of gastric mucosa, basal acid secretion, H+back -diffusion, gastric mucosal damage index, NO, prostaglandin E2(PGE2) and tumor necrosis factor-α (TNF-α) were determined respectively, and the pathological changes of gastric mucosa were also observed by microscope. ResultsCompared with cirrhosis group and the control group, the ulcer bottom necrotic material, gastric neutrophil infiltration and UI of the treatment group were all decreased significantly (P<0.01), GMBF value, GP values, serum NO, PGE2, TNF-α were all significantly increased. ConclusionsOmeprazole has an important protective effect on gastric mucosal and it can increase gastric mucosal blood flow and related to many factors.

Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats

The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct-ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2. FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis.

Nebivolol treatment increases splanchnic blood flow and portal pressure in cirrhotic rats via modulation of nitric oxide signalling

We evaluated the effects of nebivolol, a third generation beta-blocker capable of increasing NO-bioavailability on portal pressure, and on splachnic and systemic haemodynamics in a cirrhotic portal hypertensive rat model. Male Sprague-Dawley rats underwent sham operation (SO) or bile duct ligation (BDL). When cirrhosis was fully developed, the animals were orally treated with low-dose (5 mg/kg) or high-dose (10 mg/kg) nebivolol (NEBI) or vehicle (VEH) for 7 days. Heart rate (HR), mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Portosystemic collateral blood flow (PSCBF) was quantified using radioactive microspheres. Hepatic and splanchnic NOx levels and GSH/GSSG ratios (RedOx state) were determined using commercially available kits. BDL-VEH rats showed increased HR, PP and PSCBF, whereas MAP was decreased compared to SO-VEH rats. Nebivolol significantly reduced HR both in SO (P < 0.001) and BDL (P < 0.001) rats. BDL-NEBI animals had significantly higher PP (15.5 vs. 12.6 mmHg; P = 0.006) and SMABF (5.3 vs. 3.7 ml/min/100g; P = 0.016) than BDL-VEH animals. The increase in PP and SMABF was noted both in low-dose and high-dose BDL-NEBI rats. While no beneficial effects on hepatic RedOx state were observed, splanchnic NOx levels were significantly increased by NEBI treatment in a dose-dependent manner. Nebivolol treatment did not affect PSCBF in SO and BDL animals. Nebivolol increases portal pressure in cirrhotic animals by increasing splanchnic blood flow via modulation of NO signalling. Portosystemic collateral blood flow remained unchanged. These data do not support the use of nebivolol for treatment of cirrhotic patients with portal hypertension.

Zolmitriptan: A Novel Portal Hypotensive Agent Which Synergizes with Propranolol in Lowering Portal Pressure

ObjectiveOnly a limited proportion of patients needing pharmacological control of portal hypertension are hemodynamic responders to propranolol. Here we analyzed the effects of zolmitriptan on portal pressure and its potential interaction with propranolol.MethodsZolmitriptan, propranolol or both were tested in two rat models of portal hypertension: common bile duct ligation (CBDL) and CCl4-induced cirrhosis. In these animals we measured different hemodynamic parameters including portal venous pressure, arterial renal flow, portal blood flow and cardiac output. We also studied the changes in superior mesenteric artery perfusion pressure and in arterial wall cAMP levels induced by zolmitriptan, propranolol or both. Moreover, we determined the effect of splanchnic sympathectomy on the response of PVP to zolmitriptan.ResultsIn both models of portal hypertension zolmitriptan induced a dose-dependent transient descent of portal pressure accompanied by reduction of portal flow with only slight decrease in renal flow. In cirrhotic rats, splanchnic sympathectomy intensified and prolonged zolmitriptan-induced portal pressure descent. Also, propranolol caused more intense and durable portal pressure fall when combined with zolmitriptan. Mesenteric artery perfusion pressure peaked for about 1 min upon zolmitriptan administration but showed no change with propranolol. However propranolol enhanced and prolonged the elevation in mesenteric artery perfusion pressure induced by zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of β2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by β2-agonists.ConclusionZolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combination therapy deserves consideration for patients with portal hypertension failing to respond to non-selective beta-blockers.

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

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