Development Of Portal Hypertension Research Articles

Cholestasis after Kasai operation predicts portal hypertension in native liver survivors of biliary atresia: a multicenter study.

This study evaluated portal hypertension (PHT) and its predictors among native liver survivors (NLS) of biliary atresia (BA) after Kasai portoenterostomy (KPE). This was a multicenter study using prospectively collected data. The subjects were patients who remained transplant-free for 5years after KPE. Their status of PHT was evaluated and variables that predicted PHT were determined by regression analysis and receiver operating characteristic (ROC) curve. Six centers from East Asia participated in this study and 320 subjects with KPE between 1980 to 2018 were analyzed. The mean follow-up period was 10.6 ± 6.2years. At the 5th year after KPE, PHT was found in 37.8% of the subjects (n = 121). Patients with KPE done before day 41 of life had the lowest percentage of PHT compared to operation at older age. At 12months after KPE, PHT + ve subjects had a higher bilirubin level (27.1 ± 11.7 vs 12.3 ± 7.9µmol/L, p = 0.000) and persistent jaundice conferred a higher risk for PHT (OR = 12.9 [9.2-15.4], p = 0.000). ROC analysis demonstrated that a bilirubin level above 38µmol/L at 12months after KPE predicted PHT development (sensitivity: 78%, specificity: 60%, AUROC: 0.75). In BA, early KPE protects against the development of PHT among NLSs. Patients with persistent cholestasis at one year after KPE are at a higher risk of this complication. They should receive a more vigilant follow-up. Level III.

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions.

Chronic liver disease (CLD) and its complications constitute a significant cause of mortality and morbidity worldwide. Most deaths are secondary to the decompensation of cirrhosis and evolution of portal hypertension (PHTN). Since disease progression reversal is hardly attainable after decompensated cirrhosis develops, it is essential to intervene early with a therapeutic agent or regimen that could prevent or slow disease evolution. Thus far, there has been no agreed-upon medication to help in the fight against the development of cirrhosis or its decompensation. While early data depicted statins as harmful agents for the liver, current evidence from preclinical and clinical studies suggests that they might have positive impact on CLD. Low-quality evidence supports the fact that statins reduce mortality in CLD. Moderate-quality evidence suggests that statins reduce the risk of hepatic decompensation, variceal bleeding, and mortality, especially among patients with compensated cirrhosis. Combining this data with the long track-record of safety and tolerability of statins and their potential benefits in hepatocellular carcinoma (HCC) risk reduction, hepatologists might soon rely on statins to achieve better outcomes in their CLD and cirrhotic patients without significant additional costs. This review describes the rationale behind the use of statins in patients with CLD and cirrhosis. It sheds light on the current preclinical and clinical studies that reflect beneficial effects of the use of different types and doses of statins in the treatment of patients with different types and stages of CLD and cirrhosis. It also emphasizes the need for designing and developing additional large prospective interventional randomized control trials (RCTs) to better evaluate the association between statin exposure and the risk of fibrosis progression and development of cirrhosis in patients with non-cirrhotic CLDs, the risk of progression of PHTN in patients with cirrhosis, and the mortality rates in patients with cirrhotic or non-cirrhotic CLDs.

Bleeding oesophageal varices in a 9 months old infant as a complication of neonatal umbilical catheterization – A case report

Esophageal variceal bleeding following portal hypertension (PHT) is rare in children but associated with significant morbidity and mortality. Neonatal umbilical catheterization is a risk factor for portal vein thrombosis and subsequent development of PHT. We report the case of a 9-month-old male infant that presented with upper gastrointestinal bleeding from esophageal varices. He was delivered at 32 weeks of gestation and had neonatal umbilical catheterization for intravenous fluids and antibiotics administration. Barium meal done after resuscitation revealed esophageal varices. He had a blood transfusion while on admission and was discharged home on oral propranolol. This case report highlights a rare case of bleeding esophageal varices secondary to PHT occurring in an infant who had neonatal umbilical catheterization.

Changes in Doppler parameters of portal pressure after interventional management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has many options for management; some of them are complicated by development of portal hypertension (PHT). Doppler ultrasound is an effective method to diagnose and monitor PHT changes after HCC ablation procedures. The aim of this study is to investigate changes in portal pressure hemodynamics of HCC patients following treatment with different interventional strategies: radiofrequency ablation (RFA), microwave ablation (MWA), and transarterial chemoembolization (TACE). A total of 60 patients with HCC were divided into three main groups, and each group received a different type of therapy (RFA, MWA, and TACE). Full medical record and basic investigations were performed including Doppler ultrasound and upper GIT endoscopy for evaluation of PHT parameters, and then repeated after three months of ablation. RFA is associated with the increased splenic artery resistive index, while MWA has no significant impact on PHT indices. TACE has led to a marked increase in liver vascular index with significant decrease in hepatic artery resistive index and PHI after treatment. No significant changes in esophageal varices were observed by upper GIT endoscopy following all ablation methods. RFA is quite safe but associated with degree of PHT. On the contrary, TACE is associated with improved PHT parameters. MWA has no significant association to development of PHT following the technique. Doppler ultrasound could be used as a reliable and effective method of evaluation of PHT post ablation for HCC.

Glycyrrhizinate reduces portal hypertension in isolated perfused rat livers with chronic hepatitis

To investigate the effects of diammonium glycyrrhizinate (Gly) on portal hypertension (PHT) in isolated portal perfused rat liver (IPPRL) with carbon tetrachloride (CCl₄)-induced chronic hepatitis. PHT model was replicated with CCl₄ in rats for 84 d. Model was identified by measuring the ascetic amounts, hepatic function, portal pressure in vivo, splenic index, and pathological alterations. Inducible nitric oxide synthase (iNOS) in liver was assessed by immunohistochemistry. IPPRLs were performed at d₀, d₂₈, d₅₆, and d₈₄. After phenylephrine-induced constriction, Gly was geometrically used to reduce PHT. Gly action was expressed as median effective concentration (EC₅₀) and area under the curve (AUC). Underlying mechanism was exploited by linear correlation between AUC values of Gly and existed iNOS in portal triads. PHT model was confirmed with ascites, splenomegaly, serum biomarkers of hepatic injury, and elevated portal pressure. Pathological findings had shown normal hepatic structure at d₀, degenerations at d₂₈, fibrosis at d₅₆, cirrhosis at d₈₄ in PHT rats. Pseudo lobule ratios decreased and collagen ratios increased progressively along with PHT development. Gly does dose-dependently reduce PHT in IPPRLs with CCl₄-induced chronic hepatitis. Gly potencies were increased gradually along with PHT development, characterized with its EC₅₀ at 2.80 × 10⁻¹⁰, 3.03 × 10⁻¹¹, 3.77 × 10⁻¹¹ and 4.65×10⁻¹¹ mol/L at d₀, d₂₈, d₅₆ and d₈₄, respectively. Existed iNOS was located at hepatocyte at d₀, stellate cells at d₂₈, stellate cells and macrophages at d₅₆, and macrophages in portal triads at d₈₄. Macrophages infiltrated more into portal triads and expressed more iNOS along with PHT development. AUC values of Gly were positively correlated with existed iNOS levels in portal triads. Gly reduces indirectly PHT in IPPRL with CCl₄-induced chronic hepatitis. The underlying mechanisms may relate to rescue NO bioavailability from macrophage-derived peroxynitrite in portal triads.

Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats

To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling. PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot. PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31⁺ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA⁺ smooth muscle cells of arterioles and in the CD31⁺ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2. Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.

Current concepts on the role of nitric oxide in portal hypertension

Portal hypertension (PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis. Portal pressure can be increased by a rise in portal blood flow, an increase in vascular resistance, or the combination. In cirrhosis, the primary factor leading to PHT is an increase in intra-hepatic resistance to blood flow. Although much of this increase is a mechanical consequence of architectural disturbances, there is a dynamic and reversible component that represents up to a third of the increased vascular resistance in cirrhosis. Many vasoactive substances contribute to the development of PHT. Among these, nitric oxide (NO) is the key mediator that paradoxically regulates the sinusoidal (intra-hepatic) and systemic/splanchnic circulations. NO deficiency in the liver leads to increased intra-hepatic resistance while increased NO in the circulation contributes to the hyperdynamic systemic/splanchnic circulation. NO mediated-angiogenesis also plays a role in splanchnic vasodilation and collateral circulation formation. NO donors reduce PHT in animals models but the key clinical challenge is the development of an NO donor or drug delivery system that selectively targets the liver.

Functional aspects on the pathophysiology of portal hypertension in cirrhosis

Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)and CIBERehd, SpainPortal hypertension is a severe and frequent complication ofchronic liver disease. Its consequences, bleeding from gastro-esophageal varices and portal hypertensive gastropathy, ascites,spontaneous bacterial peritonitis, hepatorenal syndrome, hepato-pulmonary/portopulmonary syndromes, and hepatic encephalop-athy, represent the first cause of death and liver transplantationin patients with cirrhosis. The primary factor in the developmentof portal hypertension is a marked increase in hepatic vascularresistance (HVR) to portal blood flow, which was classicallyattributed to distortion of the liver architecture inherent to cir-rhosis. However, over the past 20 years, a better understandingof the liver microcirculation has demonstrated that a dynamiccomponent due to an increased hepatic vascular tone furthercontributes to augment HVR. Secondarily to the increased HVR,there is a progressive splanchnic vasodilatation that incrementsportal blood flow, which aggravates and perpetuates the portalhypertension syndrome [1] (Fig. 1).Intrahepatic vascular regulationThe analysis of the structural factors (fibrosis, vascular remodel-ing, vascular occlusion, nodule formation) contributing toincrease HVR is out of the scope of this review that will focuson the dynamic component of the increased HVR.During progression to cirrhosis, sinusoidal endothelial cells(SEC) become dysfunctional and among other features acquire avasoconstrictor phenotype, characterized by elevated productionof vasoconstrictors and reduced release of vasodilators. Theresulting imbalance promotes the contraction of different cellsof the cirrhotic liver, such as hepatic stellate cells (HSC), portalmyofibroblasts and vascular smooth muscle cells that lead toincreased hepatic vascular tone and portal pressure. HSC in turnalso experience a profound phenotypical transformation, withmorphologic and functional consequences: loss of vitamin Adroplets, alpha-smooth muscle actin overexpression, hyper-response to vasoconstrictors and enhanced proliferative and fibr-ogenic activity. Interestingly, in experimental models of cirrhosis,strategies aimed at improving the hepatic vascular tone by tar-geting SEC have also been shown to improve liver fibrosis. Thismay be due to the fact that cellular phenotype alterations sharepathophysiological mechanisms, but also because SEC phenotypeamelioration positively affects HSC phenotype [2].Increase of vasoconstrictors in the liverIncreasedactivityof several endogenous vasoconstrictors,such asendothelin, norepinephrine, angiotensin II, vasopressin, leukotri-enes, and thromboxane A

Morphological and Biomechanical Remodeling of the Hepatic Portal Vein in a Swine Model of Portal Hypertension

To obtain the morphological and biomechanical remodeling of portal veins in swine with portal hypertension (PHT), so as to provide some mechanical references and theoretical basis for clinical practice about PHT. Twenty white pigs were used in this study, 14 of them were subjected to both carbon tetrachloride- and pentobarbital-containing diet to induce experimental liver cirrhosis and PHT, and the remaining animals served as the normal controls. The morphological remodeling of portal veins was observed. Endothelial nitric oxide synthase expression profile in the vessel wall was assessed at both mRNA and protein level. The biomechanical changes of the hepatic portal veins were evaluated through assessing the following indicators: the incremental elastic modulus, pressure-strain elastic modulus, volume elastic modulus, and the incremental compliance. The swine PHT model was successfully established. The percentages for the microstructural components and the histological data significantly changed in the experimental group. Endothelial nitric oxide synthase expression was significantly downregulated in the portal veins of the experimental group. Three incremental elastic moduli (the incremental elastic modulus, pressure-strain elastic modulus, and volume elastic modulus) of the portal veins from PHT animals were significantly larger than those of the controls (P < 0.05), whereas the incremental compliance of hepatic portal vein decreased. Our study suggests that the morphological and biomechanical properties of swine hepatic portal veins change significantly during the PHT process, which may play a critical role in the development of PHT and serve as potential therapeutic targets during clinical practice.

Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy

Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding sampling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis. Clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual's risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application.

HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension

Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV-HCV co-infection. Data of 74 interferon-naïve HIV-HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV-HCV patients had rapid progression of fibrosis [0.201 +/- 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 +/- 13 years), high HCV viral loads (4.83 x 10(6) IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = -0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV-HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/microL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV-HCV co-infection and largely preserved CD4+ cell counts.

Portal Hypertension in Children With Wilms' Tumor: A Report From the National Wilms' Tumor Study Group

This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT). Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors. Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors (p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin (p = 0.32) and 2.8 for females (p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs. <or=15 Gy was 2.5 (p = 0.001); it was 2.4 for a maximum liver dose of >15 Gy vs. <or=15 Gy (p = 0.001). There was a strong association between higher doses of liver RT (>15 Gy) and the development of PHTN among WT patients.

Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI(2)), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI(2) biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1(-/-), and COX-2(-/-) mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI(2) biosynthesis were determined 1-7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI(2) biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1(-/-) mice with NS398 or COX-2(-/-) mice with SC560 restricted PGI(2) biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI(2) biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI(2) rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone.

Comparison of three research models of portal hypertension in mice: macroscopic, histological and portal pressure evaluation

The characterization of mice models of portal hypertension (PHT) is lacking in the literature. Therefore, the aim of the present study was to make a histological approach during development of PHT in two models of cirrhosis with PHT compared with one model of isolated PHT. The model of isolated PHT was developed by partial portal vein ligation (PPVL). Two portal hypertensive cirrhotic mice models were developed either by common bile duct ligation (CBDL) or administration of carbon tetrachloride (CCl(4)) subcutaneously (twice weekly, 1 ml/kg). These models represent, respectively, a secondary biliary cirrhosis and alcoholic cirrhosis. Mice were killed at several time points to evaluate liver changes by histological and ultrastructural methods. A correlation was made with portal pressure measurements. Histology revealed the absence of fibrosis or cirrhosis in PPVL mice. They developed an isolated portal hypertension. After CBDL induction, the mice developed the characteristics of cirrhosis after 6 weeks, with simultaneous increase in portal pressures. Fifty percent of the mice had ascites at that time point. Sixteen weeks after administration of CCl(4), a micronodular cirrhotic aspect of the liver was seen associated with signs of portal hypertension. This is the first descriptive study of three widely used animal models in mice, allowing the study of pathophysiological changes in cirrhosis and portal hypertension. The PPVL in mice leads to a model of isolated portal hypertension. Secondary biliary cirrhosis developed after 6 weeks of common bile duct ligation in 50% of the mice that developed ascites. Subcutaneous injection of CCl(4) for 16 weeks induces cirrhosis and portal hypertension, without ascites. Moreover, the present study is the first description of a cirrhotic model in mice developed by subcutaneous injections of CCl(4). Well-described mice models will facilitate use of knock-out or transgenic mice and lead to a better understanding of the underlying molecular pathways in the field of portal hypertension and cirrhosis.

Portal Hypertension Secondary to Myelofibrosis: A Study of Three Cases

In patients with idiopathic myelofibrosis (IM), portal hypertension (PHT) without thrombosis of the hepatic or splenoportal veins is infrequent. To ascertain the mechanisms responsible for the development of PHT in IM and their therapeutic implications. Color Doppler ultrasound with portal flow quantification, hepatic hemodynamic studies, and histological examinations of the liver biopsies were performed in three IM patients with PHT in whom hepatic and splenoportal thrombosis were ruled out. Two patients showed sinusoidal PHT (increased hepatic venous pressure gradient), normal portal flow, and massive myeloid metaplasia of the liver. Transjugular intrahepatic portosystemic shunt (TIPS) was indicated for variceal bleeding and ascites unresponsive to medical therapy, and resulted in an adequate control of these PHT complications. At the time of TIPS placement, direct portal pressure measurement showed a marked presinusoidal component in the PHT. A third patient died as a consequence of the IM before treatment of PHT could be instituted. This patient showed an extremely increased portal flow and lesser hepatic infiltration. IM patients with PHT might have a marked presinusoidal component contributing to PHT that is underestimated by hepatic vein catheterization. Treatment of the complications of PHT might not differ from that of patients with cirrhosis.

Longitudinal prostaglandin E 2 generation in various organs during evolution of experimental portal hypertension

It has been suggested that the arteriolar vasodilatation and hyperdynamic circulation observed in rats with partial portal vein ligation (PPVL) is caused by increased splanchnic and systemic delivery of vasodilator substances. The aims of our study were to determine organ-specific generation of prostaglandin E 2 (PGE 2) in rats with PPVL during the evolution of portal hypertension. Rats with PPVL and sham-operated (S) rats were studied in the first, third, fourth and 14th postoperative days. They were anesthetized and splenic pulp pressure and blood pressure were measured. Spleen, colon and lungs were removed and the splenic, pulmonary and mucosal colonic PGE 2 were determined. All PPVL rats developed sequential hemodynamic changes compatible with evolving portal hypertension. Splenic pulp pressure was higher in PPVL rats compared with S rats during all days of the study. Within the group of PPVL the splenic pulp pressure was higher in the first postoperative day and decreased in the ensuing days. No changes in splenic and colonic PGE 2 generation were noted during the study period. Pulmonary PGE 2 generation increased significantly in the first postoperative day in PPVL rats compared with S rats. However, similar increase was observed on the third postoperative day in S rats. PGE 2 probably has no role in splanchnic hemodynamic changes during evolution of portal hypertension. Pulmonary PGE 2 generation may increase as a response to increased portal pressure, or to abdominal surgery.

Tipos evolutivos de hipertensión portal prehepática en la rata

A long-term study of the prehepatic portal hypertension model by triple stenosing ligation of the portal vein in the rat. A cluster analysis of the animals in the different evolutive stages of portal hypertension (1 1/2, 6, 12 and 14 months) has been carried out. This analysis has made it possible to identify three homogeneous groups (A, B and C) in relationship to the liver weight. The animals with liver atrophy (group C) show a decrease of body, splenic and testicular weights as well as a higher development of the portosystemic collateral circulation in relation to the A and B groups. The percentage of animals belonging to the group C decrease progressively during the evolution of portal hypertension and those animals corresponding to the group A, in which is superior the liver weight, increase, while the B group does not change.

Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: Role in the hyperdynamic circulation

Portal hypertension (PHT) is characterized by splanchnic hyperemia due to enhanced production of vasodilator substances. Enhanced vasodilation and increased splanchnic blood flow contribute to the elevated portal pressure characteristic of PHT. The aim of this study was to determine whether cyclooxygenase (Cox) expression is altered in PHT vessels and whether chronic inhibition of this enzyme impacts on splanchnic blood flow in PHT. PHT was created in Sprague-Dawley rats by a partial portal vein ligation. Control animals were sham operated. Plasma 6-keto-PGF1alpha (prostaglandin F1alpha) levels were significantly elevated in PHT after 2 days as compared with sham and remained elevated up to day 15. Treatment with indomethacin (2 mg/kg i.p. daily for 15 days) resulted in a significant decrease in 6-keto-PGF1alpha levels, which was concomitant with a significant decrease in superior mesenteric artery blood flow (Qsma) after 15 days in PHT rats. Cox-I expression was differentially enhanced in the PHT superior mesenteric artery and thoracic aorta during the development and progression of PHT. In contrast, Cox-II messenger RNA (mRNA) and protein expression was not detected in either of these vessels throughout the development of PHT. These data suggest that PHT is associated with enhanced Cox-I expression within the splanchnic vasculature concomitant with elevated plasma prostacyclin levels and a significant pressor response to indomethacin in PHT animals. We conclude that enhanced Cox-I expression results in increased prostacyclin levels that partially contribute to the maintenance of the hyperemia typical of PHT.

Evolution of portal hypertension in rats with CCL4 induced liver disease

Evolution of portal hypertension in rats with CCL4 induced liver disease

Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model.

In rats with portal hypertension induced by partial ligation of the portal vein, we have recently demonstrated an increased portal venous inflow that becomes an important factor in the maintenance of portal hypertension. The sequence of events that leads into this circulatory disarray is unknown. We evaluated chronologically the chain of hemodynamic changes that occurred after portal hypertension was induced by partial ligation of the portal vein. In this model it is possible to follow, from the initiation of the portal-hypertensive state, the interaction between blood flow and resistance in the portal system as well as the relation between the development of portal-systemic shunting and the elevated portal venous inflow. The study was performed in 45 portal-hypertensive rats and in 29 sham-operated rats. Blood flow and portal-systemic shunting were measured by radioactive microsphere techniques. The constriction of the portal vein was immediately followed by a resistance-induced portal hypertension characterized by increased portal resistance (9.78 +/- 0.89 vs. 4.18 +/- 0.71 dyn X s X cm-5 X 10(4), mean +/- SE, P less than 0.01), increased portal pressure (17.7 +/- 0.9 vs. 9.5 +/- 0.6 mmHg, P less than 0.001), and decreased portal venous inflow (3.93 +/- 0.26 vs. 6.82 +/- 0.49 ml X min-1 X 100 g body wt-1, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)