Lack of detrimental or therapeutic effects of cyclooxygenase inhibition in bile duct-ligated rats with hepatic encephalopathy

BACKGROUND: The pathogenetic mechanisms of hepatic encephalopathy (HE) are not fully understood. Cerebral blood flow regulated by cyclooxygenase (COX) may be involved in the development of HE. There are no comprehensive data concerning the effects of COX inhibition on HE in chronic liver disease. METHODS: Male Sprague-Dawley rats weighing 240-270 g at the time of surgery were selected for experiments. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Those rats were then divided into two groups to receive i.p. injection of indomethacin (5 mg/kg per day) or distilled water for 7 days from day 36 to day 42 after BDL. The control group consisted of rats receiving a sham operation. Severity of encephalopathy was assessed by counts of motor activity. Plasma levels of tumor necrosis factor (TNF)-alpha and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), and liver biochemistry tests were determined after treatment. RESULTS: The motor activity in both groups of BDL rats were significantly lower than that of the control group (P < 0.001). As compared with the BDL rats treated with distilled water, BDL rats treated with indomethacin had significant lower levels of 6-keto-PGF(1alpha), but the motor activity, TNF-alpha levels and serum biochemistry tests were not significantly different between both BDL groups. CONCLUSIONS: Chronic indomethacin administration did not have significantly detrimental or therapeutic effects on the severity of encephalopathy in BDL rats.     

Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: A model of hepatic encephalopathy in cirrhosis

Studies of the pathogenesis of hepatic encephalopathy are hampered by the lack of a satisfactory animal model. We examined the neurological features of rats after bile duct ligation fed a hyperammonemic diet (BDL+HD). Six groups were studied: sham, sham pair-fed, hyperammonemic, bile duct ligation (BDL), BDL pair fed, and BDL+HD. The BDL+HD rats were made hyperammonemic via an ammonia-containing diet that began 2 weeks after operation. One week later, the animals were sacrificed. BDL+HD rats displayed an increased level of cerebral ammonia and neuroanatomical characteristics of hepatic encephalopathy (HE), including the presence of type II Alzheimer astrocytes. Both BDL and BDL+HD rats showed activation of the inflammatory system. BDL+HD rats showed an increased amount of brain glutamine, a decreased amount of brain myo-inositol, and a significant increase in the level of brain water. In coordination tests, BDL+HD rats showed severe impairment of motor activity and performance as opposed to BDL rats, whose results seemed only mildly affected. In conclusion, the BDL+HD rats displayed similar neuroanatomical and neurochemical characteristics to human HE in liver cirrhosis. Brain edema and inflammatory activation can be detected under these circumstances.     

胆碱酯酶抑制剂对血管性痴呆大鼠认知功能的影响

目的观察胆碱酯酶抑制剂对血管性痴呆(VaD)大鼠海马CA1区细胞凋亡、血管内皮生长因子(VEGF)及神经元型一氧化氮合酶(nNOS)的影响。方法将45只雄性SD大鼠,随机分为假手术组、模型组、治疗组,每组15只大鼠。采用双侧颈总动脉永久性结扎法建立VaD模型,假手术组和模型组用生理盐水2 ml灌胃,治疗组用多奈哌齐进行灌胃。造模后1个月,采用Morris水迷宫检测大鼠的学习记忆能力,用TUNEL检测海马CA1区神经细胞凋亡,用免疫组织化学染色方法检测大鼠海马CA1区VEGF、nNOS阳性细胞表达。结果与模型组比较,假手术组和治疗组大鼠第2天起逃避潜伏期明显缩短;海马CA1区神经细胞凋亡显著减少;海马CA1区VEGF和nNOS阳性细胞表达明显升高,差异有统计学意义(P<0.05)。结论多奈哌齐可能通过减少VaD大鼠海马CA1区细胞凋亡,上调VEGF、nNOS的表达,从而改善VaD大鼠的认知功能。     

吸烟对阿尔茨海默病大鼠认知功能和海马神经元病理变化的影响

目的观察吸烟对阿尔茨海默病(AD)大鼠认知功能和海马神经元病理变化的影响。方法雄性SD大鼠18只,随机分为吸烟组和不吸烟组,每组9只。在海马注射β淀粉样蛋白_(25-23)建立AD大鼠模型的基础上,AD大鼠吸烟1 2周,穿梭箱实验和Morris水迷宫检测学习记忆功能,HE、Bielschowski's镀银染色法观察海马神经元的病理改变,电镜观察海马组织的超微结构变化。结果吸烟组主动回避能力和被动回避能力及空间探索能力较不吸烟组明显下降(P<0.01);吸烟组海马CA1、CA3、齿状回神经细胞数目减少,神经纤维增粗、肿胀、轴突深染。结论 AD大鼠吸烟后,认知功能损害加重,大鼠海马神经元损伤明显加重,胶质细胞变性更明显。     

肝纤维化过程中去甲肾上腺素各受体亚型表达的动态变化

目的 研究肝纤维化过程中去甲肾上腺素各受体亚型表达的动态变化.方法 胆总管结扎法建立大鼠肝纤维化模型,HE,Masson染色观察肝脏病理形态学变化;免疫组织化学法检测肝星状细胞活化指标α-平滑肌肌动蛋白(α-SMA)的表达情况;Western blot和实时荧光定量PCR检测α-肾上腺素受体(AR)、β1-AR、β2-AR蛋白和mRNA的表达水平.对数据进行单因素方差分析,LSD检验及相关分析.结果 HE及Masson三色染色显示:随着造模时间延长肝纤维化程度逐渐加重.α-SMA免疫组织化学染色显示:随着肝纤维化的发展,大鼠肝组织中α-SMA阳性细胞明显增多,造模1、2、3,4周时分别为10.58%±1.75%,24.14%±2.02%、29.74%±2.59%,34.28%±2.01%,而假手术组为4.12%±1.51%,P＜0.01.Western blot检测结果显示,造模1～4周大鼠肝组织α-AR、β1-AR,β2-AR蛋白表达量均明显升高(P＜0.05).实时荧光定量PCR结果证实,随着肝纤维化的发展,α-AR、β1-AR、β2-AR mRNA表达水平均逐渐上升(P＜0.01).α-SMA与α-AR、β1-AR、β2-AR蛋白表达水平的相关分析显示,α-SMA与α-AR、β1-AR及β2-AR呈正相关,r值分别为0.564,0.753和0.606.结论 胆总管结扎法成功建立胆汁淤积性大鼠肝纤维化模型,在肝纤维化形成过程中肝星状细胞表达α-SMA增加.随着肝纤维化的进展,α-AR、β1-AR、β2-AR蛋白及mRNA水平明显增加,且与α-SMA呈正相关.     

肌肽在大鼠脑缺血再灌注损伤中的神经保护作用

目的：探讨肌肽对实验性脑缺血再灌注的神经保护作用。方法：按Pulsinelli法律立大鼠四血管结扎全脑不完全缺血模型,实验选用同种系雄性大鼠,随机分为三组,假手术组,对照组和治疗组,使用电子自旋共振波谱法,硫代巴比妥酸显色和海马CA1区细胞计数观察了肌肽对缺血再灌注损伤后脑组织氧自由基含量,脂质过氧化物生成量和细胞丢失的作用。结果．显示使用肌肽的治疗组的氧自由基和脂质过氧化物的生成量均显著代于对照组（P＜0．01）,而假手术组和使用肌肽的治疗组的海马CA1区锥体细胞数明显高于盐水对照组（P＜0．001）。结论：本实验证明肌肽对脑缺血再灌注有明显的神经保护作用。     

芹菜素通过激活Nrf2/HO-1通路改善血管性痴呆大鼠的认知功能

[目的]研究芹菜素(APG)对血管性痴呆(VD)大鼠认知功能的保护作用及机制。[方法]通过结扎双侧颈总动脉复制VD大鼠模型,设置假手术组、模型组、APG低剂量组、APG高剂量组和尼莫地平(NMP)组,每组30只。APG低剂量组、高剂量组分别1次/天腹腔注射20、40 mg/kg APG,NMP组1次/天腹腔注射2 mg/kg NMP,假手术组和模型组给予生理盐水,疗程28天。Morris水迷宫实验检测大鼠的认知功能,HE染色和TUNEL染色观察海马体CA1区神经元病理特点和凋亡状况,通过电子显微镜观察神经元超微结构变化,分光光度法检测海马体丙二醛(MDA)含量和超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性;RT-PCR和Western blot检测海马体核因子E2相关因子2(Nrf2)、血红素加氧酶1(HO-1)mRNA和蛋白的表达。[结果]与模型组相比,APG高剂量组和NMP组大鼠的认知功能明显改善;海马体CA1区神经元数量、形态结构病理学改变、超微结构改变和凋亡状况均明显改善,病理分级和凋亡指数(AI)降低;海马体MDA含量降低,SOD、GSH-Px活性升高,N...     

Impairment of short term memory in rats with hepatic encephalopathy due to bile duct ligation

Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to cognitive deficits. Different animal models for the study of HE have demonstrated learning and memory impairment and a number of neurotransmitter systems have been proposed to be involved in this. Recently, it was described that bile duct-ligated (BDL) rats exhibited altered spatio-temporal locomotor and exploratory activities and biosynthesis of neurotransmitter GABA in brain cortices. Therefore, the aim of this study was to evaluate cognition in the same animal model. Male adult Wistar rats underwent common bile duct ligation (BDL rats) or manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent object recognition behavioral task. The BDL rats developed chronic liver failure and exhibited a decreased discrimination index for short term memory (STM) when compared to the control group. There was no difference in long term memory (LTM) as well as in total time of exploration in the training, STM and LTM sessions between the BDL and control rats. Therefore, the BDL rats demonstrated impaired STM for recognition memory, which was not due to decreased exploration.     

Neuroprotective effects of guanosine administration on behavioral,brain activity,neurochemical and redox parameters in a rat model of chronic hepatic encephalopathy

It is well known that glutamatergic excitotoxicity and oxidative stress are implicated in the pathogenesis of hepatic encephalopathy (HE). The nucleoside guanosine exerts neuroprotective effects through the antagonism against glutamate neurotoxicity and antioxidant properties. In this study, we evaluated the neuroprotective effect of guanosine in an animal model of chronic HE. Rats underwent bile duct ligation (BDL) and 2 weeks later they were treated with i.p. injection of guanosine 7.5 mg/kg once a day for 1-week. We evaluated the effects of guanosine in HE studying several aspects: a) animal behavior using open field and Y-maze tasks; b) brain rhythm changes in electroencephalogram (EEG) recordings; c) purines and glutamate levels in the cerebral spinal fluid (CSF); and d) oxidative stress parameters in the brain. BDL rats presented increased levels of glutamate, purines and metabolites in the CSF, as well as increased oxidative damage. Guanosine was able not only to prevent these effects but also to attenuate the behavioral and EEG impairment induced by BDL. Our study shows the neuroprotective effects of systemic administration of guanosine in a rat model of HE and highlights the involvement of purinergic system in the physiopathology of this disease.     

Age-related changes of NGF, BDNF, parvalbumin and neuronal nitric oxide synthase immunoreactivity in the mouse hippocampal CA1 sector

We investigated the age-related alterations in nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), parvalbumin and neuronal nitric oxide synthase (nNOS) immunoreactivity of the mouse hippocampal CA1 sector. NGF and BDNF immunoreactivity was unchanged in the hippocampal CA1 pyramidal neurons from 2 to 50-59 weeks of birth. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector from 40-42 to 50-59 weeks of birth. On the other hand, the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. Our results indicate that NGF and BDNF immunoreactivity was unaltered in the hippocampal CA1 pyramidal neurons during aging processes. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector during aging processes. The present study also shows that the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. These results demonstrate that the expression of glial NGF and BDNF may play a key role for helping survival and maintenance of pyramidal neurons and neuronal functions in the hippocampal CA1 sector during aging processes. Furthermore, our findings suggest that parvalbumin- and nNOS-positive interneurons in the hippocampal CA1 sector are resistant to aging processes. Moreover, our findings suggest that nitric oxide synthesized by the nNOS may play some role for neuronal growth during postnatal development.     

Hepatic encephalopathy influences high-affinity uptake of transmitter glutamate and aspartate into the hippocampal formation

The present work was carried out to study the influence of ammonia and factors from sera and cerebrospinal fluid (CSF) from patients with different degrees of chronic liver diseases on [³H]D-aspartate (Asp) and [³H]L-glutamate (Glu) high-affinity uptake into the rat hippocampal formation. For comparison, high-affinity uptake of Glu and Asp was determined in human hippocampal brain tissue obtained at autopsy from cirrhotic patients dying in hepatic coma and from control brains free from neurological, psychiatric, or hepatic diseases. Sera and CSF from patients with chronic liver failure and hepatic encephalopathy (HE) were seen to reduce dramatically Glu and Asp uptake into rat hippocampal dendritic layers. A close inverse relationship was found to exist between the level of ammonia in the sera and the inhibition of uptake, both phenomena correlating highly with the extent of liver failure. The present findings, obtained after dilution of sera from patients with HE while maintaining initial ammonium levels, elucidate, however, that ammonia alone cannot account for the reduction in Glu/Asp uptake capacity. The inhibition of Asp uptake into human hippocampal formation of patients dying in hepatic coma was even more pronounced when compared to that found in rat hippocampus incubated in sera and CSF from patients. Glu/Asp uptake into brain tissue is supposed to be an important factor in the pathogenesis of HE accompanying liver dysfunctions.     

Infection and the progression of hepatic encephalopathy in acute liver failure

BACKGROUND & AIMS: Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection. METHODS: We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies. RESULTS: On multivariate analysis, acquisition of infection during stage I-II HE (P < 0.01), increased leukocyte levels at admission (P < 0.01), and decreased platelet count (P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (P < 0.05) and AST levels (P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and >or=2 components of SIRS, P < 0.05). CONCLUSIONA: This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.     

Effect of hepatic iron concentration reduction on hepatic fibrosis and damage in rats with cholestatic liver disease

AIM: To assess the effect of iron reduction after phlebotomy in rats with "normal" hepatic iron concentration (HIC) on the progression of hepatic fibrosis, as a result of bile duct ligation (BDL). METHODS: Rats underwent phlebotomy before or after sham operation or BDL. Animals undergone only BDL or sham operation served as controls. Two weeks after surgery, indices of hepatic damage and fibrosis were evaluated. RESULTS: Phlebotomy lowered HIC. Phlebotomy after BDL was associated with body weight increase, lower hepatic weight, less portal hypertension, less periportal necrosis, less portal inflammation, lower hepatic activity index score and higher albumin levels. On the other hand, phlebotomy before BDL was associated with body weight decrease and hepatic activity index score increase. Phlebotomy after sham operation was not associated with any hepatic or systemic adverse effects. CONCLUSION: Reduction of HIC after induction of liver damage may have beneficial effects in BDL rats. However, iron deficiency could induce impairment of liver function and may make the liver more susceptible to insults like BDL.     

Role of diabetes mellitus on hepatic encephalopathy

Hepatic encephalopathy is the main cognitive dysfunction in cirrhotic patients associated with impaired prognosis. Hyperammonemia plus inflammatory response do play a crucial role on hepatic encephalopathy. However, in some patients HE appeared without hyperammonemia and patients with increased levels of ammonia could not show cognitive dysfunction. This has led to investigate other factors that could act in a synergistic way. Diabetes mellitus and insulin resistance are characterized by releasing and enhancing these pro-inflammatory cytokines and, additionally, has been related to hepatic encephalopathy. Indeed, patients with diabetes showed raised risk of over hepatic encephalopathy in comparison with non-cirrhotics. Type 2 diabetes mellitus could impair hepatic encephalopathy by different mechanisms that include: a) increasing glutaminase activity; b) impairing gut motility and promoting constipation, intestinal bacterial overgrowth and bacterial translocation. Despite of insufficient clarity about the practicability of anti-diabetic therapy and the most efficacious therapy, we would have to pay a special attention to the management of type 2 diabetes mellitus and insulin resistance in cirrhotic patients.     

A 1H nuclear magnetic resonance‐based metabonomic approach for grading hepatic encephalopathy and monitoring the effects of therapeutic hypothermia in rats

Background: There are no good biomarkers for grading hepatic encephalopathy (HE) and monitoring the effectiveness of therapeutic measures. Methods: We applied ¹H nuclear magnetic resonance (NMR)‐based metabonomics of brain samples obtained from acute liver failure rats sacrificed after ligation of the hepatic artery (at 6 h, precoma and coma stages), sham‐operated controls and mild hypothermia (35 °C) for 6 or 15 h as a therapeutic measure. Results: Partial least square discriminant analysis established a classification model that scored the severity of encephalopathy. Animals treated with hypothermia did not develop manifestations of encephalopathy and were graded accordingly using the NMR‐based metabonomic approach. Hypothermic animals showed lower levels of alanine and lactate as well as higher levels of N‐acetylaspartate and myo‐inositol compared with normothermic animals. The course of metabolic deterioration was more rapid in the brainstem than in the cortex. Conclusion: Metabonomic analysis is capable of grading HE, detecting regional differences and monitoring the protective effects of hypothermia. This approach elucidates differences of brain energetic metabolism and compensatory osmotic response to explain the effects of hypothermia.     

Diagnosis and Prognostic Significance of Minimal Hepatic Encephalopathy in Patients with Cirrhosis of Liver

Background and Aims  

Minimal hepatic encephalopathy is the mildest form of the spectrum of hepatic encephalopathy (HE) that impairs health-related quality of life. We assessed (1) the usefulness of psychometric hepatic encephalopathy score and critical flicker frequency for the diagnosis of minimal hepatic encephalopathy, and (2) prognostic significance of minimal hepatic encephalopathy.     

The ability of 17 β-estradiol to attenuate intrahepatic vasoconstriction to endothelin-1 in female rats is lost in cirrhosis

Background and rationale. The control of Endothelin-1 (ET-1)-mediated intrahepatic vasoconstriction in cirrhosis is beneficial for the alleviation of relevant complications. Cirrhosis is accompanied by hypogonadism and altered sex hormone status. Besides- sex hormones have vasoactive effects- but it is unknown if they influence vascular function in cirrhosis. This study aimed to investigate the roles of sex hormones in hepatic vascular reactions to ET-1 in cirrhosis. Liver cirrhosis was induced in Spraque-Dawley male and female rats with common bile duct ligation (BDL). Sham-operated (Sham) rats were controls. On the 43rd day after operations- intrahepatic vascular concentration-response curves to ET-1 were obtained with the following preincubatioins: 1) vehicle; 2) 17β-estradiol; 3) progesterone; 4) testosterone. Livers from sham and BDL rats were dissected for real-time polymerase chain reaction analysis of estrogen- progesterone and testosterone receptors.Results. Compared with sham males perfused with vehicle- sham females presented higher perfusion pressure changes to ET-1 which was reversed only by 17β-estradiol. In cirrhosis- compared with males- 17β-estradiol no longer attenuated vascular responsiveness to ET-1 in females. In females- BDL rats had lower hepatic estrogen receptor α(ERα) mRNA expression than that in sham rats.Conclusions. The sham females showed a stronger intrahepatic vascular constrictive effect to ET-1 than sham males- which could be reversed by 17β-estradiol. However- the influence of 17β-estradiol was lost in cirrhotic females- which may be attributed- at least partly- to intrahepatic ERa down-regulation in females with cirrhosis.     

天麻乙酸乙酯提取物对血管性痴呆大鼠海马CA1区锥体细胞的影响

目的观察天麻乙酸乙酯提取物对血管性痴呆模型大鼠海马CA1区锥体细胞的影响。方法采用双侧颈总动脉永久性结扎法,造成慢性脑灌注不足所致SD大鼠血管性痴呆模型。造模6周后,40只大鼠随机分为5组,假手术组、模型组、尼莫地平组、天麻乙酸乙酯提取物高剂量组(高剂量组)和天麻乙酸乙酯提取物低剂量组(低剂量组),每组8只。给药3周后,HE染色检测海马锥体细胞的变化。结果与假手术组比较,模型组大鼠海马CA1区锥体细胞数目明显减少(P<0.01);与模型组比较,尼莫地平组和高剂量组大鼠海马CA1区锥体细胞数目明显增多(P<0.01),低剂量组大鼠海马CA1区锥体细胞数目无明显变化(P>0.05)。结论天麻乙酸乙酯提取物能改善血管性痴呆大鼠脑组织海马CA1区锥体细胞的病理改变。     

Multiparameter magnetic resonance imaging of liver fibrosis in a bile duct ligation mouse model

BACKGROUNDBile duct ligation (BDL) in animals is a classical method for mimicking cholestatic fibrosis. Although different surgical techniques have been described in rats and rabbits, mouse models can be more cost-effective and reproducible for investigating cholestatic fibrosis. Magnetic resonance imaging (MRI) has made great advances for noninvasive assessment of liver fibrosis. More comprehensive liver fibrotic features of BDL on MRI are important. However, the utility of multiparameter MRI to detect liver fibrosis in a BDL mouse model has not been assessed.AIMTo evaluate the correlation between the pathological changes and multiparameter MRI characteristics of liver fibrosis in a BDL mouse model.METHODSTwenty-eight healthy adult male balb/c mice were randomly divided into four groups: sham, week 2 BDL, week 4 BDL, and week 6 BDL. Multiparameter MRI sequences, included magnetic resonance cholangiopancreatography, T1-weighted, T2-weighted, T2 mapping, and pre- and post-enhanced T1 mapping, were performed after sham and BDL surgery. Peripheral blood and liver tissue were collected after MRI. For statistical analysis, Student’s t-test and Pearson’s correlation coefficient were used.RESULTSFour mice died after BDL surgery; seven, six, five and six mice were included separately from the four groups. Signal intensities of liver parenchyma showed no difference on TI- and T2-weighted images. Bile duct volume, ΔT1 value, T2 value, and the rate of liver fibrosis increased steadily in week 2 BDL, week 4 BDL and week 6 BDL groups compared with those in the sham group (P < 0.01). Alanine aminotransferase and aspartate transaminase levels initially surged after surgery, followed by a gradual decline over time. Strong correlations were found between bile duct volume (r = 0.84), T2 value (r = 0.78), ΔT1 value (r = 0.62), and hepatic fibrosis rate (all P < 0.01) in the BDL groups.CONCLUSIONThe BDL mouse model induces changes that can be observed on MRI. The MRI parameters correlate with the hepatic fibrosis rate and allow for detection of cholestatic fibrosis.     

Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension.

Factors that increase resistance to blood flow through the hepatic sinusoids when portal hypertension occurs in the absence of significant hepatic fibrosis are not completely understood. Experiments were designed to test the hypothesis that endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal vascular resistance in a bile duct- ligated noncirrhotic portal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of portal vein taken from BDL rats was tested. The effect of ET-1 and NO on intrahepatic resistance in an isolated perfused liver was studied, and localization of ET-1 in the liver was identified by immunohistochemistry. Portal vein rings in BDL rats showed increased maximal tension in response to ET-1, as well as a shift of the dose-response curve to the left as compared with sham-operated animals. Removal of the endothelium further increased contractility. In isolated perfused liver studies, ET-1 increased portal resistance in both sham operated and BDL rats. The endothelin Type A receptor antagonist BQ 123 lowered the high portal resistance in BDL rats to levels comparable with sham operated animals. Infusion of L-arginine lowered resistance to a much smaller extent. In livers from BDL rats, ET-1 was localized in periportal and pericentral hepatocytes and hepatic sinusoidal cells. We conclude that in a BDL model of portal hypertension where distortion of hepatic architecture by fibrosis is minimal, increased resistance to portal blood flow may be mediated by ET-1.