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Abdel-Razik A, Mousa N, Abdelsalam M, Abdelwahab A, Tawfik M, Tawfik AM, Hasan AS, Elhelaly R, El-Wakeel N, Eldars W. Endothelin-1/Nitric Oxide Ratio as a Predictive Factor of Response to Therapy With Terlipressin and Albumin in Patients With Type-1 Hepatorenal Syndrome. Front Pharmacol 2020; 11:9. [PMID: 32076410 PMCID: PMC7006449 DOI: 10.3389/fphar.2020.00009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 01/06/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND AND PURPOSE Predictors of response to type-1 hepatorenal syndrome (HRS) therapy are urgently needed. This study's purpose is to evaluate the proposed predictors in these patients. METHODS Forty-two type-1 HRS patients with cirrhosis were treated with albumin and terlipressin. Clinical, biochemical, and demographic parameters taken at the onset of therapy and changes in endothelin-1/nitric oxide (ET-1/NO) ratio during therapy were analyzed to check their predictive value. RESULTS Response to treatment (serum creatinine level <1.5 mg/dL at the end of therapy) was shown in 20 patients (48%). Independent predictive variables of response to therapy were early reduction of ET-1/NO ratio ≥0.15 at day 3 of therapy and serum bilirubin baseline <8 mg/dL (area under the receiver operating characteristic curve, 0.751; P < 0.001; specificity, 55%; sensitivity, 85%). Response rates in patients with serum bilirubin level <8 and ≥8 mg/dL were 63% and 20%, respectively (P = 0.008). The corresponding values in patients with an early reduction of ET-1/NO ratio ≥0.15 and <0.15 on day 3 were 85% and 13.6%, respectively (P < 0.001). CONCLUSIONS Early reduction of ET-1/NO ratio and lower serum bilirubin baseline can predict response to type-1 HRS therapy with albumin and terlipressin. Alternative therapy should be investigated for nonresponder type-1 HRS patients.
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Affiliation(s)
- Ahmed Abdel-Razik
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nasser Mousa
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mostafa Abdelsalam
- Nephrology and Dialysis Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Abdelwahab
- Nephrology and Dialysis Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mona Tawfik
- Nephrology and Dialysis Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed M. Tawfik
- Diagnostic & Interventional Radiology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmad S. Hasan
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rania Elhelaly
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Niveen El-Wakeel
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Waleed Eldars
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Ponziani FR, Zocco MA, Cerrito L, Gasbarrini A, Pompili M. Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications. Expert Rev Gastroenterol Hepatol 2018; 12:641-656. [PMID: 29806487 DOI: 10.1080/17474124.2018.1481747] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 05/24/2018] [Indexed: 02/07/2023]
Abstract
The gut liver axis is an operative unit that works to protect the human body against potentially harmful substances and microorganisms, maintaining the homeostasis of the immune system. Liver cirrhosis profoundly alters this complex system. The intestine becomes more permeable allowing the translocation of bacteria, bacterial products and fragments into the portal circulation, triggering an abnormal local and systemic inflammatory response and a condition of perpetual immunologic alarm. This immune-inflammatory disorder related to dysbiosis is involved in the development of liver damage and liver cirrhosis complications and increases intestinal permeability in a vicious circle. Areas covered: The most relevant studies on bacterial translocation, the mechanism of intestinal barrier dysfunction and its consequences in patients with liver cirrhosis have been revised through a PubMed search. Data have been discussed with particular regard to their significance in clinical practice. Expert commentary: The assessment of bacterial translocation and intestinal permeability is not currently used in clinical practice but may be useful to stratify patients' prognosis.
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Affiliation(s)
- Francesca Romana Ponziani
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maria Assunta Zocco
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Lucia Cerrito
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Antonio Gasbarrini
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maurizio Pompili
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
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Ueno T, Saka R, Takama Y, Yamanaka H, Tazuke Y, Bessho K, Okuyama H. Onset ages of hepatopulmonary syndrome and pulmonary hypertension in patients with biliary atresia. Pediatr Surg Int 2017; 33:1053-1057. [PMID: 28871319 DOI: 10.1007/s00383-017-4136-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2017] [Indexed: 10/18/2022]
Abstract
PURPOSE Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are extrahepatic complications of biliary atresia (BA). Their detection is sometimes delayed, which may result in missed opportunities for liver transplantation. The aim of this study was to determine the onset ages of HPS and PoPH in BA patients. METHODS BA patients followed at our institution were identified. Patients visited our clinic for routine blood work, as well as regular electrocardiography, chest X-rays, and arterial blood gas tests. Lung perfusion scintigraphy and cardiac ultrasound were performed to diagnose HPS. Cardiac catheterization was conducted to diagnose PoPH. RESULTS The study population consisted of 88 BA patients. The median follow-up duration was 11.6 years (range 0.8-26.0 years). Six patients (6.8%) developed HPS and three patients (3.4%) developed PoPH. The median age of onset of HPS was significantly younger than that of PoPH (HPS: 4 years, PoPH: 15 years, P < 0.019). Two patients (66%) with PoPH died, while all patients with HPS survivied. CONCLUSION The onset of HPS was significantly earlier than that of PoPH. The mortality rate was high in patients with PoPH. Teenagers with BA should receive routine cardiac echocardiograms to detect PH in its early stages.
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Affiliation(s)
- Takehisa Ueno
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Ryuta Saka
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichi Takama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroaki Yamanaka
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuko Tazuke
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University of Graduation School of Medicine, Suita, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Sakamoto Y, Sakai M, Watari T. Hepatic and Plasma Endothelin-1 in Dogs with Chronic Hepatitis. J Vet Intern Med 2017; 31:764-769. [PMID: 28295621 PMCID: PMC5435058 DOI: 10.1111/jvim.14687] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 01/11/2017] [Accepted: 02/09/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Endothelin (ET)-1 is a 21-amino-acid peptide with potent vasoactive properties, which increases intrahepatic resistance in patients with chronic hepatitis (CH) or cirrhosis. ET-1 concentrations have not been investigated in dogs with CH. HYPOTHESIS/OBJECTIVES This study compared hepatic and plasma ET-1 levels in healthy dogs and in dogs with CH, and examined the relationship between the plasma ET-1 level and portal vein pressure in dogs with CH. ANIMALS Fourteen healthy dogs and twenty dogs with CH were used in this study. METHODS Prospective case-control study. Hepatic ET-1 mRNA expression was determined by real-time reverse transcription polymerase chain reaction, and hepatic and plasma ET-1 levels were assessed using ELISA. Splenic pulp pressure (SPP), as an indicator of portal vein pressure, was measured laparoscopically. RESULTS Hepatic ET-1 mRNA levels were 3.7 times higher in dogs with CH than in healthy dogs (P = .008). The median hepatic and plasma ET-1 protein levels were significantly higher in dogs with CH than in healthy dogs (13.20 pg/mg wet liver vs. 3.42 pg/mg wet liver, P = .004, and 0.99 pg/mL vs. 0.71 pg/mL, P = .013, respectively). Moreover, there was a weak but significant correlation between plasma ET-1 level and SPP in dogs with CH (P = .036; rs = 0.53). CONCLUSIONS AND CLINICAL IMPORTANCE The results indicate that ET-1 might play an important role in the pathogenesis of portal hypertension caused by CH.
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Affiliation(s)
- Y Sakamoto
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - M Sakai
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - T Watari
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
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Liangpunsakul S, Agarwal R. Altered circadian hemodynamic and renal function in cirrhosis. Nephrol Dial Transplant 2017; 32:333-342. [PMID: 28186574 DOI: 10.1093/ndt/gfw014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 01/17/2016] [Indexed: 11/13/2022] Open
Abstract
Background Given that alterations in systemic hemodynamics have a profound influence on renal function in patients with cirrhosis, it is surprising that circadian variations in blood pressure (BP) and renal electrolyte excretion have scarcely been studied. Our aims were to define the relationship of 24-h ambulatory BP changes with renal tubular function and to determine the influence of endotoxemia on BP and urinary parameters. Methods Forty healthy controls served as a comparator to 20 cirrhotic patients. They underwent 24-h ambulatory BP monitoring and 24-h urine collection. Results Subjects with cirrhosis demonstrated significant diurnal variations in urinary excretion of sodium (57.7 µmol/min day versus 87 µmol/min night) and creatinine (826 µg/min day versus 1202 µg/min night). Increasing severity of cirrhosis was associated with a progressive reduction in ambulatory awake systolic (P-trend = 0.015), diastolic (P-trend < 0.001) and mean BP (P-trend < 0.001). In patients with cirrhosis, the magnitude of change in BP from awake to sleep state was blunted for systolic BP (5% reduction, P = 0.039) and pulse rate (2% reduction, P < 0.001). The amplitude of variation in pulse rate was blunted with increasing severity of cirrhosis (controls 6.5, Child-Pugh Class A 5.3, Child B 3.4, Child C 1.2, P = 0.03) and the acrophase was right-shifted with increasing severity of cirrhosis. Compared with sleep state, during the awake state, endotoxin was associated with less sodium excretion and a lower systolic BP. Compared with the awake state, endotoxin was associated with a higher sleeping pulse rate (P < 0.001). Conclusions Patients with cirrhosis have altered diurnal profiles in renal tubular function and blood pressure that appear to be related to endotoxemia. Determining whether endotoxemia is causally related to these perturbations will require interventional studies.
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Affiliation(s)
- Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.,R.L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Rajiv Agarwal
- R.L. Roudebush VA Medical Center, Indianapolis, IN, USA.,Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Fukui H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J Hepatol 2015; 7:425-442. [PMID: 25848468 PMCID: PMC4381167 DOI: 10.4254/wjh.v7.i3.425] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 12/14/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
A “leaky gut” may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin, activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.
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Lin BY, Zhou L, Geng L, Zheng ZY, Jia JJ, Zhang J, Yao J, Zheng SS. High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation. World J Gastroenterol 2015; 21:3317-3324. [PMID: 25805939 PMCID: PMC4363762 DOI: 10.3748/wjg.v21.i11.3317] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 10/14/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF).
METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes.
RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT.
CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF.
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Agasti AK, Mahajan AU, Phadke AY, Nathani PJ, Sawant P. Comparative randomized study on efficacy of losartan versus propranolol in lowering portal pressure in decompensated chronic liver disease. J Dig Dis 2013; 14:266-71. [PMID: 23280243 DOI: 10.1111/1751-2980.12025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study aimed to compare the efficacy of losartan, an angiotensin II receptor antagonist, with propranolol on portal hypertension in patients with decompensated chronic liver disease. METHODS In all, 30 patients with Child-Pugh B cirrhosis and large varices without any prior therapy for portal hypertension were randomized to either losartan (n = 15) or propranolol (n = 15). Clinical, biochemical and hemodynamic parameters including hepatic venous pressure gradient (HVPG), wedged hepatic venous pressure (WHVP), mean arterial blood pressure (MABP) and free hepatic venous pressure (FHVP) were measured at baseline and after 4-week therapy. Patients with HVPG < 12 mmHg were regarded as responders. RESULTS An equal number of responders were seen in both groups (6/15, 40.0%). The reduction of WHVP and HVPG was greater in the losartan group than in the propranolol group, although no significant differences between them were found. Heart rate decreased more in the propranolol arm than in the losartan arm (P < 0.01); however, no correlation between the decrease of heart rate and the reduction of HVPG was observed. One patient in the losartan group, although a responder, had gastrointestinal bleeding 2 months after the drug administration, but the varices were small under endoscopy and did not require definitive therapy. The fall of MABP was greater with losartan, with no statistical difference between the two groups. CONCLUSION The effect of losartan was comparable to propranolol in reducing portal pressure in decompensated Child-Pugh B chronic liver disease.
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Affiliation(s)
- Ananta Kumar Agasti
- Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and Hospital, Mumbai, India.
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Uehara H, Akahoshi T, Kawanaka H, Hashimoto N, Nagao Y, Tomikawa M, Taketomi A, Shirabe K, Hashizume M, Maehara Y. Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis. Hepatol Res 2012; 42:1039-47. [PMID: 22594838 DOI: 10.1111/j.1872-034x.2012.01021.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Splenectomy or partial splenic embolism has been reported to improve liver function in patients with hypersplenism and liver dysfunction. The aim of this study was to investigate the mechanism of improvement after splenectomy. METHODS Liver cirrhosis was induced by bile duct ligation (BDL). Rats underwent sham operation, splenectomy (Sp group), BDL, or BDL plus splenectomy (BDL + Sp group), and were subjected to experiments at 2 weeks after the operation. Portal venous pressure (PVP) and hepatic tissue blood flow (HTBF) were measured in each group. The plasma concentration of endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS), RhoA and Rho-kinase expressions were studied. RESULTS There were significant differences in PVP (17.9 ± 0.91 vs 23.3 ± 3.91 cmH(2) O; P < 0.01) and HTBF (16.6 ± 1.72 vs 13.3 ± 1.82 mL/min; P < 0.01) between the BDL + Sp and BDL groups. In the liver of BDL rats, eNOS phosphorylation and NOx levels were decreased, accompanied by RhoA activation compared with the BDL + Sp group. Splenectomy decreased serum ET-1 levels, RhoA activation and consequently increased eNOS phosphorylation. CONCLUSION ET-1 derived from the spleen might increase intrahepatic resistance by downregulating Rho signaling in liver cirrhosis. Splenectomy for splenomegaly in liver cirrhosis might partially improve liver function by enhancing intrahepatic microcirculation.
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Affiliation(s)
- Hideo Uehara
- Departments of Surgery and Science Disaster and Emergency Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
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Ling L, Kuc RE, Maguire JJ, Davie NJ, Webb DJ, Gibbs P, Alexander GJM, Davenport AP. Comparison of endothelin receptors in normal versus cirrhotic human liver and in the liver from endothelial cell-specific ETB knockout mice. Life Sci 2012; 91:716-22. [PMID: 22365955 DOI: 10.1016/j.lfs.2012.02.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 01/20/2012] [Accepted: 02/03/2012] [Indexed: 01/06/2023]
Abstract
AIMS Endothelin (ET) antagonists show promise in animal models of cirrhosis and portal hypertension. The aim was to pharmacologically characterise the expression of endothelin receptors in human liver, hepatic artery and portal vein. MAIN METHODS Immunofluorescence staining, receptor autoradiography and competition binding assays were used to localise and quantify ET receptors on hepatic parenchyma, hepatic artery and portal vein in human cirrhotic or normal liver. Additional experiments were performed to determine the affinity and selectivity of ET antagonists for liver ET endothelin receptors. An endothelial cell ET(B) knockout murine model was used to examine the function of sinusoid endothelial ET(B) receptors. KEY FINDINGS ET(B) receptors predominated in normal human liver and displayed the highest ratio (ET(B):ET(A) 63:47) compared with other peripheral tissues. In two patients examined, liver ET(B) expression was up-regulated in cirrhosis (ET(B):ET(A) 83:17). Both sub-types localised to the media of normal portal vein but ET(B) receptors were downregulated fivefold in the media of cirrhotic portal vein. Sinusoid diameter was fourfold smaller in endothelial cell ET(B) knockout mice. The liver morphology of ET(B) knockout mice was markedly different to normal murine liver, with loss of the wide spread sinusoidal pattern. In the knockout mice, sinusoids were reduced in both number and absolute diameter, while large intrahepatic veins were congested with red blood cells. SIGNIFICANCE These data support a role for the ET system in cirrhosis of the liver and suggest that endothelial ET(B) blockade may cause sinusoidal constriction which may contribute to hepatotoxicity associated with some endothelin antagonists.
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Affiliation(s)
- Lowell Ling
- Clinical Pharmacology Unit, Box 110 Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
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Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis. Eur J Clin Pharmacol 2011. [PMID: 22101624 DOI: 10.1007/s00228-011-1157-6.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2022]
Abstract
PURPOSE To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. METHODS The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. RESULTS Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. CONCLUSION In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.
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Lebrec D, Bosch J, Jalan R, Dudley FJ, Jessic R, Moreau R, Garcia-Pagan JC, Mookerjee RP, Chiossi E, Van Giersbergen PLM, Kusic-Pajic A, Dingemanse J. Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis. Eur J Clin Pharmacol 2011; 68:533-41. [PMID: 22101624 DOI: 10.1007/s00228-011-1157-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 10/24/2011] [Indexed: 12/12/2022]
Abstract
PURPOSE To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. METHODS The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. RESULTS Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. CONCLUSION In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.
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Affiliation(s)
- Didier Lebrec
- Unité 773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, INSERM, Paris, France
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Iizuka M, Murata T, Hori M, Ozaki H. Increased contractility of hepatic stellate cells in cirrhosis is mediated by enhanced Ca2+-dependent and Ca2+-sensitization pathways. Am J Physiol Gastrointest Liver Physiol 2011; 300:G1010-21. [PMID: 21393429 DOI: 10.1152/ajpgi.00350.2010] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Activation of hepatic stellate cells (HSCs) results in cirrhosis and portal hypertension due to intrahepatic resistance. Activated HSCs increase their contraction after receptor agonist stimulation; however, the signaling pathways for the regulation of contraction are not fully understood. The aim of this study was to elucidate the change in contractile mechanisms of HSCs after cirrhotic activation. The expression pattern of contractile regulatory proteins was analyzed with quantitative RT-PCR and Western blotting. The phosphorylation levels of myosin light chain (MLC), 17-kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17), and MLC phosphatase targeting subunit 1 (MYPT1) after endothelin-1 (ET-1) stimulation in culture-activated HSCs were measured using phosphorylation-specific antibodies. In vivo-activated HSCs were isolated from rats subjected to bile duct ligation and repeated dimethylnitrosoamine injections. HSCs showed increased expression of not only α-smooth muscle actin, but also the contractile regulatory proteins MLC kinase (MLCK), Rho kinase 2 (ROCK2), and CPI-17 during HSC activation in vitro. In culture-activated HSCs, ET-1 increased phosphorylation of CPI-17 at Thr18, which was markedly inhibited by the PKC inhibitor Ro-31-8425. ET-1 induced phosphorylation of MYPT1 at Thr853, which was suppressed by the ROCK inhibitor Y-27632. ET-1 induced sustained phosphorylation of MLC at Thr18/Ser19, which was inhibited by both Ro-31-8425 and Y-27632. Consistent with the data obtained from the in vitro study, HSCs isolated from cirrhotic rats showed increased expression of α-smooth muscle actin, MLCK, CPI-17, and ROCK2 compared with HSCs from nontreated rats. Furthermore, MLC phosphorylation in in vivo-activated HSCs was increased, according to enhanced phosphorylation of CPI-17 and MYPT1 in the presence of ET-1. These results suggest that activated HSCs may participate in constriction of hepatic sinusoids in the cirrhotic liver through both Ca(2+)-dependent (MLCK pathway) and Ca(2+)-sensitization mechanism (CPI-17 and MYPT1 pathways).
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Affiliation(s)
- Masateru Iizuka
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan
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Cavasin MA, Semus H, Pitts K, Peng Y, Sandoval J, Chapo J, Plato CF. Acute effects of endothelin receptor antagonists on hepatic hemodynamics of cirrhotic and noncirrhotic rats. Can J Physiol Pharmacol 2011; 88:636-43. [PMID: 20628429 DOI: 10.1139/y10-038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hepatic and circulating endothelin-1 (ET-1) are increased in patients with cirrhosis and in cirrhotic animals. However, the distinct roles of ET receptor subtypes ETA and ETB in cirrhosis and portal hypertension (PHT) have not been clearly elucidated. Thus, we studied the effects of selective ET-1 antagonists (ETA-ant or ETB-ant) and nonselective ET-1 antagonist (ETA/B-ant) on hepatic hemodynamics in cirrhotic rats. Liver fibrosis and PHT were induced by complete bile duct ligation (BDL) in rats. Two weeks after BDL or sham surgery, hemodynamic responses were measured during intraportal infusion of incremental doses of the following ET-ants: (i) BQ-123, (ii) BQ-788, and (iii) bosentan. After equilibration with vehicle, doses of ET-ants were infused for 30 min periods, and steady-state systemic and hepatic hemodynamics, portal venous pressure (PVP), and hepatic blood flow (HBF) were measured. BDL induced significant PHT and elevated concentrations of plasma ET-1 compared with sham. ETA-ant decreased PVP of cirrhotic rats but had no effect on sham, whereas ETB-ant increased PVP in sham but had no effect in BDL. Nonselective ETA/B-ant decreased PVP of BDL similarly to ETA-ant. Both ETA-ant and ETB-ant decreased local HBF, whereas a nonselective antagonist did not change HBF in sham; however no significant changes were observed in HBF of BDL rats with any of the antagonists. These findings suggest ETA activation contributes to PHT in cirrhotic rats, whereas ETB-mediated portal depressor effects are attenuated in cirrhotic rats compared with noncirrhotic rats.
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Affiliation(s)
- Maria A Cavasin
- University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
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15
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Helle F, Iversen BM, Chatziantoniou C. Losartan increases NO release in afferent arterioles during regression of l-NAME-induced renal damage. Am J Physiol Renal Physiol 2010; 298:F1170-7. [DOI: 10.1152/ajprenal.00056.2009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Inhibition of nitric oxide synthesis (NOS) induces hypertension and heavy proteinuria. Renal structure and function have shown striking improvement after interventions targeting ANG II or endothelin (ET) receptors in rats recovering after long-term NOS inhibition. To search for mechanisms underlying losartan-assisted regression of renal disease in rodents, we measured NO release and contractility to ET in afferent arterioles (AAs) from Sprague-Dawley rats recovering for 2 wk after 4 wk of NG-nitro-l-arginine methyl ester treatment. Losartan administration during the recovery period decreased blood pressure (113 ± 4 vs. 146 ± 5 mmHg, P < 0.01), reduced protein/creatinine ratio more (proteinuria decrease: Δ1,836 ± 214 vs. Δ1,024 ± 180 mg/mmol, P < 0.01), and normalized microvascular hypertrophy (AA media/lumen ratio: 1.74 ± 0.05 vs. 2.09 ± 0.08, P < 0.05) compared with no treatment. In diaminofluorescein-FM-loaded AAs from losartan-treated animals, NO release (% of baseline) was increased compared with untreated animals after stimulation with 10−7 M ACh (118 ± 4 vs. 90 ± 7%, t = 560 s, P < 0.001) and 10−9 M ET (123 ± 4 vs. 101 ± 5%, t = 560 s, P < 0.001). There was also a blunted contractile response to 10−7 M ET in AAs from losartan-treated animals compared with untreated animals (Δ4.01 ± 2.9 vs. Δ14.6 ± 1.7 μm, P < 0.01), which disappeared after acute NOS inhibition (Δ10.7 ± 3.7 vs. Δ12.5 ± 2.9 μm, not significant). Contractile dose responses to ET (10−9, 10−8, 10−7 M) were enhanced by NOS inhibition and blunted by exogenous NO (10−2 mM S-nitroso- N-acetyl-penicillamine) in losartan-treated but not in untreated vessels. Reducing blood pressure similar to losartan with hydralazine did not improve AA hypertrophy, ET-induced contractility, ET-induced NO release, and NO sensitivity. In conclusion, blockade of the local action of ANG II improved endothelial function in AAs, a mechanism that is likely to contribute to the beneficial effects of AT1aR antagonism during the recovery of renal function after long-term NOS inhibition in rats.
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Affiliation(s)
- Frank Helle
- Institut National de la Santé et de la Recherche Médicale U702, Hôpital Tenon, Paris
- Renal Research Group, Institute of Medicine, University of Bergen, Bergen; and
- Haukeland University Hospital, Bergen, Norway
| | - Bjarne M. Iversen
- Renal Research Group, Institute of Medicine, University of Bergen, Bergen; and
- Haukeland University Hospital, Bergen, Norway
| | - Christos Chatziantoniou
- Institut National de la Santé et de la Recherche Médicale U702, Hôpital Tenon, Paris
- Pierre et Marie Curie University, Paris, France
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16
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Gross P, Renn C, Waldherr R, Seifert M, Von Baehr R, Hocher B. Potential Role of Endothelin in the Physiological and Pathological Regulation of Kidney Function. ACTA ACUST UNITED AC 2009. [DOI: 10.3109/10623329309102313] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Abstract
BACKGROUND Endothelin receptor antagonists (ERAs) have recently become prominent therapies for pulmonary arterial hypertension, and are being explored clinically in several areas, including resistant hypertension, idiopathic pulmonary fibrosis, and cancer. OBJECTIVE To review the available preclinical and clinical data surrounding ERAs and their potential role to treat portal hypertension. METHODS A systematic search of peer-reviewed publications was performed using PubMed and Ovid/Medline/EMBASE databases. RESULTS Several preclinical in vivo studies have evaluated ERAs in models of portal hypertension. The majority of these studies employ nonselective ERAs, and support the hypothesis that endothelin participates in the development and maintenance of portal hypertension. A limited number of studies have addressed whether ET(A) receptor-selective ERAs provide an advantage over nonselective agents in ameliorating the effects of portal hypertension, and the majority of these data indicate that selective ERAs may be sufficient. Very few clinical studies have evaluated ERAs in portal hypertension patients. What has been described in humans supports a role for endothelin, but is not sufficient to draw conclusions regarding ERA selectivity. CONCLUSION While preclinical evidence suggests a role for endothelin and ERAs in portal hypertension, scant and equivocal clinical data highlight a need for human studies with current selective and nonselective ERAs.
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Affiliation(s)
- Kelly R Pitts
- Gilead Sciences Inc., In Vitro Biology, 7575 West 103rd Avenue, Westminster, Colorado 80021, USA.
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Rafailidis S, Ballas K, Psarras K, Pavlidis T, Emoniotou E, Papamichali R, Kalodimos G, Marakis G, Sakadamis A, Koukoulis G. Effect of early bosentan administration on the development of esophageal varices in cirrhotic rats: experimental study in Wistar rats. J Gastroenterol 2008; 43:897-904. [PMID: 19012044 DOI: 10.1007/s00535-008-2243-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2008] [Accepted: 06/17/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND This study was conducted to investigate the effect of chronic bosentan administration on the development of esophageal varices in carbon tetrachloride-induced cirrhosis in rats. METHODS For the development of liver cirrhosis and esophageal varices, 60 rats underwent ligation of the left adrenal vein, followed by phenobarbital and carbon tetrachloride administration. Two weeks after the beginning of carbon tetrachloride administration, rats were separated into two groups. In group I, comprising 30 rats, bosentan was continuously administered throughout the study, whereas in group II, also 30 rats, placebo instead of bosentan was continuously administered. Hemodynamic studies and morphometric analysis of the lower esophagus were performed after complete induction of cirrhosis. The total number of veins counted in the submucosa, the number of submucosal veins/mm(2) of submucosa, the total submucosal area occupied by vessels, the mean cross-sectional vessel area, the relative submucosal area (percentage) occupied by vessels, and the area of the single most-dilated submucosal vein were studied. RESULTS Bosentan induced a significant (P < 0.05) decrease in portal pressure, while morphometric analysis revealed a significant reduction (P < 0.05) of all parameters studied in bosentan-treated rats, except in the total and relative number of submucosal veins. CONCLUSIONS Bosentan administration seemed to significantly attenuate dilation of submucosal veins in the lower esophagus of cirrhotic rats. This effect was mainly attributed to a decrease in the portal pressure induced by chronic bosentan administration.
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Affiliation(s)
- Savas Rafailidis
- Second Propedeutical Department of Surgery, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
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Wong F, Moore K, Dingemanse J, Jalan R. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome. Hepatology 2008; 47:160-8. [PMID: 17886336 DOI: 10.1002/hep.21940] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05). CONCLUSION An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.
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Affiliation(s)
- Florence Wong
- Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Canada.
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20
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Yamaguchi E, Yamanoi A, Ono T, Nagasue N. Experimental investigation of the role of endothelin-1 in idiopathic portal hypertension. J Gastroenterol Hepatol 2007; 22:1134-40. [PMID: 17608860 DOI: 10.1111/j.1440-1746.2006.04822.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The authors' previous report revealed that endothelin-1 might be released from B lymphocytes in cirrhotic patients with hypersplenism. Other investigators have shown that persistent exposure to environmental contaminants including arsenic might induce idiopathic portal hypertension. The aim of this study was to experimentally identify how endothelin-1 is involved in the development of idiopathic portal hypertension and which cells produce endothelin-1 in the spleen. METHODS Portal pressure and venous endothelin-1 concentrations were measured in rats that were given sodium arsenate orally for long periods, and endothelin-1 expression levels in the spleen were assessed by staining. In a second experiment, B and T lymphocytes and monocyte-derived macrophages cultured from healthy human peripheral blood were stimulated with sodium arsenite, sodium arsenate, lipopolysaccharide and interferon-gamma. Endothelin-1 concentrations in the supernatants were measured by ELISA. RESULTS Arsenic exposure gradually increased portal pressure and venous endothelin-1 levels in rats. Endothelin-1 concentration in the supernatant did not change in every cell type stimulated with arsenic, but it increased in B lymphocytes and monocyte-derived macrophages treated with lipopolysaccharide and interferon-gamma. CONCLUSIONS The in vivo study indicated that arsenic might elevate portal pressure through mechanisms involving endothelin-1. In the in vitro study, lipopolysaccharide and interferon-gamma clearly induced endothelin-1 synthesis not only in monocyte-derived macrophages but also in B lymphocytes, although arsenic treatment did not affect those cells. This study partially supports the hypothesis that idiopathic portal hypertension might be promoted by endothelin-1 overproduction from splenic B lymphocytes in response to certain substances.
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Affiliation(s)
- Emi Yamaguchi
- Department of Digestive and General Surgery, School of Medicine, Shimane University, Izumo, Japan.
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Boursier J, Asfar P, Joly-Guillou ML, Calès P. Infection et rupture de varice œsophagienne au cours de la cirrhose. ACTA ACUST UNITED AC 2007; 31:27-38. [PMID: 17273129 DOI: 10.1016/s0399-8320(07)89324-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Endotoxemia and bacterial infection are frequent in patients with cirrhosis. They alter systemic and splanchnic hemodynamics, worsen coagulation disorders, impair liver function and thus may induce variceal bleeding. In variceal bleeding, bacterial infection favours failure to control bleeding, early rebleeding, and death. In patients with cirrhosis and variceal bleeding, antibiotic-prophylaxis decreases bacterial infection and the incidence of early rebleeding, and, more important, significantly decreases the death rate in these patients.
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Affiliation(s)
- Jérôme Boursier
- Laboratoire HIFIH, UPRES EA 3859, IFR 132, Université, Angers
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Abstract
Increased understanding of the hyperdynamic circulation syndrome has resulted in novel therapeutic approaches, some of which have already reached clinical practice. Central to the hyperdynamic circulation syndrome is an imbalance between the increase in different vasodilators (foremost among which is nitric oxide) and the compensatory increase in vasoconstrictors--usually accompanied by a blunted response. This chapter discusses the role of endothelin in the pathogenesis of the syndrome and in future treatment approaches. A relatively new area of research in this field is the role of infection and inflammation in the initiation and maintenance of the hyperdynamic circulation syndrome. The use of antibiotics in the setting of acute variceal bleeding is standard practice. Studies have suggested that chronic manipulation of the intestinal flora could have beneficial effects in the treatment of portal hypertension. The bile salts are another novel and interesting target. Although their vasoactive properties have been known for some time, recent data demonstrate that their effects could be central in the pathogenesis of the hyperdynamic circulation syndrome, and that manipulation of the composition of the bile acid pool could be a therapeutic approach to portal hypertension. Finally, hypoxia and angiogenesis play a role in the development of portal hypertension and the formation of collaterals. This role needs to be further defined but it appears likely that this phenomenon is yet another target for therapeutic intervention.
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Affiliation(s)
- Jürg Reichen
- Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 31 POB 49, 3010 Berne, Switzerland.
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Barth F, Gerber PJ, Reichen J, Dufour JF, Nicod LP. Efficiency and safety of bosentan in child C cirrhosis with portopulmonary hypertension and renal insufficiency. Eur J Gastroenterol Hepatol 2006; 18:1117-9. [PMID: 16957519 DOI: 10.1097/01.meg.0000231749.60889.f7] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Bosentan has lately been described as a successful therapeutic agent for portopulmonary hypertension consecutive to child A cirrhosis. This is the first report of the effect of this substance with advanced liver cirrhosis (child C) and renal insufficiency. Low doses of bosentan (initially twice 31.25 mg/day and then 62.5 mg/day) increased cardiac output and allowed correction of renal insufficiency; it allowed one to stop the requirement of oxygen and not only improved the 6-min walking test by more than 400 m, but also decreased the severity of the liver cirrhosis to child B stadium. This suggests that patients, who would be excluded from a liver transplantation program because of their portopulmonary hypertension, could profit from a careful therapy with bosentan.
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Affiliation(s)
- Florian Barth
- Clinic and Policlinic of Pneumology, Inselspital, Switzerland
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Abstract
AbstractThis article summarizes the literature on current definition, suggested pathogenetic mechanisms and the role of laboratory assessment in the differential diagnosis of hepatorenal syndrome (HRS) from other causes of renal disease that may arise during hepatic cirrhosis and some diseases affecting both liver and kidney. It should be remembered that the main theory suggested for the pathogenesis of HRS is the arterial vasodilation hypothesis of portal hypertension, ending in type 1 and type 2 HRS, but there is no consensus supporting either mechanism as a solid theory for initiation of HRS pathogenesis to date. No laboratory test can firmly establish a diagnosis of HRS, which is mainly based on the absence of any specific cause of renal failure. Laboratory and ultrasonographic tests based on non-invasive techniques are being investigated as possible diagnostic approaches.
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Affiliation(s)
- Selda Demirtaş
- University of Ufuk, Faculty of Medicine, Department of Biochemistry, Ankara, Turkey
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Kai S, Bandoh T, Ohta M, Matsumoto T, Tominaga M, Kitano S. Expression of endothelin receptors in the gastric mucosa of portal hypertensive rats. J Gastroenterol Hepatol 2006; 21:242-50. [PMID: 16460481 DOI: 10.1111/j.1440-1746.2006.04158.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Portal hypertensive gastropathy is an abnormal circulatory state in gastric mucosa with vascular dilatation due to portal hypertension. The aim of the present study was to evaluate expression of endothelin receptors and their roles in the portal hypertensive gastric mucosa. METHODS Portal hypertensive rats were generated by staged portal vein occlusion. Expression of endothelin-A receptor and endothelin-B receptor mRNA was examined by reverse transcriptase-polymerase chain reaction, and protein were examined by immunohistochemistry. The changes of mucosal microcirculation by endothelin receptor antagonists were measured with in vivo microscope. RESULTS Expression of endothelin-A receptor mRNA was increased significantly in portal hypertensive rats in comparison with sham-operated control rats (P < 0.05). There was no significant difference between the two groups in endothelin-B receptor mRNA expression. Vessels of the gastric mucosa were dilated, and intravessel blood flow was increased significantly in the portal hypertensive group (P < 0.05). Diameters of mucosal vessels and blood flow were increased significantly by endothelin-A receptor antagonist (BQ-485) in the portal hypertensive rats. Endothelin-B receptor antagonist (IRL-1038) had no significant effect on mucosal microcirculation. CONCLUSION These data suggest that increased expression of endothelin-A receptor in the portal hypertensive gastric mucosa may be related to the regulation of gastric microcirculation.
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Affiliation(s)
- Seiichiro Kai
- Department of Surgery I, Oita University Faculty of Medicine, Oita, Japan.
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Curgunlu A, Vural P, Canbaz M, Erten N, Karan MA, Tascioglu C. Plasma nitrate/nitrite and endothelin-1 in patients with liver cirrhosis. J Clin Lab Anal 2005; 19:177-81. [PMID: 16170811 PMCID: PMC6807778 DOI: 10.1002/jcla.20074] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The aims of this study were to examine the plasma nitrate/nitrite (NOx; two end products of nitric oxide metabolism) and endothelin-1 (ET-1) concentrations in patients with liver cirrhosis, and to investigate whether there is a relationship between these two vasoactive parameters and the course of disease. Twenty-eight patients with liver cirrhosis (11 HBV-related, four HCV-related, four alcohol-related, and nine with idiopathic etiology) and 25 healthy subjects (controls) were included in the study. The venous plasma concentrations of NOx and ET-1 were significantly higher (P<0.01 and P<0.001) in the patients with cirrhosis than in the controls. A significant increase in ET-1 was observed in the Child B subgroup vs. Child A (P<0.05), and in the Child C subgroup vs. either subgroup A or B (P<0.05). There were no statistical differences between study subgroups (Child A-C) in the mean of NOx values. Plasma NOx and ET-1 were significantly increased in patients with ascites compared to those without ascites (P<0.05 and P<0.01). Increased nitric oxide synthesis may be a compensation mechanism against endothelial injury. The highest ET-1 levels in Child C and moderately increased ET-1 levels in Child B, and the lower increase of ET-1 levels in Child A patients suggest that plasma ET-1 increases with the progression of the disease. The fact that NOx and ET-1 levels were higher in patients with decompensated cirrhosis (patients with ascites) than in those with compensated cirrhosis (patients without ascites), and the presence of a strong correlation between ET-1, NOx, and the degree of varices, supports the suggestion that there is a relationship between NOx, ET-1, and portal hypertension. Our study demonstrates that increased ET and nitric oxide metabolism is associated with the hemodynamic alterations induced by portal hypertension.
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Affiliation(s)
- Asli Curgunlu
- Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul, Turkey
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Hetz H, Bauer M, Lahner D, Faybik P, Winning J, Ankersmit HJ, Bacher A, Krenn CG. Endothelin activation and postoperative renal failure after human liver transplantation. Liver Transpl 2005; 11:1201-6. [PMID: 16184572 DOI: 10.1002/lt.20477] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Renal failure is an established risk factor for impaired patient outcome after orthotopic liver transplantation (OLT). As the endothelin pathway is known to be involved in the development of acute renal failure (ARF), we designed a study to clarify its role in ARF following OLT. Twenty consecutive patients with intact kidney function scheduled for their first OLT were prospectively studied. Plasma big endothelin-1 (ET-1) levels were measured before surgery, after graft reperfusion, and on the first and second postoperative day. According to postoperative glomerular filtration rate (GFR), patients were assigned to the acute renal dysfunction group (ARDF) and the non-ARDF group. Each patient's GFR was estimated according to the 4-variable formula used in the modification of diet in renal disease before surgery, daily within the first postoperative week, and at 1, 3, 12, and 24 months after surgery. Postoperative mean big ET-1 levels correlated significantly with the maximum percent decrease of GFR within 3 days after OLT (P < 0.01). The proportion of patients who developed ARDF was significantly correlated to mean postoperative big ET-1 quartiles (P < 0.01). In the ARDF group, the percent decrease of GFR within 24 months was significantly higher (P < 0.05) as compared to the non-ARDF group. In conclusion, patients who develop ARDF immediately after OLT do not fully recover to baseline regarding long-term kidney function. Short-term GFR was significantly correlated with postoperative big ET-1 plasma levels, suggesting renal dysfunction is mediated by the activated endothelin system.
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Affiliation(s)
- Hubert Hetz
- Department of Anesthesiology and General Intensive Care, Medical University of Vienna, General Hospital, Vienna, Austria.
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Yokoyama Y, Nimura Y, Nagino M, Bland KI, Chaudry IH. Current Understanding of Gender Dimorphism in Hepatic Pathophysiology1. J Surg Res 2005; 128:147-56. [PMID: 15939435 DOI: 10.1016/j.jss.2005.04.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2005] [Revised: 01/15/2005] [Accepted: 04/08/2005] [Indexed: 10/25/2022]
Abstract
Studies have shown gender dimorphic response of the liver for various hepatic stresses including ischemia/reperfusion, hemorrhagic shock-resuscitation, hepatectomy, liver cirrhosis, endotoxemia, and chronic alcoholic consumption. The mechanisms responsible for the gender dimorphic response include differences in pro-inflammatory cytokine release, production of reactive oxygen species, and alteration in hepatic vasoregulatory action. These effects were shown to be modulated by circulating sex steroid levels. In this regard, modulation of sex steroid levels by agents/drugs has been proposed as a therapeutic option for preventing hepatic damage in various hepatic stress models. Further elucidation of precise mechanisms responsible for the gender-related differences in the hepatic pathophysiology is essential for the potential clinical application of sex hormone modulation therapy. In this article, current progress in our understanding the gender difference in the hepatic pathophysiology under the condition of hepatic stress is reviewed and discussed.
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Affiliation(s)
- Yukihiro Yokoyama
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA
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29
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Güney Duman D, Tüney D, Bilsel S, Benli F, Karan S, Avsar E, Ozdogan O, Tözün N. Octreotide in liver cirrhosis: a salvage for variceal bleeding can be a gunshot for kidneys. Liver Int 2005; 25:527-35. [PMID: 15910489 DOI: 10.1111/j.1478-3231.2005.01119.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The renal effects of octreotide, used for bleeding esophageal varices in cirrhosis, are controversial. METHODS Fourteen cirrhotic patients (Child-Pugh; A/B/C: 1/12/1) were enrolled. Plasma nitrite and endothelin (ET) levels, urinary nitrite output, free water clearance (FWC) and fractional excretion of filtered sodium (FENa) were measured and renal Doppler ultrasound was carried out. Octreotide was infused at a rate of 0.75 microg/kg/h for 3 h after a bolus of 0.75 microg/kg body weight. All the parameters were reevaluated during octreotide administration while the patients acted as their own controls. RESULTS Octreotide induced significant reductions in urinary nitrite, FENa and FWC. Plasma ET levels increased (baseline: 6.7 pg/ml, octreotide: 8.4 pg/ml), whereas the plasma nitrite level did not change significantly after octreotide infusion. Overall, no significant change in renal resistive index (RRI) could be demonstrated on Doppler after octreotide administration. However, patients with elevated baseline RRI values had significantly more deterioration in FWC and FENa compared with patients with normal RRI in response to octreotide. CONCLUSION A marked decrease in FENa, FWC and urinary nitrite output, together with a significant increase in plasma ET level in response to octreotide, may indicate renal dysfunction in cirrhotic patients. This deleterious renal effect of octreotide may be more enhanced in patients with elevated baseline RRI.
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Affiliation(s)
- Deniz Güney Duman
- Subdivision of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey.
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Dimoulios P, Kolios G, Notas G, Matrella E, Xidakis C, Koulentaki M, Tsagarakis N, Kouroumalis A, Kouroumalis E. Ursodeoxycholic acid reduces increased circulating endothelin 2 in primary biliary cirrhosis. Aliment Pharmacol Ther 2005; 21:227-34. [PMID: 15691296 DOI: 10.1111/j.1365-2036.2005.02307.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Endothelins and nitric oxide regulate sinusoidal blood flow and the perfusion of the peribiliary vascular plexus. AIMS To study the serum and hepatic vein concentration of ET-1, ET-2, ET-3 and nitric oxide in patients with primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment. METHODS Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. Endothelins were measured with commercial enzyme-linked immunosorbent assays and nitrites/nitrates with a modification of Griess reaction. RESULTS The ET-1 and ET-3 levels were similar in patients and controls. Primary biliary cirrhosis patients had the highest serum ET-2 (P < 0.001) compared with other groups. Nitrites/nitrates was increased in primary biliary cirrhosis (P < 0.05) compared with normal. ET-2 and nitric oxide were similar in all primary biliary cirrhosis stages. Ursodeoxycholic acid significantly decreased ET-2 in all stages (I and II: P < 0.05 and III and IV: P < 0.01) and increased nitric oxide (P < 0.05) in early primary biliary cirrhosis. Hepatic vein ET-1 and ET-3 were higher in viral cirrhosis patients, but only in primary biliary cirrhosis a significant difference for ET-1 and ET-3 between hepatic and peripheral veins was found. CONCLUSIONS Increased ET-2 is an early defect in primary biliary cirrhosis that is significantly reduced by the ursodeoxycholic acid treatment. The possibility of a more generalized endothelial cell dysfunction in primary biliary cirrhosis requires further investigation.
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Affiliation(s)
- P Dimoulios
- Department of Gastroenterology, University Hospital Heraklion and Liver Research Laboratory of University of Heraklion, Crete, Greece
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31
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Guo CY, Wu JY, Wu YB, Zhong MZ, Lu HM. Effects of endothelin-1 on hepatic stellate cell proliferation, collagen synthesis and secretion, intracellular free calcium concentration. World J Gastroenterol 2004; 10:2697-700. [PMID: 15309721 PMCID: PMC4572195 DOI: 10.3748/wjg.v10.i18.2697] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the effects of endothelin-1 (ET-1) on hepatic stellate cells (HSCs) DNA uptake, DNA synthesis, collagen synthesis and secretion, inward whole-cell calcium concentration ([Ca2+]i) as well as the blocking effect of verapamil on ET-1-stimulated release of inward calcium (Ca2+) of HSC in vitro.
METHODS: Rat hepatic stellate cells (HSCs) were isolated and cultivated. 3H-TdR and 3H-proline incorporation used for testing DNA uptake and synthesis, collagen synthesis and secretion of HSCs cultured in vitro; Fluorescent calcium indicator Fura-2/AM was used to measure [Ca2+]i inward HSCs.
RESULTS: ET-1 at the concentration of 5 × 10-8 mol/L, caused significant increase both in HSC DNA synthesis (2247 ± 344 cpm, P < 0.05) and DNA uptake (P < 0.05) when compared with the control group. ET-1 could also increase collagen synthesis (P < 0.05 vs control group) and collagen secretion (P < 0.05 vs control group). Besides, inward HSC [Ca2+] i reached a peak concentration (422 ± 98 mol/L, P < 0.001) at 2 min and then went down slowly to165 ± 51 mol/L (P < 0.01) at 25 min from resting state (39 ± 4 mol/L) after treated with ET-1. Verapamil (5 mol/L) blocked ET-1-activated [Ca2+]i inward HSCs compared with control group (P < 0.05). Fura-2/AM loaded HSC was suspended in no Ca2+ buffer containing 1 mol/L EGTA, 5 min later, 10-8 mol/L of ET-1 was added, [Ca2+]i inward HSCs rose from resting state to peak 399 ± 123 mol/L, then began to come down by the time of 20 min. It could also raise [Ca2+]i inward HSCs even without Ca2+ in extracellular fluid, and had a remarkable dose-effect relationship (P < 0.05). Meanwhile, verapamil could restrain the action of ET-1 (P < 0.05).
CONCLUSION: Actions of ET-1 on collagen metabolism of HSCs may depend on the transportation of inward whole-cell calcium.
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Affiliation(s)
- Chuan-Yong Guo
- Department of Gastroenterology, Shanghai Tenth People Hospital of Tongji University, Shanghai 200072, China.
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Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai M, Inoue Y, Tejima K, Nishikawa T, Watanabe N, Omata M, Fujiwara K. Sphingosine 1-phosphate enhances portal pressure in isolated perfused liver via S1P2 with Rho activation. Biochem Biophys Res Commun 2004; 320:754-759. [PMID: 15240112 DOI: 10.1016/j.bbrc.2004.04.207] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2004] [Indexed: 12/13/2022]
Abstract
Although structural changes are most important to determine vascular resistance in portal hypertension, vasoactive mediators also contribute to its regulation. Hepatic stellate cells (HSCs) are assumed to play a role in modulating intrahepatic vascular resistance based on their residence in the space of Disse and capacity to contract. Because sphingosine 1-phosphate (S1P) has been shown to stimulate HSC contractility, we wondered if S1P could regulate portal pressure. S1P at 0.5-5 microM increased portal pressure in isolated rat perfused liver. This effect was abrogated in the presence of a binding antagonist for S1P2, JTE-013. Perfusion of isolated rat liver with 5 microM S1P increased Rho activity in the liver, and co-perfusion with JTE-013 cancelled S1P-induced Rho activation. Because S1P is present in human plasma at approximately 0.2 microM, S1P might readily regulate portal vascular tone in physiological and pathological status. The antagonist for S1P2 merits consideration for treatment of portal hypertension.
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Affiliation(s)
- Hitoshi Ikeda
- Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Hashimoto T, Yoneda M, Shimada T, Kurosawa M, Terano A. Intraportal nicotine infusion in rats decreases hepatic blood flow through endothelin-1 and both endothelin A and endothelin B receptors. Toxicol Appl Pharmacol 2004; 196:1-10. [PMID: 15050402 DOI: 10.1016/j.taap.2003.09.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2003] [Accepted: 09/02/2003] [Indexed: 12/22/2022]
Abstract
Smoking has been demonstrated to aggravate liver injury. Nicotine, a major pharmacological component of tobacco smoke, affects a multitude of functions. Smoking and nicotine induce synthesis of endothelin (ET)-1. The effect of intraportal infusion of nicotine on hepatic circulation and an involvement of ET-1 and ET receptor in the action of nicotine were investigated in rats. Nicotine (0-100 microg/kg/h) was infused into the portal vein of urethane-anesthetized rats, and changes of hepatic blood flow were evaluated. Intraportal infusion of nicotine dose-dependently decreased hepatic blood flow and increased portal pressure without any alteration of heart rate or arterial blood pressure. This action of intraportal nicotine was completely abolished by pretreatment of ET-1 antibody. Either BQ485 (ET(A) receptor antagonist) or BQ788 (ET(B) receptor antagonist) partially reversed the effect of nicotine, and combination of BQ788 and BQ485 completely abolished it. These findings suggest that nicotine inhibits hepatic circulation through ET-1, and ET(A) and ET(B) receptor.
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Affiliation(s)
- Takashi Hashimoto
- Department of Gastroenterology, Dokkyo University School of Medicne, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan
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Yokoyama Y, Toth B, Kitchens WC, Schwacha MG, Bland KI, Chaudry IH. Role of thromboxane in producing portal hypertension following trauma-hemorrhage. Am J Physiol Gastrointest Liver Physiol 2003; 285:G1293-9. [PMID: 14613921 DOI: 10.1152/ajpgi.00268.2003] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Thromboxane A2 (TXA2) and endothelin-1 (ET-1) have been proposed as the important vasoconstrictors that increase portal venous resistance in paracrine or autocrine fashion. We hypothesized that the hepatic damage following trauma-hemorrhage (T-H) is induced by the impaired hepatic circulation due to the increased production of vasoconstrictors such as ET-1 and TXA2 by the liver. To test this, male Sprague-Dawley rats (n = 6/group) were subjected to trauma (i.e., midline laparotomy) and hemorrhage (35-40 mmHg for 90 min followed by fluid resuscitation) or sham operation. At 2 or 5 h after the end of resuscitation, the liver was isolated and perfused and portal inflow pressure, bile flow, and release of ET-1 and thromboxane B2 (TXB2; a stable metabolite of TXA2) into the perfusate were measured. The level of portal pressure was higher at 5 h following T-H compared with 2 h after T-H and sham. The portal pressure was inversely correlated to the amount of bile production. Furthermore, the bile flow was significantly correlated to the hepatic damage as evidenced by release of lactate dehydrogenase into the perfusate. The level of ET-1 at 5 h following T-H in the perfusate after 30 min of recirculation did not show any difference from sham. However, the levels of TXB2 in the T-H group were significantly higher than those in sham at that interval. These results indicate that the increased release of TXA2 but not ET-1 following T-H might be responsible for producing the increased portal resistance, decreased bile production, and hepatic damage.
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Affiliation(s)
- Yukihiro Yokoyama
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA
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35
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De BK, Bandyopadhyay K, Das TK, Das D, Biswas PK, Majumdar D, Mandal SK, Ray S, Dasgupta S. Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol 2003; 98:1371-6. [PMID: 12818283 DOI: 10.1111/j.1572-0241.2003.07497.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Losartan, an angiotensin II receptor blocker, has portal hypotensive effects. This study evaluates the effect of losartan on portal pressure after 14 days and compares it with that of propranolol. METHODS A total of 39 individuals with cirrhosis were randomized into two groups of 19 and 20 patients each and were treated with losartan and propranolol, respectively. Hepatic venous pressure gradient was measured at baseline and on day 14 of therapy. Responders to therapy had hepatic venous pressure gradient reduction of >/=20% of baseline value. RESULTS With losartan, 15 of 19 (78.94%) patients were responders and with propranolol, nine of 20 (45%) patients were responders (p < 0.05). Although the hepatic venous pressure gradient reduction (i.e., percentage from baseline) with losartan (26.74 +/- 21.7%) was higher than with propranolol (14.52 +/- 32%), the difference was not significant. The reduction in hepatic venous pressure gradient with losartan was contributed mainly by a significant drop of wedge hepatic venous pressure from 32.42 +/- 6.61 mm of Hg to 28.31 +/- 5.09 mm of Hg (p < 0.05) compared to that with propranolol, which was from 34.55 +/- 5.41 mm of Hg to 32.75 +/- 8.13 mm of Hg (p > 0.05). Responders among alcohol-abusing patients were significantly higher with losartan (81.8%) compared to those on propranolol (27.2%; p < 0.05). In the losartan group, all seven nonascitic cirrhotic individuals, as compared with two of five in the propranolol group, responded to the drugs. During the study, no significant side effects were observed in either group (who were not receiving diuretics) or in follow-up with diuretics. CONCLUSIONS Losartan is as effective as propranolol in reducing portal pressure in cirrhotic patients who are not receiving diuretics. Losartan is also superior to propranolol for achieving target level hepatic venous gradient for prevention of variceal bleeding in nonascitic and alcohol-abusing cirrhotic patients.
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Affiliation(s)
- Binay K De
- Department of Medicine, Institute of Post Graduate Medical Education and Research, Calcutta, India
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36
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Reinehr R, Fischer R, Häussinger D. Regulation of endothelin-A receptor sensitivity by cyclic adenosine monophosphate in rat hepatic stellate cells. Hepatology 2002; 36:861-73. [PMID: 12297833 DOI: 10.1053/jhep.2002.35623] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Sensitization of the endothelin-A receptor (ET(A)) occurs during HSC transdifferentiation, but the underlying mechanisms remained unclear. Sensitization of ET(A) was studied in quiescent and activated hepatic stellate cells (HSC) at the levels of receptor phosphorylation, localization, endothelin (ET)-1-induced Ca(2+) signals, and cell contraction. The endothelin-1 (ET-1) concentrations required to obtain an ET(A)-mediated Ca(2+) signal in 50% of HSC cultured for 1 to 2 or 10 days were approximately 1.2 and 0.012 nmol/L, respectively. This transdifferentiation-dependent sensitization of ET(A) was accompanied by receptor translocation to the plasma membrane. Cyclic AMP rapidly desensitized ET(A) in activated HSC and shifted their ET-1 responsiveness from picomolar to nanomolar concentrations with respect to Ca(2+) signals and HSC contraction. ET(A) desensitization also occurred in response to prostaglandin E(2), adenosine, or ET(B) stimulation. Desensitization by cAMP in activated HSC was accompanied by an increased Ser/Thr phosphorylation of ET(A) and their rapid internalization. Quiescent HSC exhibited Ser/Thr phosphorylation of the ET(A) protein, which was not affected by cAMP. In conclusion, the ET(A) response in HSC is regulated by protein kinase A (PKA)-dependent receptor phosphorylation and internalization. This may explain the transdifferentiation-dependent sensitization of HSC towards ET-1 and its reversal by cAMP and ET(B) activation.
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Affiliation(s)
- Roland Reinehr
- Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich-Heine-Universität, Düsseldorf, Germany
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37
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Helmy A, Hayes PC. Contribution of endothelin-1 to the circulatory and renal abnormalities in patients with cirrhosis and portal hypertension. J Pediatr Gastroenterol Nutr 2002; 35:139-43. [PMID: 12187287 DOI: 10.1097/00005176-200208000-00007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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38
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Bakr AM, Abdalla AF, El-Marsafawy H, Abu-Hashem I, El-Regal ME, Amer T, Abdel-Khalik MK, Mostafa H, A-Kader HH. Plasma endothelin-1 concentrations in children with cirrhosis and their relationship to renal function and the severity of portal hypertension. J Pediatr Gastroenterol Nutr 2002; 35:149-53. [PMID: 12187289 DOI: 10.1097/00005176-200208000-00009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Plasma endothelin-1 (ET-1) is a potent vasoconstrictor peptide involved in the pathogenesis of several disorders. Endothelin-1 concentrations are increased in adult patients with cirrhosis. However, little is known about ET-1 concentrations in children with cirrhosis. METHODS Radioimmune assay was used to measure plasma ET-1 concentrations in 19 children with cirrhosis (8 patients with ascites, and 11 without ascites), and 11 age- and sex-matched healthy children. The plasma ET-1 concentrations were correlated with the mean blood pressure, creatinine clearance, and severity of portal hypertension, as measured by portal flow volume and portal flow velocity. RESULTS Patients with cirrhosis and ascites had increased plasma ET-1 concentrations compared with patients who did not have ascites (6.8 pg/mL +/- 0.62 pg/mL vs. 4.6 pg/mL +/- 0.35 pg/mL; mean +/- SEM; < 0.01) and controls (3.6 pg/mL +/- 0.27 pg/mL; mean +/- SEM; < 0.0005). Plasma ET-1 concentrations were higher in patients with cirrhosis who did not have ascites compared with controls ( < 0.005). No significant differences were observed between concentrations of the patients with cholestasis and those without cholestasis (5.4 pg/mL +/- 0.52 pg/mL vs. 5.2 +/- 0.32 pg/mL; mean +/- SEM; = 0.1). Plasma ET-1 concentrations correlated positively with the mean blood pressure ( = 0.58; < 0.05) and negatively with renal function, as measured by creatinine clearance ( = -0.7; <0.005). However, no correlation was detected between ET-1 concentrations and portal flow volume ( = -0.02; = 0.4) or portal flow velocity ( = -0.16; = 0.4). CONCLUSIONS Plasma ET-1 concentrations are increased in children with cirrhosis, with or without ascites, compared with controls. Patients with cirrhosis and ascites have increased ET-1 concentrations compared with those without ascites. The degree of increase does not relate to the severity of portal hypertension. This increase tends to maintain systemic blood pressure but is associated with a decrease in renal function.
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Affiliation(s)
- A M Bakr
- Department of Pediatrics, Radiology, and Clinical Pathology, Mansoura University Children's Hospital, Mansoura, Egypt
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Monasterolo LA, Ochoa JE, Elías MM. Rat renal function four days after bile-duct ligation: effects of indomethacin and vasoactive agents. Ren Fail 2002; 24:111-26. [PMID: 12071586 DOI: 10.1081/jdi-120004089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The purpose of this study was to assess the effects of the cyclooxygenase inhibitor, indomethacin, and some vasoactive agents on the renal functional parameters during the early liver injury induced by four days bile duct ligation (BDL). Wistar rats with four days-BDL and control-sham operated were used. Renal function was measured in anesthetized rat treated with a single dose of indomethacin (control, 0.3, 1.0, 3.0 mg/kg b.w.; i.v.) one hour before clearance studies. Sulindac effects were also evaluated (5 mg/kg b.w., i.p). Isolated rat kidney preparations from control and BDL donor rats were used to study renal vascular response to noradrenaline, carbachol or sodium nitroprusside. The bile duct ligation promoted a diminished renal cortical plasma flow (RCPF) on the fourth day post surgery accompanied with a diminution in the glomerular filtration rate (GFR), increased filtration fraction and increased fractional excretion of water and sodium. Indomethacin 0.3 mg/kg induced an increase in GFR and RCPF, maintaining the high filtration fraction in BDL rats. The other doses did not alter these parameters as compared with bile duct ligated rats without treatment, but indomethacin 3 mg/kg caused a significant increase in filtration fraction. Indomethacin induced dose-dependent diminution in natriuresis in sham and BDL groups. Sulindac did not modify hemodynamic parameters, but induced antinatriuresis and antidiuresis in both experimental groups. Maximal vascular responses to noradrenaline measured in isolated rat kidneys were statistically diminished in BDL-rats as compared with controls (C, n=7; 35.0+/-2.3 mmHg ml(-1) min; BDL-rats, n=5; 23.8+/-0.7 mmHg ml(-1) min; p<0.02), without changes in EC15. Maximal relaxation induced by sodium nitroprusside in the phenylephrine (PHE)-pre-constricted renal vasculature in control preparations did not differ from that observed in BDL group (C: n=6; 49.5+/-2.3%). Values of EC50 were 1.26+/-0.07 microM (n=6) in control preparations and 0.34+/-0.03 microM (n=4) in kidneys from BDL-rats (p<0.001). Carbachol induced a biphasic relaxation of PHE-pre-constricted renal vasculature. No differences in maximal responses were found. EC50 value of the second phase in BDL group was significantly decreased compared to control preparations (C: n=6, 0.47+/-0.05 microM; BDL: n=6, 0.22+/-0.03 microM p<0.001). The present results show that the altered renal function after a short time post bile duct ligation is determined, at least in part, by increased release of arachidonic derivatives in vascular bed and tubular cells. At this stage of liver injury, the alteration in the renal vascular response to different vasoactive agents is remarkable.
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Affiliation(s)
- Liliana A Monasterolo
- Area Farmacología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, República Argentina
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40
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Lladó L, Ramos E, Figueras J, Serrano T, Torras J, Rafecas A, Fabregat J, Lama C, Busquets J, Dalmau A, Sabaté A, Jaurrieta E. Influence of endothelin-1 on hemodynamics during liver transplantation with and without temporary portocaval shunt: results of a clinical randomized study. Liver Transpl 2002; 8:27-33. [PMID: 11799482 DOI: 10.1053/jlts.2002.30338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aims of this study are to analyze the influence of endothelin-1 (ET-1) on hemodynamic evolution during liver transplantation (LT) and study the role of a temporary portacaval shunt in ET-1 synthesis. Forty LTs in patients with cirrhosis were studied. Two groups were analyzed: the first group had a temporary portacaval shunt during the anhepatic phase, and the second group did not. Portal and systemic ET-1 levels were measured at several times. At the end of the anhepatic phase, systemic (16.1 +/- 6.5 pg/mL) and portal (19.2 +/- 7 pg/mL) ET-1 levels increased, whereas they decreased after reperfusion (systemic, 11.8 +/- 7.1 pg/mL; portal, 13.2 +/- 6.8 pg/mL). Portal flow at the beginning of LT correlated with systemic ET-1 levels (R2 = 0.3; P =.004). A temporary portacaval shunt reduced portal pressure during the anhepatic phase, but did not modify ET-1 levels. Patients with reperfusion syndrome had greater systemic ET-1 levels in the anhepatic phase (19.1 +/- 6.9 v 15.1 +/- 6.1 pg/mL; P =.07). Although there is a relationship between ET-1 levels and portal flow and reperfusion syndrome, no clear clinical effect on hemodynamics could be shown. Creation of a portacaval shunt made no change in ET-1 levels.
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Affiliation(s)
- Laura Lladó
- Department of Surgery, Liver Transplant Unit, Ciudad Sanitaria Universitaria Bellvitge, University of Barcelona, Spain
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Hasegawa T, Kimura T, Sasaki T, Okada A. Plasma endothelin-1 level as a marker reflecting the severity of portal hypertension in biliary atresia. J Pediatr Surg 2001; 36:1609-12. [PMID: 11685683 DOI: 10.1053/jpsu.2001.27929] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND/PURPOSE The aim of this study was to examine if the plasma endothelin-1 (ET-1), a potent vasoconstrictor, level may reflect the severity of portal hypertension associated with liver cirrhosis in biliary atresia (BA). METHODS Forty-eight postoperative BA patients aged 6 months to 20 years were studied. Plasma ET-1 was measured by a sandwich method of enzyme immunoassay. ET-1 was compared with Child's score and laboratory data. ET-1 levels were compared among groups of patients with various degrees of histologic fibrosis and portal hypertension. RESULTS Plasma ET-1 was 5.3 +/- 3.5 pg/mL in BA, higher than in controls (3.1 +/- 0.8, n = 27; P <.05). ET-1 correlated with Child's score, serum total bilirubin, direct bilirubin, aspartate aminotransferase, albumin, prothrombin time, hepaplastin test, fibrinogen, cholinesterase, total cholesterol, Fischer's molar ratio, prealubumin, and hyaluronic acid, respectively (P <.05). ET-1 also correlated with the severity of histologic fibrosis, gastroesophageal varices, the presence of splenomegaly, ascites, venous dilatation on the abdominal wall, or pulmonary vascular abnormalities. In 4 patients undergoing liver transplantation (LTx), ET-1 after LTx was lower than that before LTx (P <.05). CONCLUSION Plasma ET-1 level may be a useful index reflecting the severity of cirrhosis and portal hypertension in BA.
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Affiliation(s)
- T Hasegawa
- Department of Pediatric Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita City, Osaka, 565-0871 Japan
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Saibara T, Ono M, Iwasaki S, Maeda T, Onishi S, Hayashi And Y, Enzan H. Effects of ethanol on L-arginine transport in rat Ito cells in relation to nitric oxide production. Alcohol Clin Exp Res 2001. [PMID: 11410740 DOI: 10.1111/j.1530-0277.2001.tb02416.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Nitric oxide (NO) is a potent mediator of hepatic sinusoidal hemodynamics that is synthesized in the hepatic stellate cells (Ito cells, fat-storing cells) and affects these cells. NO production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L-arginine. The precise mechanism that controls NO production in stellate cells was characterized recently. METHODS Kinetic analysis of L-arginine transport and reverse transcription-polymerase chain reaction for cationic amino acid transporter (CAT) were carried out by using stellate cells prepared from the male Wistar rat. The effect of ethanol on L-arginine transport and NO production of stellate cells was assessed in the presence of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. RESULTS The L-arginine transport system functioning in the hepatic stellate cells was system y+, possibly mediated by CAT-1 and CAT-2B (Km approximately 50 microM). IFN-gamma in combination with TNF-alpha induced NO production with an enhancement in CAT-2B mRNA expression and L-arginine transport, whereas L-arginine transport and NO production were suppressed by coincubated ethanol. CONCLUSIONS In hepatic stellate cells, ethanol has suppressive effects on NO production and extracellular L-arginine transport in the presence of TNF-alpha and IFN-gamma. The estimated Km of L-arginine transporter in hepatic stellate cells is very similar to the physiological L-arginine concentration in portal vein. Our findings may support the merit of further studies on the modulation of NO production via access to portal blood L-arginine concentration to control disturbed hepatic sinusoidal blood flow in patients with alcoholic liver disease.
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Affiliation(s)
- T Saibara
- First Department of Medicine, Kochi Medical School, Nankoku 783, Japan.
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43
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Bruno CM, Neri S, Sciacca C, Caruso L. Plasma endothelin-1 levels in liver cirrhosis. INTERNATIONAL JOURNAL OF CLINICAL & LABORATORY RESEARCH 2001; 30:169-72. [PMID: 11289706 DOI: 10.1007/s005990070002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The role of circulating endothelin- , a potent vasoconstricting peptide, in liver cirrhosis is still controversial. It has been postulated that endothelin-1 may play a role in the circulatory derangement occurring in cirrhotic subjects, and increased plasma endothelin-1 levels have been reported in these patients. In this study we looked for a relationship between the severity of the liver disease according to Child's classification and plasma endothelin-1 concentrations in a group of cirrhotic patients compared with a healthy control group. Twenty-two cirrhotic patients and 10 healthy controls, matched for sex and age, were selected for study after informed consent. The etiology of cirrhosis was posthepatitis B in 8 of 22 cases, posthepatitis C in 13 of 22 cases, and alcoholism in 1 patient. According to Child's classification, 6 patients were in class A, 6 in class B, and 10 in class C. Plasma endothelin-1 was measured by a commercial RIA kit (Amersham UK). Mean +/- SD plasma endothelin-1 levels were 8.8 +/- 0.9 pg/ml in controls and 9.2 +/- 1.1 pg/ml in all cirrhotic patients (P > 0.05). In each sub-group of cirrhotics, plasma endothelin- was 8.6 +/- 1.2 pg/ml in Child A, 8.9 +/- 1.9 pg/ml in Child B, and 10.6 +/- 1.5 pg/ml in Child C groups, respectively. There were no statistical differences between control subjects and Child A and B cirrhotic patients (P > 0.05). A significant increase in endothelinl was observed only in the Child C group versus either group A or B (P = 0.004). Our results show that alterations of circulating endothelin-1 do not occur in all cirrhotic patients; higher plasma levels than controls are only detectable in patients with more-severe hepatic failure. We do not know whether increased endothelin-1 levels are a consequence of hemodynamic disorders occurring in the advanced phase of liver cirrhosis or play a pathogenic role.
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Affiliation(s)
- C M Bruno
- Department of Internal Medicine, University of Catania, Italy
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44
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Saibara T, Ono M, Iwasaki S, Maeda T, Onishi S, Hayashi And Y, Enzan H. Effects of ethanol on L-arginine transport in rat Ito cells in relation to nitric oxide production. Alcohol Clin Exp Res 2001; 25:39S-45S. [PMID: 11410740 DOI: 10.1097/00000374-200106001-00010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Nitric oxide (NO) is a potent mediator of hepatic sinusoidal hemodynamics that is synthesized in the hepatic stellate cells (Ito cells, fat-storing cells) and affects these cells. NO production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L-arginine. The precise mechanism that controls NO production in stellate cells was characterized recently. METHODS Kinetic analysis of L-arginine transport and reverse transcription-polymerase chain reaction for cationic amino acid transporter (CAT) were carried out by using stellate cells prepared from the male Wistar rat. The effect of ethanol on L-arginine transport and NO production of stellate cells was assessed in the presence of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. RESULTS The L-arginine transport system functioning in the hepatic stellate cells was system y+, possibly mediated by CAT-1 and CAT-2B (Km approximately 50 microM). IFN-gamma in combination with TNF-alpha induced NO production with an enhancement in CAT-2B mRNA expression and L-arginine transport, whereas L-arginine transport and NO production were suppressed by coincubated ethanol. CONCLUSIONS In hepatic stellate cells, ethanol has suppressive effects on NO production and extracellular L-arginine transport in the presence of TNF-alpha and IFN-gamma. The estimated Km of L-arginine transporter in hepatic stellate cells is very similar to the physiological L-arginine concentration in portal vein. Our findings may support the merit of further studies on the modulation of NO production via access to portal blood L-arginine concentration to control disturbed hepatic sinusoidal blood flow in patients with alcoholic liver disease.
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Affiliation(s)
- T Saibara
- First Department of Medicine, Kochi Medical School, Nankoku 783, Japan.
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45
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Kojima H, Sakurai S, Kuriyama S, Yoshiji H, Imazu H, Uemura M, Nakatani Y, Yamao J, Fukui H. Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo. J Hepatol 2001; 34:805-11. [PMID: 11451162 DOI: 10.1016/s0168-8278(01)00045-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Endothelin-1 has been suggested to play a key role in cirrhotic portal hypertension, but a role of its receptors in vivo is not fully elucidated. METHODS Biliary cirrhosis was induced by bile duct ligation. Expressions of endothelin-1 and its receptors were evaluated by radioimmunoassay and/or reverse-transcription polymerase chain reaction. Hemodynamics were studied using endothelin receptor agonist or antagonist. RESULTS Portal pressure and hepatic endothelin-1 concentrations progressively increased in parallel after bile duct ligation. Gene expression of hepatic prepro-endothelin-1 and endothelin B receptor enhanced after bile duct ligation, while that of endothelin A receptor was unchanged. Intraportal administration of endothelin-1 or endothelin B receptor agonist sarafotoxin 6c (0.5 nmol/kg, respectively) progressively raised portal pressure in both sham and cirrhotic rats. Portal hypertensive effect of sarafotoxin 6c was more intense in cirrhotic rats than sham animals. Neither endothelin A receptor antagonist FR139317 (1 mg/kg) nor endothelin B receptor antagonist BQ788 (1 mg/kg) alone ameliorated cirrhotic portal hypertension. Only the combined endothelin A and B blockade was associated with a decrease in portal pressure in cirrhotic rats. CONCLUSIONS These results indicate that endothelin-1 plays a major role in cirrhotic portal hypertension through endothelin receptor subtype B together with subtype A in vivo.
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MESH Headings
- Animals
- Azepines/pharmacology
- Blood Pressure
- Endothelin Receptor Antagonists
- Endothelin-1/genetics
- Endothelin-1/physiology
- Endothelins/genetics
- Gene Expression
- Hemodynamics
- Hypertension, Portal/etiology
- Hypertension, Portal/genetics
- Hypertension, Portal/physiopathology
- Indoles/pharmacology
- Liver/physiopathology
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/physiopathology
- Oligopeptides/pharmacology
- Piperidines/pharmacology
- Protein Precursors/genetics
- RNA/genetics
- Radioimmunoassay
- Rats
- Receptor, Endothelin A
- Receptor, Endothelin B
- Receptors, Endothelin/genetics
- Receptors, Endothelin/physiology
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- H Kojima
- Third Department of Internal Medicine, Nara Medical University, Kashihara-shi, Japan.
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46
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Petkova SB, Huang H, Factor SM, Pestell RG, Bouzahzah B, Jelicks LA, Weiss LM, Douglas SA, Wittner M, Tanowitz HB. The role of endothelin in the pathogenesis of Chagas' disease. Int J Parasitol 2001; 31:499-511. [PMID: 11334935 DOI: 10.1016/s0020-7519(01)00168-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Infection with Trypanosoma cruzi causes a generalised vasculitis of several vascular beds. This vasculopathy is manifested by vasospasm, reduced blood flow, focal ischaemia, platelet thrombi, increased platelet aggregation and elevated plasma levels of thromboxane A(2) and endothelin-1. In the myocardium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are observed. Immunohistochemistry studies employing anti-endothelin-1 antibody revealed increased expression of endothelin-1, most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1, endothelin converting enzyme and endothelin-1 were observed in the infected myocardium. When T. cruzi-infected mice were treated with phosphoramidon, an inhibitor of endothelin converting enzyme, there was a decrease in heart size and severity of pathology. Mitogen-activated protein kinases and the transcription factor activator-protein-1 regulate the expression of endothelin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extracellular signal regulated kinase. In addition, the activator-protein-1 DNA binding activity, as determined by electrophoretic mobility shift assay, was increased. Increased expression of cyclins A and cyclin D1 was observed in the myocardium, and immunohistochemistry studies revealed that interstitial cells and vascular and endocardial endothelial cells stained intensely with antibodies to these cyclins. These data demonstrate that T. cruzi infection of the myocardium activates extracellular signal regulated kinase, activator-protein-1, endothelin-1, and cyclins. The activation of these pathways is likely to contribute to the pathogenesis of chagasic heart disease. These experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identification of these pathways provides possible targets for therapeutic interventions to ameliorate or prevent the development of cardiomyopathy during T. cruzi infection.
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Affiliation(s)
- S B Petkova
- Department of Pathology, Albert Einstein College of Medicine, Jacobi Medical Center, 1300 Morris Park Avenue, 10461, Bronx, NY, USA
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47
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Notas G, Xidakis C, Valatas V, Kouroumalis A, Kouroumalis E. Levels of circulating endothelin-1 and nitrates/nitrites in patients with virus-related hepatocellular carcinoma. J Viral Hepat 2001; 8:63-9. [PMID: 11155153 DOI: 10.1046/j.1365-2893.2001.00269.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A balance between endothelins (ET) and nitric oxide (NO) might interfere with liver haemodynamics and disease progression in various liver diseases. Increased levels of endothelin 1 (ET-1) and nitrites and nitrates (NOx, the end products of NO metabolism) have been reported in hepatocellular carcinoma (HCC), but the balance has not been studied. The purpose of this study was to assess the ratio of NOx to ET-1 in patients with virus-related hepatocellular carcinoma and to investigate its correlation with the extent of the disease. Eighteen patients with virus-related HCC (six Okuda stage I, six Okuda stage II and six Okuda stage III) were included in the study and were compared with 22 patients with viral cirrhosis (14 decompensated, eight compensated) and seven normal controls. ET-1 was measured with an ELISA assay and NOx with a modification of the Griess reaction. Patients with virus-related HCC had the highest levels of circulating ET-1 and NOx (13.24 +/- 0.82 pg/ml and 112.28 +/- 18.56 micromol/l) compared to compensated cirrhosis (9.47 +/- 0.50 pg/ml, P < 0.004 and 54.47 +/- 2.36 micromol/l, P < 0.01), decompensated cirrhosis (9.57 +/- 0.32 pg/ml, P < 0.001 and 90.20 +/- 11.23 micromol/l, NS) and normal controls (8.84 +/- 0.61 pg/ml, P < 0.001 and 51.17 +/- 6.18 micromol/l, P < 0.01). There was a significant increase of ET-1 and NOx at HCC stage III compared to HCC stages I and II, cirhotics and controls. HCC stage III patients also had a NOx/ET-1 ratio that was higher than HCC stages I and II patients, normal controls and patients with compensated cirrhosis. Virus-related HCC patients have high levels of circulating ET-1, compared to compensated or decompensated cirrhosis. Highest levels of ET-1 are produced in Okuda III tumours. NOx are also increased but only in Okuda stage III tumours. The NOx/ET-1 ratio is increased in virus-related HCC and DC. This increase may account for the known increase in tumour blood flow.
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Affiliation(s)
- G Notas
- Department of Gastroenterology, Liver Research Laboratory, Heraklion Crete, Greece
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Valeriano V, Funaro S, Lionetti R, Riggio O, Pulcinelli G, Fiore P, Masini A, De Castro S, Merli M. Modification of cardiac function in cirrhotic patients with and without ascites. Am J Gastroenterol 2000; 95:3200-5. [PMID: 11095342 DOI: 10.1111/j.1572-0241.2000.03252.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Abnormalities in cardiac function have been reported in liver cirrhosis, suggesting a latent cardiomyopathy in these patients. In this study we investigated cardiac function in cirrhotic patients and in controls. METHODS A total of 20 cirrhotic patients without previous or ongoing ascites, 20 cirrhotic patients with moderate-to-severe ascites, and 10 healthy controls were studied by two-dimensional Doppler echocardiography. Cardiac dimensions and left and right ventricular function were evaluated. The left ventricular geometric pattern was calculated according to Ganau's criteria. Diastolic function was evaluated by the peak filling velocity of E wave and A wave, E/A ratio, and deceleration time of E wave. The pulmonary systolic arterial pressure was also estimated in patients with tricuspid insufficiency. RESULTS Right and left atrium and right ventricle diameters were significantly enlarged in cirrhotic patients versus controls. E/A ratio was decreased (p < 0.05) in patients with ascites (0.9 +/- 0.2) versus those without ascites (1.3 +/- 0.4) and controls (1.3 +/- 1). The estimated pulmonary systolic arterial pressure was slightly elevated in patients with ascites (35 +/- 5 mm Hg, six patients) versus those with no ascites (28 +/- 5, 10 patients) and controls (27 +/- 8, 6 controls, analysis of variance, p < 0.05). The pattern of left ventricular geometry was normal in the majority of patients. Nitrite and nitrate levels were increased in cirrhotics irrespective of the presence of ascites. CONCLUSIONS Liver cirrhosis is associated with enlarged right cardiac chambers. Diastolic dysfunction and mild pulmonary hypertension are evident in cirrhotic patients with ascites. These changes do not depend on variations in the left ventricular geometry.
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Affiliation(s)
- V Valeriano
- II Gastroenterologia e Dipartimento di Medicina Clinica, Università degli Studi di Roma La Sapienza, Rome, Italy
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Loer SA, Kalweit G, Tarnow J. Effects of ventilation and nonventilation on pulmonary venous blood gases and markers of lung hypoxia in humans undergoing total cardiopulmonary bypass. Crit Care Med 2000; 28:1336-40. [PMID: 10834675 DOI: 10.1097/00003246-200005000-00013] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To assess the effects of lung oxygenation and ventilation vs. lung collapse on pulmonary markers of lung hypoxia. DESIGN A prospective, nonrandomized, nonblinded comparative study. SETTING University department of anesthesiology and cardiothoracic surgery. SUBJECTS Twelve adult patients undergoing coronary bypass grafting requiring total cardiopulmonary bypass. INTERVENTIONS Single lung ventilation during total cardiopulmonary bypass (tidal volume, 150 mL; respiratory rate, 6 breaths/min; inspiratory oxygen fraction, 0.5) while the contralateral lung was allowed to collapse completely without oxygenation. MEASUREMENTS AND MAIN RESULTS At the beginning and at the end of total cardiopulmonary bypass (duration, 59-65 mins), blood was aspirated from the right and left pulmonary veins and the radial artery for measurement of blood gases and concentrations of endothelin-1, big-endothelin, thromboxane B2, lactate, and lactate dehydrogenase. Nonventilation during total cardiopulmonary bypass compared with ventilation resulted in lower pulmonary venous P(O2) values (57+/-15 torr [7.6+/-2.0 kPa] vs. 103+/-23 torr [13.7+/-3.1 kPa]) and higher thromboxane B2 concentrations (488+/-95 pg/mL vs. 434+/-92 pg/mL). The concentrations of endothelin-1, big-endothelin, lactate, and lactate dehydrogenase in the pulmonary veins did not differ significantly between nonventilated and ventilated lungs. CONCLUSIONS Development of pulmonary tissue hypoxia during 1 hr of nonventilation and cardiopulmonary bypass with completely inhibited pulmonary arterial blood flow is unlikely, suggesting that enough oxygen is stored in or is provided to the collapsed lung. Thus, nonventilation during total cardiopulmonary bypass does not appear to contribute to postoperative respiratory dysfunction by causing pulmonary tissue hypoxia. These results, however, do not exclude that mechanical factors of ventilation might benefit the lung during cardiopulmonary bypass.
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Affiliation(s)
- S A Loer
- Department of Anesthesiology, Heinrich-Heine-University, Düsseldorf, Germany
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50
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Nagasue N, Dhar DK, Yamanoi A, Emi Y, Udagawa J, Yamamoto A, Tachibana M, Kubota H, Kohno H, Harada T. Production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis. Hepatology 2000; 31:1107-14. [PMID: 10796886 DOI: 10.1053/he.2000.6596] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This study was aimed to evaluate the source of endothelin-1 (ET-1) in cirrhotic patients. ET-1 is implicated in the pathogenesis of portal hypertension. However, the mechanism and source for increased plasma ET-1 in cirrhotic patients are still obscure. Plasma ET-1 levels in systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood were measured in 23 patients with cirrhosis and 8 controls with normal liver. Fourteen removed spleens were immunohistochemically studied for ET-1, CD34, CD68, and CD20. In situ hybridization was done to localize ET-1 messenger RNA (mRNA). In cirrhosis, ET-1 levels in both SMV and SPV were higher than in SV. ET-1 in SV and SPV were significantly higher in cirrhotic patients than in control patients. Three groups of cells in the spleen expressed both protein and mRNA of ET-1: endothelial cells in the sinus, which were also stained for CD34; cells in the germinal center; and cells in the marginal zone of lymphoid sheaths and follicles, which were also stained for CD20 but not for CD34 and CD68. The ET-1 concentration released from the spleen was in parallel with the grade of ET-1 expression in the spleen. The spleen is one of the major sites of ET-1 release in cirrhotic patients. Endothelial cells of the splenic sinus and possibly B lymphocytes in the germinal center and marginal zone of lymphoid sheaths and follicles seem to be the sites of ET-1 production in the spleen.
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Affiliation(s)
- N Nagasue
- Second Department of Surgery, Shimane Medical University, Izumo,
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