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1
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Sudden death due to cirrhotic cardiomyopathy: An autopsy case report. J Forensic Leg Med 2022; 89:102369. [DOI: 10.1016/j.jflm.2022.102369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/03/2022] [Accepted: 05/04/2022] [Indexed: 11/21/2022]
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Tadelle A. QT Interval Prolongation in Cirrhotic Cardiomyopathy. RESEARCH REPORTS IN CLINICAL CARDIOLOGY 2022. [DOI: 10.2147/rrcc.s371615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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de Souza SLB, Mota GAF, Gregolin CS, do Nascimento M, Luvizotto RAM, Bazan SGZ, Sugizaki MM, Barbisan LF, Cicogna AC, do Nascimento AF. Exercise Training Attenuates Cirrhotic Cardiomyopathy. J Cardiovasc Transl Res 2021; 14:674-684. [PMID: 32246321 DOI: 10.1007/s12265-020-09997-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 03/25/2020] [Indexed: 12/22/2022]
Abstract
Cirrhotic cardiomyopathy is a condition where liver cirrhosis is associated with cardiac dysfunction. Triggers and blockers of cirrhotic cardiomyopathy are poorly understood, which might compromise the prognosis of chronic liver disease patients. We tested whether exercise training would reduce liver damage induced by thioacetamide and prevent liver cirrhosis-associated cardiomyopathy. Wistar rats were divided into three groups: control, thioacetamide (TAA), or TAA plus exercise. Thioacetamide increased liver weight and serum alanine aminotransferase and aspartate aminotransferase levels. Also, TAA treatment was involved with hepatic nodule formation, fibrotic septa, inflammatory infiltration, and hepatocyte necrosis. The exercise group presented with a reduction in liver injury status. We found that liver injury was associated with disordered cardiac hypertrophy as well as diastolic and systolic dysfunction. Exercise training attenuated cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment. These results provided insights that exercise training can mitigate cirrhotic cardiomyopathy phenotype. Graphical Abstract Exercise training attenuated liver injury as well as cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment.
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Affiliation(s)
- Sérgio Luiz Borges de Souza
- Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Gustavo Augusto Ferreira Mota
- Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Cristina Schmitt Gregolin
- Institute of Health Sciences, Federal University of Mato Grosso (UFMT), Avenida Alexandre Ferronato, n°1200, Setor Industrial, Sinop, Mato Grosso, 78.556-267, Brazil
| | - Milena do Nascimento
- Institute of Health Sciences, Federal University of Mato Grosso (UFMT), Avenida Alexandre Ferronato, n°1200, Setor Industrial, Sinop, Mato Grosso, 78.556-267, Brazil
| | - Renata Azevedo Melo Luvizotto
- Institute of Health Sciences, Federal University of Mato Grosso (UFMT), Avenida Alexandre Ferronato, n°1200, Setor Industrial, Sinop, Mato Grosso, 78.556-267, Brazil
| | - Silmeia Garcia Zanati Bazan
- Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Mário Mateus Sugizaki
- Institute of Health Sciences, Federal University of Mato Grosso (UFMT), Avenida Alexandre Ferronato, n°1200, Setor Industrial, Sinop, Mato Grosso, 78.556-267, Brazil
| | - Luis Fernando Barbisan
- Department of Morphology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Antonio Carlos Cicogna
- Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - André Ferreira do Nascimento
- Institute of Health Sciences, Federal University of Mato Grosso (UFMT), Avenida Alexandre Ferronato, n°1200, Setor Industrial, Sinop, Mato Grosso, 78.556-267, Brazil.
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Matyas C, Haskó G, Liaudet L, Trojnar E, Pacher P. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat Rev Cardiol 2021; 18:117-135. [PMID: 32999450 DOI: 10.1038/s41569-020-0433-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2020] [Indexed: 12/11/2022]
Abstract
The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.
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Affiliation(s)
- Csaba Matyas
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Lucas Liaudet
- Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Eszter Trojnar
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
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Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World J Gastroenterol 2020; 26:6111-6140. [PMID: 33177789 PMCID: PMC7596642 DOI: 10.3748/wjg.v26.i40.6111] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/28/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
| | - Harinda Rajapaksha
- School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia
| | | | - Peter W Angus
- Department of Gastroenterology, Austin Health, Heidelberg, VIC 3084, Australia
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia
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Shenoda B, Boselli J. Vascular syndromes in liver cirrhosis. Clin J Gastroenterol 2019; 12:387-397. [PMID: 30980261 DOI: 10.1007/s12328-019-00956-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 02/20/2019] [Indexed: 02/08/2023]
Abstract
Liver cirrhosis is associated with multiple vascular syndromes affecting almost all body systems. Many of these syndromes are directly related to impaired liver function and sometimes reversible after liver transplantation while others arise secondary to portal hypertension and ascites. Altered expression of angiogenic and vasoactive compounds (most importantly nitric oxide), endothelial dysfunction, dysregulated neurohormonal control, and systemic inflammatory state play differential roles in mediating homeostatic instability and abnormal vasogenic response. Important vascular features encountered in liver disease include portal hypertension, splanchnic overflow, abnormal angiogenesis and shunts, portopulmonary syndrome, hepatopulmonary syndrome, and systemic hyperdynamic circulation. Redistribution of effective circulatory volume deviating from vital organs and pooling in splanchnic circulation is also encountered in liver patients which may lead to devastating outcomes as hepatorenal syndrome. Etiologically, vascular syndromes are not isolated phenomena and vascular dysfunction in one system may lead to the development of another in a different system. This review focuses on understanding the pathophysiological factors underlying vascular syndromes related to chronic liver disease and the potential links among them. Many of these syndromes are associated with high mortality, thus it is crucial to look for early biomarkers for these syndromes and develop novel preventive and therapeutic strategies.
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Affiliation(s)
- Botros Shenoda
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Joseph Boselli
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA. .,Drexel Internal Medicine, 205 N. Broad Street, Philadelphia, 19107, USA.
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Carvalho MVH, Kroll PC, Kroll RTM, Carvalho VN. Cirrhotic cardiomyopathy: the liver affects the heart. ACTA ACUST UNITED AC 2019; 52:e7809. [PMID: 30785477 PMCID: PMC6376321 DOI: 10.1590/1414-431x20187809] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 12/04/2018] [Indexed: 12/14/2022]
Abstract
Cirrhotic cardiomyopathy historically has been confused as alcoholic cardiomyopathy. The key points for diagnosis of cirrhotic cardiomyopathy have been well explained, however this entity was neglected for a long time. Nowadays the diagnosis of this entity has become important because it is a factor that contributes significantly to morbidity-mortality in cirrhotic patients. Characteristics of cirrhotic cardiomyopathy are a hyperdynamic circulatory state, altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, particularity QT interval prolongation. The pathogenesis includes impaired function of beta-receptors, altered transmembrane currents and overproduction of cardiodepressant factors, such as nitric oxide, cytokines and endogenous cannabinoids. In addition to physical signs of hyperdynamic state and heart failure under stress conditions, the diagnosis can be done with dosage of serum markers, electrocardiography, echocardiography and magnetic resonance. The treatment is mainly supportive, but orthotopic liver transplantation appears to improve this condition although the prognosis of liver transplantation in patients with cirrhotic cardiomyopathy is uncertain.
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Affiliation(s)
- M V H Carvalho
- Departamento de Cirurgia, Faculdade de Medicina de Jundiaí, Jundiaí, SP, Brasil
| | - P C Kroll
- Hospital de Transplante E.J. Zerbini, São Paulo, SP, Brasil
| | - R T M Kroll
- Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil
| | - V N Carvalho
- Hospital Municipal Dr. Mario Gatti, Campinas, SP, Brasil
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Di Pascoli M, Sacerdoti D, Pontisso P, Angeli P, Bolognesi M. Molecular Mechanisms Leading to Splanchnic Vasodilation in Liver Cirrhosis. J Vasc Res 2017; 54:92-99. [PMID: 28402977 DOI: 10.1159/000462974] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/06/2017] [Indexed: 12/12/2022] Open
Abstract
In liver cirrhosis, portal hypertension is a consequence of enhanced intrahepatic vascular resistance and portal blood flow. Significant vasodilation in the arterial splanchnic district is crucial for an increase in portal flow. In this pathological condition, increased levels of circulating endogenous vasodilators, including nitric oxide, prostacyclin, carbon monoxide, epoxyeicosatrienoic acids, glucagon, endogenous cannabinoids, and adrenomedullin, and a decreased vascular response to vasoconstrictors are the main mechanisms underlying splanchnic vasodilation. In this review, the molecular pathways leading to splanchnic vasodilation will be discussed in detail.
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Affiliation(s)
- Marco Di Pascoli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University of Padova, Padua, Italy
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Goldberg DS, Fallon MB. The Art and Science of Diagnosing and Treating Lung and Heart Disease Secondary to Liver Disease. Clin Gastroenterol Hepatol 2015; 13:2118-27. [PMID: 25934564 PMCID: PMC4618073 DOI: 10.1016/j.cgh.2015.04.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/13/2015] [Accepted: 04/14/2015] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at risk of extrahepatic complications related to cirrhosis and portal hypertension, as well as organ-specific complications of certain liver diseases. These complications can compromise quality of life, while also increasing morbidity and mortality before and after liver transplantation. Patients with chronic liver disease are at risk for pulmonary complications of hepatopulmonary syndrome and portopulmonary syndrome; the cardiac complication fall under the general concept of cirrhotic cardiomyopathy, which can affect systolic and diastolic function, as well as cardiac conduction. In addition, patients with certain diseases are at risk of lung and/or cardiac complications that are specific to the primary disease (ie, emphysema in α-1-antitrypsin deficiency) or occur with increased incidence in certain conditions (ie, ischemic heart disease associated with nonalcoholic steatohepatitis). This article focuses on the epidemiology, clinical presentation, pathogenesis, treatment options, and role of transplantation for lung and heart diseases secondary to liver disease, while also highlighting select liver diseases that directly affect the lungs and heart.
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Affiliation(s)
- David S Goldberg
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Michael B Fallon
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
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Pathophysiology of Portal Hypertension. PANVASCULAR MEDICINE 2015. [PMCID: PMC7153457 DOI: 10.1007/978-3-642-37078-6_144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The bases of our current knowledge on the physiology of the hepatic portal system are largely owed to the work of three pioneering vascular researchers from the sixteenth and the seventeenth centuries: A. Vesalius, W. Harvey, and F. Glisson. Vesalius is referred to as the founder of modern human anatomy, and in his influential book, De humani corporis fabrica libri septem, he elaborated the first anatomical atlas of the hepatic portal venous system (Vesalius 2013). Sir William Harvey laid the foundations of modern cardiovascular research with his Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (Harvey 1931) in which he established the nature of blood circulation. Finally, F. Glisson characterized the gastrointestinal-hepatic vascular system (Child 1955). These physiological descriptions were later complemented with clinical observations. In the eighteenth and nineteenth centuries, Morgagni, Puckelt, Cruveilhier, and Osler were the first to make the connection between common hepatic complications – ascites, splenomegaly, and gastrointestinal bleeding – and obstruction of the portal system (Sandblom 1993). These were the foundations that allowed Gilbert, Villaret, and Thompson to establish an early definition of portal hypertension at the beginning of the twentieth century. In this period, Thompson performed the first direct measurement of portal pressure by laparotomy in some patients (Gilbert and Villaret 1906; Thompson et al. 1937). Considering all these milestones, and paraphrasing Sir Isaac Newton, if hepatologists have seen further, it is by standing on the shoulders of giants. Nowadays, our understanding of the pathogenesis of portal hypertension has largely improved thanks to the progress in preclinical and clinical research. However, this field is ever-changing and hepatologists are continually identifying novel pathological mechanisms and developing new therapeutic strategies for this clinical condition. Hence, the aim of this chapter is to summarize the current knowledge about this clinical condition.
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Effect of biliary cirrhosis on neurogenic relaxation of rat gastric fundus and anococcygeus muscle: role of nitric oxide pathway. Dig Dis Sci 2014; 59:2675-81. [PMID: 24898099 DOI: 10.1007/s10620-014-3225-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 05/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cirrhosis, associated with a host of hemodynamic abnormalities, could affect the gastrointestinal (GI) tract motility. On the other hand, the nonadrenergic noncholinergic (NANC) neurotransmission has been shown to play a pivotal role in GI tract motility and has been linked with release of nitric oxide (NO) on electrical stimulation. In this study, we investigated the effect of biliary cirrhosis on the neurogenic relaxation of rat gastric fundus and anococcygeus muscle and also the possible role of nitric oxide system in this manner. METHODS Isolated gastric fundus and anococcygeus strips of sham-operated and biliary cirrhotic (4 weeks after bile duct ligation) rats were mounted under tension in a standard organ bath. Electrical stimulation was applied to obtain NANC-mediated relaxations in precontracted gastric fundus and anococcygeus muscle. The neurogenic relaxations were examined in the presence of different doses of NO synthase inhibitor, N (w)-Nitro-L-Arginine Methyl Ester (L-NAME). The concentration-dependent relaxant responses to the NO donor sodium nitroprusside were also evaluated. RESULTS The neurogenic relaxation of both gastric fundus and anococcygeus muscle was significantly (P < 0.001) increased in cirrhotic animals. L-NAME (0.03-1,000 µM) inhibited relaxations in both groups in a dose-dependent manner (P < 0.001), but cirrhotic groups were more resistant to the inhibitory effects of L-NAME (P < 0.01). Sodium nitroprusside-mediated relaxations were similar in two groups. CONCLUSIONS This study for the first time demonstrated that cirrhosis increases the NO-mediated neurogenic relaxation of both rat gastric fundus and anococcygeus muscle, suggesting a crucial role for the neurogenic NO in the pathophysiology of disturbed GI motility in cirrhosis.
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Saracyn M, Ząbkowski T, Zdanowski R, Brytan M, Patera J, Nowak Z, Kade G, Wańkowicz Z. Effect of nitric oxide pathway regulation on water/sodium balance and renal function in a rodent model of acute liver and renal failure. Med Sci Monit 2014; 20:1735-44. [PMID: 25270512 PMCID: PMC4186324 DOI: 10.12659/msm.890757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The pathomechanism of acute hepatorenal syndrome (HRS), a particular form of acute renal failure that occurs in the course of acute liver injury, is still poorly understood. The aim of our study was to estimate the influence of the activation and inhibition of the nitric oxide pathway on the water/sodium balance and development of acute renal failure in the course of HRS. MATERIAL AND METHODS We used male Sprague-Dawley rats in the acute galactosamine (Ga1N) model of HRS. The nitric oxide synthase (NOS) inhibitors L-NAME and L-arginine were administered intraperitoneally before and after liver damage. RESULTS HRS developed in all tested groups. L-NAME increased osmotic clearance and urine volume more effectively before liver injury. Furthermore, administration of L-NAME increased creatinine clearance both before and after Ga1N injection. A double dose of L-NAME did not yield further improvement before Ga1N injection, but improved creatinine clearance after Ga1N intoxication. Injection of L-arginine increased sodium excretion and urine volume, but only after liver injury. Moreover, L-arginine injected after Ga1N caused significant improvement of the creatinine clearance in a dose-dependent manner. CONCLUSIONS Our study shows that inhibition of the nitric oxide pathway improves parameters of water and sodium balance and prevents development of acute renal failure in the course of acute liver injury and liver failure. Activation of the nitric oxide system also has a favorable influence on water/sodium balance and renal failure, but only after liver injury.
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Affiliation(s)
- Marek Saracyn
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
| | - Tomasz Ząbkowski
- Department of Urology, Military Institute of Medicine, Warsaw, Poland
| | - Robert Zdanowski
- Department of Regenerative Medicine, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Marek Brytan
- Department of Pharmacology and Toxicology, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Janusz Patera
- Department of Pathology, Military Institute of Medicine, Warsaw, Poland
| | - Zbigniew Nowak
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
| | - Grzegorz Kade
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
| | - Zofia Wańkowicz
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
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Serna E, Mauricio MD, Lluch P, Segarra G, Cortina B, Lluch S, Medina P. Basal release of nitric oxide in the mesenteric artery in portal hypertension and cirrhosis: role of dimethylarginine dimethylaminohydrolase. J Gastroenterol Hepatol 2013; 28:880-6. [PMID: 23302093 DOI: 10.1111/jgh.12119] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Increased basal release of nitric oxide (NO) in the splanchnic circulation contributes to elevated plasma levels of NO observed in decompensated cirrhosis. We evaluated in rat mesenteric arteries whether the differences in basal release of NO, revealed by asymmetric dimethylarginine (ADMA)- and N(G) -nitro-L-arginine methyl ester (L-NAME)-induced contractions, were associated with changes in messenger RNA (mRNA) expression of endothelial NO synthase (eNOS) and dimethylarginine dimethylaminohydrolases (DDAHs). METHODS Rat small mesenteric arteries from 14 Sham-control, from 14 with partial portal vein ligation (PPVL), and from 14 with bile duct excision (BDE)-induced cirrhosis were precontracted under isometric conditions with norepinephrine, and additional contractions were induced with ADMA and L-NAME. mRNA expression of eNOS, DDAH-1, and DDAH-2 in mesenteric arteries were evaluated by real-time polymerase chain reaction. RESULTS ADMA and L-NAME caused concentration- and endothelium-dependent contractions. pD2 values to L-NAME were similar in all groups. In contrast, pD2 values to ADMA were similar in PPVL and BDE but were significantly lower than those of the L-NAME and the Sham groups. Relaxation to acetylcholine was not modified by ADMA or L-NAME but was abolished by charybdotoxin plus apamin. There was an increased mRNA expression of eNOS, DDAH-1, and DDAH-2 in mesenteric arteries from PPVL and BDE compared with the Sham group. CONCLUSION Basal release of NO is increased in mesenteric arteries of PPVL and BDE rats. The rise in expression of DDAHs indicates a higher degradation of ADMA. This would result in an increased generation of endothelial NO and mesenteric vasodilation.
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Affiliation(s)
- Eva Serna
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
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Chuang CL, Huang HC, Chang CC, Lee FY, Wu JC, Lee SD. Chronological changes in renal vascular reactivity in portal hypertensive rats. Eur J Clin Invest 2013; 43:267-76. [PMID: 23293840 DOI: 10.1111/eci.12040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Circulatory dysfunction in portal hypertension is characterized by increased cardiac output, decreased systemic vascular resistance, a fall in mean arterial pressure secondary to splanchnic and systemic vasodilation and hence renal hypoperfusion. Previous studies have disclosed that renal vasculatures of portal hypertensive rats had lower perfusion pressure and hyporesponsiveness to endogenous vasoconstrictors. However, the sequences of altered renal haemodynamics have never been described. This study aimed to explore the evolution of renal vascular hyporeactivity and associated mechanisms during portal hypertension. MATERIALS AND METHODS All rats were randomized into partial portal vein ligation (PVL) or shamed surgery. Isolated kidney perfusion was performed at postoperative day 1, 4, 7 and 14, respectively, to evaluate chronologically renal vascular response to endothelin-1. Renal arteries and kidneys were harvested for further analysis. RESULTS Impaired renal vascular reactivity to endothelin-1 developed 1 week following PVL. There were extensive up-regulations of vasodilative nitric oxide synthase (NOS) and cyclooxygenase-2 in renal arteries of PVL rats. Among them, the changes in endothelial NOS paralleled with the evolution of renal vascular hyporesponsiveness. Preincubation of NOS inhibitor attenuated the renal vascular hyporeactivity in PVL rats. Up-regulated NOS and down-regulated cyclooxygenase-2 in kidneys of PVL rats might play a critical role to maintain renal circulation and body fluid homoeostasis in response to systemic hypotension. CONCLUSIONS This investigation highlights the versatile nature of renal vasculatures in portal hypertension, which is replete with compensatory mechanisms. It may help to unveil potential mechanisms of severe renal dysfunction in advanced liver disease.
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Affiliation(s)
- Chiao-Lin Chuang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Bezinover D, Kadry Z, Uemura T, Sharghi M, Mastro AM, Sosnoski DM, Dalal P, Janicki PK. Association between plasma cyclic guanosine monophosphate levels and hemodynamic instability during liver transplantation. Liver Transpl 2013; 19:191-8. [PMID: 23161851 DOI: 10.1002/lt.23570] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 10/23/2012] [Indexed: 12/19/2022]
Abstract
The activation of cyclic guanosine monophosphate (cGMP) production in patients with end-stage liver disease (ESLD) has been associated with hemodynamic instability during orthotopic liver transplantation (OLT). The aim of this prospective, observational study was to investigate the involvement of cGMP in the mediation of profound hypotension during liver graft reperfusion. An additional objective was to determine whether preoperative cGMP levels are associated with intraoperative hemodynamic instability. Forty-four consecutive patients undergoing OLT were included in the study. Blood samples for cGMP analysis were obtained from (1) the radial artery before the surgical incision; (2) the radial artery, portal vein, and flush blood during the anhepatic phase; and (3) the radial artery 20 minutes after liver graft reperfusion. On the basis of a statistical analysis, the patients were divided into 2 groups: group 1 (preoperative cGMP level ≥ 0.05 μmol/L) and group 2 (preoperative cGMP level < 0.05 μmol/L). We demonstrated a significant correlation between the preoperative levels of cGMP and the amount of catecholamine required to maintain hemodynamic stability during reperfusion (r = 0.52, P < 0.001), the length of the hospital stay (r = 0.38, P = 0.01), and the length of the intensive care unit (ICU) stay (r = 0.44, P = 0.004). We also demonstrated a significantly higher intraoperative catecholamine requirement (P < 0.001) and a prolonged postoperative ICU stay (P = 0.02) in group 1 patients versus group 2 patients. In conclusion, this study demonstrates increased baseline cGMP production in patients with ESLD, which is significantly associated with severe hypotension during OLT. We suggest that preoperative levels of cGMP correlate with hemodynamic instability during liver graft reperfusion.
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Affiliation(s)
- Dmitri Bezinover
- Department of Anesthesiology, Penn State Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
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16
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Verbeke L, Nevens F, Laleman W. Bench-to-beside review: acute-on-chronic liver failure - linking the gut, liver and systemic circulation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2011; 15:233. [PMID: 22104633 PMCID: PMC3334742 DOI: 10.1186/cc10424] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The concept of acute-on-chronic liver failure (ACLF) was introduced recently to describe a subset of patients with chronic liver disease presenting with profound deterioration of liver function and rapidly evolving multi-organ failure. ACLF is frequently accompanied by the development of severe inflammatory response syndrome and has a high mortality. To date, treatment options are limited and exclusively supportive. Over the last few years, some insights have been generated in the pathophysiology of ACLF. A key role for the interaction of innate immune dysfunction, enhanced bacterial translocation from the gut, and circulatory dysfunction has been proposed. In this respect, therapeutic strategies have been examined, with variable success, in experimental studies in animals and humans. This review focuses on potentially relevant pathophysiological elements in the development of ACLF and points out promising treatment modalities in ACLF.
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Affiliation(s)
- Len Verbeke
- Department of Liver and Biliopancreatic Disorders, University Hospital Gasthuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
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17
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Martell M, Coll M, Ezkurdia N, Raurell I, Genescà J. Physiopathology of splanchnic vasodilation in portal hypertension. World J Hepatol 2010; 2:208-20. [PMID: 21160999 PMCID: PMC2999290 DOI: 10.4254/wjh.v2.i6.208] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Revised: 06/09/2010] [Accepted: 06/16/2010] [Indexed: 02/06/2023] Open
Abstract
In liver cirrhosis, the circulatory hemodynamic alterations of portal hypertension significantly contribute to many of the clinical manifestations of the disease. In the physiopathology of this vascular alteration, mesenteric splanchnic vasodilation plays an essential role by initiating the hemodynamic process. Numerous studies performed in cirrhotic patients and animal models have shown that this splanchnic vasodilation is the result of an important increase in local and systemic vasodilators and the presence of a splanchnic vascular hyporesponsiveness to vasoconstrictors. Among the molecules and factors known to be potentially involved in this arterial vasodilation, nitric oxide seems to have a crucial role in the physiopathology of this vascular alteration. However, none of the wide variety of mediators can be described as solely responsible, since this phenomenon is multifactorial in origin. Moreover, angiogenesis and vascular remodeling processes also seem to play a role. Finally, the sympathetic nervous system is thought to be involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension, although the nature and extent of its role is not completely understood. In this review, we discuss the different mechanisms known to contribute to this complex phenomenon.
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Affiliation(s)
- María Martell
- María Martell, Mar Coll, Nahia Ezkurdia, Imma Raurell, Joan Genescà, Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
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18
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Ackerman Z, Karmeli F, Pappo O. Divergent effects of irritants on the gastric mucosa in rats during various stages after bile duct ligation. J Gastroenterol Hepatol 2010; 25:1170-5. [PMID: 20594235 DOI: 10.1111/j.1440-1746.2010.06284.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Controversy exists as to whether rats after bile duct ligation (BDL) are more susceptible to gastric mucosal damage (GMD) induced by irritants. In the present study we characterize GMD after intragastric instillation of either ethanol or hydrochloric acid (HCL), 3 and 21 days after the surgical procedure. METHODS Bile duct ligation and sham operated (SO) rats were studied. RESULTS Three days after surgery, BDL rats exhibited a reduction in gastric mucosal nitric oxide synthase (NOS) activity but an increase in ethanol-induced GMD. Twenty-one days after surgery gastric mucosal prostaglandin (PG) E(2) generation in BDL rats was increased while NOS activity in both groups was similar. Ethanol-induced GMD in SO rats was higher. Pretreatment with NG-nitro-L-arginine methyl ester, prior to ethanol administration was associated with an increase in gastric mucosal PGE(2) generation: (147% in SO and 104% in BDL rats) and in GMD (176% in SO and 303% in BDL rats). HCL induced GMD was of similar magnitude in both groups in both time periods. CONCLUSIONS The gastric resistance to damage by irritants in rats with BDL is not a static phenomenon. This may result from sequential changes that occur in the gastric mucosal defense mechanisms during the evolution of liver disease.
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Affiliation(s)
- Zvi Ackerman
- Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus Campus, Jerusalem, Israel.
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19
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Theodorakis NG, Wang YN, Wu JM, Maluccio MA, Sitzmann JV, Skill NJ. Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model. Am J Physiol Gastrointest Liver Physiol 2009; 297:G792-9. [PMID: 19628654 DOI: 10.1152/ajpgi.00229.2009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Portal hypertension (PHT) is a complication of liver cirrhosis and directly increases mortality and morbidity by increasing the propensity of venous hemorrhage. There are two main underlying causations for PHT, increased hepatic resistance and systemic hyperdynamic circulation. Both are related to localized aberrations in endothelial nitric oxide synthase (eNOS) function and NO biosynthesis. This study investigates the importance of eNOS and systemic hyperdynamic-associated hyperemia to better understand the pathophysiology of PHT. Wild-type and eNOS(-/-) mice were given the hepatotoxin CCl(4) for 4-12 wk. Hepatic fibrosis was determined histologically following collagen staining. Portal venous pressure, hepatic resistance, and hyperemia were determined by measuring splenic pulp pressure (SPP), hepatic portal-venous perfusion pressure (HPVPP), abdominal aortic flow (Qao), and portal venous flow (Qpv). Hepatic fibrosis developed equally in wild-type and eNOS(-/-) CCl(4)-exposed mice. SPP, Qao, and Qpv increased rapidly in wild-type CCl(4)-exposed mice, but HPVPP did not. In eNOS(-/-) CCl(4) mice, Qao was not increased, SPP was partially increased, and HPVPP and Qpv were increased nonsignificantly. We concluded that the systemic hyperemia component of hyperdynamic circulation is eNOS dependent and precedes increased changes in hepatic resistance. Alternative mechanisms, possibly involving cyclooxygenase, may contribute. eNOS maintains normal hepatic resistance following CCl(4)-induced fibrosis. Consequently, increased portal pressure following chronic CCl(4) exposure is linked to hyperdynamic circulation in wild-type mice and increased hepatic resistance in eNOS(-/-) mice.
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Affiliation(s)
- Nicholas G Theodorakis
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
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20
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Hackworth WA, Sanyal AJ. Review: Vasoconstrictors for the treatment of portal hypertension. Therap Adv Gastroenterol 2009. [DOI: 10.1177/1756283x09102330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Vasoconstrictors have long been used in an attempt to mitigate the effects of portal hypertension. In this review, we discuss the current understanding of portal hypertension and the use of vasoconstrictors in the management of its sequlae, including variceal hemorrhage, hepatorenal syndrome, and paracentesis-induced circulatory dysfunction. Experimental and clinical evidence for the use of vasoconstrictors is considered, and several exciting recent developments are reviewed.
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Affiliation(s)
- William A. Hackworth
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA,
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21
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Kemp W, Colman J, Thompson K, Madan A, Vincent M, Chin-Dusting J, Kompa A, Krum H, Roberts S. Norfloxacin treatment for clinically significant portal hypertension: results of a randomised double-blind placebo-controlled crossover trial. Liver Int 2009; 29:427-33. [PMID: 18673434 DOI: 10.1111/j.1478-3231.2008.01850.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND While selective intestinal decontamination (SID) can alter the hyperdynamic circulatory state of cirrhosis, the impact of SID on portal pressure remains unclear especially in the setting of clinically significant portal hypertension. AIMS To examine the impact of SID with norfloxacin on portal pressure in subjects with clinically significant portal hypertension and explore the potential mechanisms by which norfloxacin exerts its haemodynamic effects. METHODS Randomised, double blind, placebo-controlled, crossover trial of norfloxacin 400 mg twice daily for 4 weeks. The portal pressure was assessed by hepatic venous pressure gradient (HVPG). Endotoxaemia was assessed by the Limulus amebocyte lysate (LAL) assay. l-arginine (l-Arg) transporter function was assessed in peripheral blood mononuclear cells (PBMCs). Plasma levels of urotensin II (UII) and tumour necrosis factor were measured before and after therapy. RESULTS Sixteen subjects with clinically significant portal hypertension (16.5+/-1.1 mmHg) completed the study. Norfloxacin therapy was not superior to placebo in reducing HVPG (13.8+/-1.0 mmHg vs 13.6+/-1.2 mmHg, P=0.3). Furthermore, no alteration in l-Arg transport was detected after 4 weeks of norfloxacin therapy. Plasma UII levels correlated positively with HVPG (P=0.01) and the Child-Pugh score (P<0.05). However, UII levels following therapy did not parallel HVPG changes. CONCLUSIONS Norfloxacin is not superior to placebo in reducing HVPG in subjects with clinically significant portal hypertension. Furthermore, norfloxacin does not appear to modulate the l-Arg transporter mechanism in this patient population. Although plasma UII correlates positively with HVPG, UII does not appear to have a direct role in modulating HVPG.
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Affiliation(s)
- William Kemp
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
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22
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Hayashi H, Shimizu K, Tani T, Takamura H, Takeshita M, Nakamura K, Ninomiya I, Fushida S, Harada SI, Kayahara M. Effect of porto-systemic shunting on NOS expression after extended hepatectomy in rats. Hepatol Res 2009; 39:78-85. [PMID: 18713274 DOI: 10.1111/j.1872-034x.2008.00404.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Several surgical procedures have been developed for reducing portal vein pressure to prevent postoperative liver injury. Nitric oxide synthase expression (NOS) induced by elevation of portal vein pressure is thought to play an important role in liver regeneration, but the details are not well understood. METHODS Rats in the control group and in the subcutaneous splenic transposition (SST) group underwent 90% partial hepatectomy. Survival and portal vein pressure were analyzed. The serum IL-6 and TNF-alpha levels were measured by enzyme-linked immunosorbent assay (ELISA). Hepatocyte proliferation and apoptosis 12 hours after hepatectomy were analyzed immunohistochemically. The protein and messenger RNA expression of inducible and endothelial NOS were analyzed using Western blotting and quantitative reverse transcriptase polymerase chain reaction, respectively. RESULTS The survival rate of the SST group was significantly higher. Portal vein pressure, TNF-alpha level and the apoptotic index were significantly lower in the SST group. Twelve hours after surgery, liver inducible NOS (iNOS) protein expression was significantly lower in the SST group. However, protein expression of endothelial NOS was not significantly different between the groups. CONCLUSION Inducible NOS expression after extended hepatectomy is related to the effects of porto-systemic shunting on the splanchnic circulation. Also, iNOS induction and concomitant nitric oxide generation appear to participate in the cytotoxicity of excessive portal pressure after extended hepatectomy.
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Affiliation(s)
- Hironori Hayashi
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan
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Abstract
Portal hypertension, a major hallmark of cirrhosis, is defined as a portal pressure gradient exceeding 5 mm Hg. In portal hypertension, porto-systemic collaterals decompress the portal circulation and give rise to varices. Successful management of portal hypertension and its complications requires knowledge of the underlying pathophysiology, the pertinent anatomy, and the natural history of the collateral circulation, particularly the gastroesophageal varices.
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Affiliation(s)
- Nagib Toubia
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, MCV, Box 980341, Richmond, VA 23298-0341, USA
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24
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The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol 2007; 41 Suppl 3:S288-94. [PMID: 17975478 DOI: 10.1097/mcg.0b013e3181468b4c] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A hyperdynamic splanchnic and systemic circulation is typical of cirrhotic patients and has been observed in all experimental forms of portal hypertension. The hyperdynamic circulation is most likely initiated by arterial vasodilatation, leading to central hypovolemia, sodium retention, and an increased intravascular volume. Arterial vasodilatation is regulated by a complex interplay of various vasodilator molecules and factors that influence the production of those vasodilator molecules. Nitric oxide (NO) has been recognized as the most important vasodilator molecule that mediates the excessive arterial vasodilatation observed in portal hypertension. The aims of this review are (1) to categorize NO synthase isoforms involved in NO overproduction; (2) to explain the mechanisms of endothelial NO synthase up-regulation; and (3) to summarize other molecules involved in the arterial vasodilatation.
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25
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Gatta A, Bolognesi M, Merkel C. Vasoactive factors and hemodynamic mechanisms in the pathophysiology of portal hypertension in cirrhosis. Mol Aspects Med 2007; 29:119-29. [PMID: 18036654 DOI: 10.1016/j.mam.2007.09.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2007] [Accepted: 09/28/2007] [Indexed: 02/08/2023]
Abstract
Portal hypertension is primarily caused by the increase in resistance to portal outflow and secondly by an increase in splanchnic blood flow, which worsens and maintains the increased portal pressure. Increased portal inflow plays a role in the hyperdynamic circulatory syndrome, a characteristic feature of portal hypertensive patients. Almost all the known vasoactive systems/substances are activated in portal hypertension, but most authors stress the pathogenetic role of endothelial factors, such as COX-derivatives, nitric oxide, carbon monoxide. Endothelial dysfunction is differentially involved in different vascular beds and consists in alteration in response both to vasodilators and to vasoconstrictors. Understanding the pathogenesis of portal hypertension could be of great utility in preventing and curing the complications of portal hypertension, such as esophageal varices, hepatic encephalopathy, ascites.
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Affiliation(s)
- Angelo Gatta
- Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
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26
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Ghasemi M, Sadeghipour H, Shafaroodi H, Nezami BG, Gholipour T, Hajrasouliha AR, Tavakoli S, Nobakht M, Moore KP, Mani AR, Dehpour AR. Role of the nitric oxide pathway and the endocannabinoid system in neurogenic relaxation of corpus cavernosum from biliary cirrhotic rats. Br J Pharmacol 2007; 151:591-601. [PMID: 17486141 PMCID: PMC2013996 DOI: 10.1038/sj.bjp.0707279] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND PURPOSE Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model. EXPERIMENTAL APPROACH Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation. KEY RESULTS The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB(1) antagonist) or capsazepine (vanilloid VR(1) antagonist), but not AM630 (CB(2) antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups. CONCLUSIONS AND IMPLICATIONS Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB(1) and vanilloid VR(1) receptors.
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Affiliation(s)
- M Ghasemi
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
- The UCL Institute of Hepatology, Department of Medicine, Royal Free and University College Medical School, UCL London, UK
| | - H Sadeghipour
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
| | - H Shafaroodi
- Department of Pharmacology, Tehran Medical Unit, Islamic Azad University of Medical Sciences Tehran, Iran
| | - B G Nezami
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
| | - T Gholipour
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
| | - A R Hajrasouliha
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
| | - S Tavakoli
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
| | - M Nobakht
- Department of Histology, Medical School, Iran University of Medical Sciences Tehran, Iran
| | - K P Moore
- The UCL Institute of Hepatology, Department of Medicine, Royal Free and University College Medical School, UCL London, UK
| | - A R Mani
- The UCL Institute of Hepatology, Department of Medicine, Royal Free and University College Medical School, UCL London, UK
| | - A R Dehpour
- Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran Tehran, Iran
- Author for correspondence:
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Yamaguchi S, Kawanaka H, Yoshida D, Maehara Y, Hashizume M. Splenic hemodynamics and decreased endothelial nitric oxide synthase in the spleen of rats with liver cirrhosis. Life Sci 2007; 80:2036-44. [PMID: 17481668 DOI: 10.1016/j.lfs.2007.03.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Revised: 02/28/2007] [Accepted: 03/05/2007] [Indexed: 01/03/2023]
Abstract
The enlarged spleen in liver cirrhosis is considered to play a role in the pathogenesis of portal hypertension, but the splenic hemodynamics and molecular mechanisms behind the phenomenon have not been elucidated. The present study aimed to examine the splenic hemodynamics associated with splenic microcirculation and congestion, and to determine the status of the endothelial nitric oxide synthase (eNOS) signaling pathway in the spleen of rats with liver cirrhosis. Liver cirrhosis was induced by bile duct ligation. In rats with bile duct ligation (BDL rats) and control rats, splenic blood flow was measured using a laser Doppler flowmeter, and splenic blood volume was measured using a near-infrared spectrophotometer. The expressions of eNOS and its upstream effectors, Akt, TNF-alpha and VEGF, in the spleen were also determined. Specific splenic blood flow was significantly decreased in BDL rats compared with control rats. Specific splenic blood volume was also decreased in BDL rats, while their total splenic blood volume, especially the deoxygenated volume, was significantly increased. The expressions of phosphorylated and total eNOS, and the eNOS phosphorylation ratio, were all significantly decreased in the spleen of BDL rats. The Akt phosphorylation ratio and TNF-alpha concentration were also decreased in the spleen of BDL rats although the expression of VEGF was increased. These findings suggest that the eNOS signaling pathway is suppressed in the spleen of cirrhotic rats, and may contribute to the measured decreases in specific blood flow and volume in the spleen of liver cirrhosis. Determination of the factors influencing the suppression of eNOS in the spleen may shed light on how liver cirrhosis results in hypodynamic intrasplenic circulation.
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Affiliation(s)
- Shohei Yamaguchi
- Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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28
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Kwon SY, Groszmann RJ, Iwakiri Y. Increased neuronal nitric oxide synthase interaction with soluble guanylate cyclase contributes to the splanchnic arterial vasodilation in portal hypertensive rats. Hepatol Res 2007; 37:58-67. [PMID: 17300699 DOI: 10.1111/j.1872-034x.2007.00005.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Splanchnic arterial vasodilation represents the pathophysiological hallmark of the hemodynamic dysfunction observed in portal hypertensive states. The role of neuronal nitric oxide synthase (nNOS) in the splanchnic arterial vasodilation remains to be elucidated. We therefore investigated: (i) if nNOS is involved in the splanchnic arterial vasodilation; and (ii) the possible interaction of nNOS with soluble guanylate cyclase (sGC) in superior mesenteric arterial (SMA) beds in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation (PVL). To determine the role of nNOS, we removed endothelial layer and measured contractile response and nitric oxide (NO) release in the presence or absence of 7-nitroindazole (7-NI, 10 muM), an nNOS-specific inhibitor. In endothelium-removed vessels, nNOS inhibitor significantly increased the contractile response to methoxamine in SMA beds isolated from the portal hypertensive rats, compared to non-treated SMA beds (106.8 +/- 10.7 vs 86.8 +/- 7.2 mmHg, P = 0.003). This effect of nNOS inhibitor was accompanied with decreased NO production in SMA of portal hypertensive rats (321.3 +/- 18.6 vs 139.5 +/- 16.9 pmol/mL/min, P = 0.0001). Unlike endothelial NOS that is located in endothelial cells, nNOS protein is highly expressed in smooth muscle layers of SMA. Furthermore, there was a significant increase in ~90 kDa nNOS protein in the portal hypertensive group, compared to the sham-operated group (P < 0.01). Interestingly, this 90 kDa nNOS was coimmunoprecipitated with sGC. In conclusion, increased nNOS expression in smooth muscle layers of arteries in the splanchnic circulation may be an additional and more efficient pathway for the activation of sGC by NO, which sustains arterial vasodilation.
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Affiliation(s)
- So Young Kwon
- Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT
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29
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Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M, Zaman Z, Verslype C, Fevery J, Nevens F. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2006; 10:R108. [PMID: 16859530 PMCID: PMC1751025 DOI: 10.1186/cc4985] [Citation(s) in RCA: 163] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Revised: 06/29/2006] [Accepted: 07/10/2006] [Indexed: 02/06/2023]
Abstract
Introduction Patients with acute-on-chronic liver failure show an aggravated hyperdynamic circulation. We evaluated, in a controlled manner, potential changes in systemic haemodynamics induced by the molecular adsorbent recirculating system (MARS) and the Prometheus system liver detoxification devices in a group of patients with acute-on-chronic liver failure. Methods Eighteen patients (51.2 ± 2.3 years old; Child–Pugh score, 12.5 ± 0.2; Maddrey score, 63.1 ± 5.0; hepatic venous pressure gradient, 17.6 ± 0.9 mmHg) with biopsy-proven alcoholic cirrhosis and superimposed alcoholic hepatitis were either treated with standard medical therapy (SMT) combined with MARS (n = 6) or Prometheus (n = 6) or were treated with SMT alone (n = 6) on three consecutive days (6 hours/session). Liver tests, systemic haemodynamics and vasoactive substances were determined before and after each session. Results Groups were comparable for baseline haemodynamics and levels of vasoactive substances. Both MARS and Prometheus decreased serum bilirubin levels (P < 0.005 versus SMT), the Prometheus device being more effective than MARS (P = 0.002). Only MARS showed significant improvement in the mean arterial pressure (Δchange, +9 ± 2.4 mmHg versus -0.3 ± 2.4 mmHg with Prometheus and -5.2 ± 2.1 mmHg with SMT, P < 0.05) and in the systemic vascular resistance index (Δchange, +131.5 ± 46.2 dyne.s/cm5/m2 versus -92.8 ± 85.2 dyne.s/cm5/m2with Prometheus and -30.7 ± 32.5 dyne.s/cm5/m2 with SMT; P < 0.05), while the cardiac index and central filling remained constant. This circulatory improvement in the MARS group was paralleled by a decrease in plasma renin activity (P < 0.05), aldosterone (P < 0.03), norepinephrine (P < 0.05), vasopressin (P = 0.005) and nitrate/nitrite levels (P < 0.02). Conclusion The MARS device, and not the Prometheus device, significantly attenuates the hyperdynamic circulation in acute-on-chronic liver failure, presumably by a difference in removal rate of certain vasoactive substances. These findings suggest conspicuous conceptual differences among the albumin dialysis devices.
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Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Alexander Wilmer
- Department of Medical Intensive Care, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Pieter Evenepoel
- Department of Nephrology, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Ingrid Vander Elst
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Marcel Zeegers
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Zahur Zaman
- Department of Laboratory Medicine, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Chris Verslype
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Johan Fevery
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
| | - Frederik Nevens
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
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Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M, Zaman Z, Verslype C, Fevery J, Nevens F. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2006. [PMID: 16859530 PMCID: PMC4092483 DOI: 10.1186/cc4455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium.
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Dancu MB, Tarbell JM. Large Negative Stress Phase Angle (SPA) attenuates nitric oxide production in bovine aortic endothelial cells. J Biomech Eng 2006; 128:329-34. [PMID: 16706582 DOI: 10.1115/1.1824120] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Hemodynamics plays an important role in cardiovascular physiology and pathology. Pulsatile flow (Q), pressure (P), and diameter (D) waveforms exert wall shear stress (WSS), normal stress, and circumferential strain (CS) on blood vessels. Most in vitro studies to date have focused on either WSS or CS but not their interaction. Recently, we have shown that concomitant WSS and CS affect EC biochemical response modulated by the temporal phase angle between WSS and CS (stress phase angle, SPA). Large negative SPA has been shown to occur in regions of the circulation where atherosclerosis and intimal hyperplasia are prevalent. Here, we report that nitric oxide (NO) biochemical secretion was significantly decreased in response to a large negative SPA of -180 deg with respect to an SPA of 0 degrees in bovine aortic endothelial cells (BAEC) at 5 h. A new hemodynamic simulator for the study of the physiologic SPA was used to provide the hemodynamic conditions of pro-atherogenic (SPA = -180 deg) and normopathic (SPA = 0 deg) states. The role of complex hemodynamics in vascular remodeling, homeostasis, and pathogenesis can be advanced by further assessment of the hypothesis that a large negative SPA is pro-atherogenic.
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Affiliation(s)
- Michael B Dancu
- Biomolecular Transport Dynamics Laboratory, Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA.
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Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006; 43:S121-31. [PMID: 16447289 DOI: 10.1002/hep.20993] [Citation(s) in RCA: 393] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.
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Affiliation(s)
- Yasuko Iwakiri
- Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT 06516, USA
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33
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Ackerman Z, Karmeli F, Pizov G, Ben-Dov I, Pappo O. Renal effects of gentamicin in chronic bile duct ligated rats. Dig Dis Sci 2006; 51:406-15. [PMID: 16534689 DOI: 10.1007/s10620-006-3145-8] [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] [Received: 02/21/2005] [Accepted: 04/20/2005] [Indexed: 12/09/2022]
Abstract
Patients with advanced cirrhosis and rats with short-term bile duct ligation (BDL) are prone to develop nephrotoxicity from aminoglycosides. In this study, we characterized the renal response to gentamicin in rats with chronic BDL. BDL and sham-operated (SO) rats were given gentamicin (20 and 40 mg/kg/d) for 7 consecutive days, starting on the 18th postoperative day. Administration of gentamicin to SO group caused a decrease in cortical and medullary prostaglandin E(2)(PGE(2)) generation. However, mild reduction in creatinine clearance and an increase in fractional excretion of sodium occurred only in the BDL rats given the high gentamicin dose. This was accompanied by a reduction in cortical and medullary PGE(2) generation and a reduction in plasma nitric oxide production. In conclusion, gentamicin administration to rats with chronic BDL causes impairment of renal function. This happens only after the occurrence of simultaneous multiple insults to the renal protective mechanisms.
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Affiliation(s)
- Zvi Ackerman
- Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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Tahseldar-Roumieh R, Ghali-Ghoul R, Lugnier C, Sabra R. Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis. Am J Physiol Heart Circ Physiol 2006; 290:H481-8. [PMID: 16373593 DOI: 10.1152/ajpheart.00507.2005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Previous studies suggested that increased activity of phosphodiesterase (PDE)5 in the kidneys of cirrhotic rats contributes to sodium retention. This study examined the role of PDE5 in the changes in vascular reactivity, hemodynamics, and sodium excretion in rats with liver cirrhosis. Four weeks after bile duct ligation (BDL) or sham operation (SO), in vitro reactivity of aortic rings to various agents and in vivo effects of a PDE5-selective inhibitor [1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4d]-pyrimidin-4-(5H)-one, DMPPO] were studied. The vasodilator responses to nitroglycerin and S-nitroso-N-acetyl-penicillamine (SNAP) in phenylephrine-precontracted rings without endothelium were attenuated in BDL compared with SO rats. Pretreatment with DMPPO (0.1 microM) enhanced these responses and eliminated the differences between the two groups. Vasodilation to DMPPO itself was also less in BDL rats. The responses to phenylephrine were attenuated in endothelium-rich aorta from BDL relative to SO rats, but they were similar in endothelium-denuded aorta and remained similar despite preincubation with SNAP (0.1 microM) alone or with SNAP and DMPPO. In vivo, BDL rats were vasodilated relative to SO rats; DMPPO (5 mg/kg i.v.) decreased arterial pressure and vascular resistance in both groups equally and caused significant increase in sodium excretion in BDL rats only. In conclusion, the results are in accordance with a possible increase in PDE5 activity in aorta and kidney of cirrhotic rats that results in reduced responses to NO donors and contributes to the increase in sodium retention. PDE5 inhibitors may ameliorate sodium retention in cirrhosis but may worsen vasodilation. Examining the effect of PDE5 inhibitors after chronic administration will be more revealing.
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Affiliation(s)
- Rima Tahseldar-Roumieh
- Dept. of Pharmacology and Therapeutics, Faculty of Medicine, American Univ. of Beirut, Beirut, Lebanon
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Abstract
Portal hypertension (PHT) is responsible for the more severe and often lethal complications of cirrhosis such as bleeding oesophageal varices, ascites, renal dysfunction and hepatic encephalopathy. Because of the combined impact of these complications, PHT remains the most important cause of morbidity and mortality in patients with cirrhosis. Over the years, it has become clear that a decrease in portal pressure is not only protective against the risk of variceal (re)bleeding but is also associated with a lower long-term risk of developing complications and an improved long-term survival. A milestone in therapy was the introduction of non-selective beta-blockers for the prevention of bleeding and rebleeding of gastro-esophageal varices. However, in practice, less than half the patients under beta-blockade are protected from these risks, supporting the overall demand for innovation and expansion of our therapeutic armamentarium. Recent advances in the knowledge of the pathophysiology of cirrhotic PHT have directed future therapy towards the increased intrahepatic vascular resistance, which, in part, is determined by an increased hepatic vascular tone. This increased vasculogenic component provides the rationale for the potential use of therapies aimed at increasing intrahepatic vasorelaxing capacity via gene therapy, liver-selective nitric oxide donors and statines on the one hand, and at antagonizing excessive intrahepatic vasoconstrictor force through the use of endothelin antagonists, angiotensin blockers, alpha(1) adrenergic antagonists or combined alpha(1)- and non-selective beta-blockers or somatostatin analogues on the other. The focus of this review is to give an update on the pathophysiology of PHT in order to elucidate these potential novel strategies subsequently.
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Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
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Ferlitsch A, Pleiner J, Mittermayer F, Schaller G, Homoncik M, Peck-Radosavljevic M, Wolzt M. Vasoconstrictor hyporeactivity can be reversed by antioxidants in patients with advanced alcoholic cirrhosis of the liver and ascites. Crit Care Med 2005; 33:2028-33. [PMID: 16148476 DOI: 10.1097/01.ccm.0000178173.27923.eb] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Hyperdynamic circulation and systemic vasodilation complicate cirrhosis of the liver and are related to vasoconstrictor hyporeactivity. We investigated whether impaired vasoconstrictor responsiveness may be overcome by antioxidants in patients with decompensated alcoholic cirrhosis. DESIGN Controlled clinical study. SETTING University setting. PATIENTS Nine patients with liver cirrhosis Child-Pugh grade C and nine healthy age-matched volunteers. INTERVENTIONS Forearm blood flow responses to intra-arterial norepinephrine, angiotensin II, and the nitric oxide synthase inhibitor N-monomethyl-l-arginine were measured by strain-gauge plethysmography and compared between groups of patients. To assess the role of oxidative stress, the antioxidant vitamin C (24 mg/min) was administered locally into the brachial artery, and forearm blood flow responses were reassessed. MEASUREMENTS AND MAIN RESULTS Plasma concentrations of vitamin C were lower in patients with cirrhosis (p < .05). In patients with cirrhosis, the reactivity to norepinephrine and angiotensin II was markedly reduced (p < .05 vs. controls). Coadministration of vitamin C completely restored the potency of vasoconstrictors to that in controls but had no effect in healthy subjects. No changes were observed in time-control experiments in cirrhosis patients (n = 3) employing vehicle coinfusion. The response to N-monomethyl-L-arginine was comparable between groups and not affected by vitamin C. CONCLUSIONS Oxidative stress with consumption of antioxidants seems to play an important role in the development of vasoconstrictor hyporeactivity in patients with cirrhosis. Antioxidant therapy may be a promising clinical approach to restore vasoconstrictor hyporeactivity in these patients.
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Affiliation(s)
- Arnulf Ferlitsch
- Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, University of Vienna, Austria
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37
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Jurzik L, Froh M, Straub RH, Schölmerich J, Wiest R. Up-regulation of nNOS and associated increase in nitrergic vasodilation in superior mesenteric arteries in pre-hepatic portal hypertension. J Hepatol 2005; 43:258-65. [PMID: 15963596 DOI: 10.1016/j.jhep.2005.02.036] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2004] [Revised: 02/03/2005] [Accepted: 02/16/2005] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS Splanchnic arterial vasodilation in portal hypertension has been attributed largely to vascular NO overproduction. Three NO-synthase (NOS) isoforms have been identified of which e(ndothelial)-NOS has been found up-regulated and i(nducible)-NOS not expressed in the splanchnic circulation in portal hypertension. So far, n(euronal)-NOS has not been investigated and hence, the current study evaluates nNOS-expression and nNOS-mediated vasorelaxation in a model of portal vein-ligated rats (PVL). METHODS Mesenteric vasculature of PVL and sham rats was evaluated for nNOS-protein (immunohistochemically and Western blotting). In vitro perfused de-endothelialized mesenteric arterial vasculature was pre-constricted with norepinephrine (EC(80)) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with the NOS-inhibitor L-NAME (10(-4)M). RESULTS nNOS was localized to the adventitia of the mesenteric arterial tree showing more intense staining and increased protein expression in PVL as compared to sham rats. PNS induced a frequency-dependent vasorelaxation, which was more pronounced in PVL rats. L-NAME abolished this difference in nerval-mediated vasorelaxation, the effect being significantly greater in PVL than in sham animals. CONCLUSIONS Perivascular nNOS-protein expression is enhanced in mesenteric arteries in portal hypertension mediating an increased nerval NO-mediated vasorelaxation. This nNOS-derived NO overproduction may play an important role in the pathogenesis of arterial vasodilation in portal hypertension.
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MESH Headings
- Animals
- Blotting, Western
- Disease Models, Animal
- Endothelium, Vascular/enzymology
- Endothelium, Vascular/pathology
- Enzyme Inhibitors/pharmacology
- Hypertension, Portal/enzymology
- Hypertension, Portal/physiopathology
- Immunohistochemistry
- Male
- Mesenteric Artery, Superior/drug effects
- Mesenteric Artery, Superior/enzymology
- Mesenteric Artery, Superior/pathology
- Mesenteric Artery, Superior/physiopathology
- NG-Nitroarginine Methyl Ester/pharmacology
- Nerve Tissue Proteins/biosynthesis
- Nitric Oxide/biosynthesis
- Nitric Oxide Synthase/biosynthesis
- Nitric Oxide Synthase Type I
- Rats
- Rats, Sprague-Dawley
- Up-Regulation/drug effects
- Up-Regulation/physiology
- Vasodilation/drug effects
- Vasodilation/physiology
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Affiliation(s)
- Lars Jurzik
- Department of Internal Medicine, University School of Medicine, 93042 Regensburg, Germany
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Erario MA, Gonzales S, Romay S, Eizayaga FX, Castro JL, Lemberg A, Tomaro ML. Role of heme oxygenase/carbon monoxide pathway on the vascular response to noradrenaline in portal hypertensive rats. Clin Exp Pharmacol Physiol 2005; 32:196-201. [PMID: 15743403 DOI: 10.1111/j.1440-1681.2005.04171.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.
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Affiliation(s)
- M A Erario
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
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Wei CL, Hon WM, Lee KH, Khoo HE. Chronic administration of aminoguanidine reduces vascular nitric oxide production and attenuates liver damage in bile duct-ligated rats. Liver Int 2005; 25:647-56. [PMID: 15910502 DOI: 10.1111/j.1478-3231.2005.01063.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Nitric oxide (NO) has been implicated in the pathogenesis of liver cirrhosis. This study investigated the activity of nitric oxide synthase (NOS) in cirrhosis induced by bile duct-ligation (BDL) with NOS inhibitors. METHOD Three days after operation, rats were randomized to receive aminoguanidine (AG, 25 mg/kg/day) or L-N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg/day) for 21 days. RESULTS Vascular NO production, which was increased in BDL cirrhotic rats, was reduced by 75% with AG but not L-NAME chronic administration. AG treatment attenuated liver damage, while L-NAME aggravated it. AG significantly suppressed inducible NOS (iNOS) expression in aorta of BDL rats at both mRNA and protein level, but much less efficient in reducing it in liver. In contrast, endothelial NOS (eNOS) expression was not markedly affected. Calcium-independent NOS activity, which was dramatically increased in aorta of BDL rats, was abolished by AG treatment. In liver, however, both calcium-dependent and -independent NOS activity were increased by AG treatment. CONCLUSION Chronic administration of AG could reduce systemic NO levels as well as suppress iNOS expression and activity in aorta of BDL rats. It also improved liver function, possibly because of its ability to increase hepatic NOS activity, and to correct the systemic hemodynamic disorders by decreasing vascular NO production.
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Affiliation(s)
- Chang-Li Wei
- Department of Paediatrics, Faculty of Medicine, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore
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40
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Wu ZY, Chen XS, Qiu JF, Cao H. Role of PGI 2 in the formation and maintenance of hyperdynamic circulatory state of portal hypertensive rats. World J Gastroenterol 2005; 11:752-5. [PMID: 15655838 PMCID: PMC4250755 DOI: 10.3748/wjg.v11.i5.752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of prostacyclin (PGI2) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.
METHODS: Ninety male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) group by injection of CCl4, prehepatic portal hypertension (PHPH) group by partial stenosis of the portal vein and sham-operation control (SO) group. One week after the models were made, animals in each group were subdivided into 4 groups: saline controlled group (n = 23), Nω-nitro-L-arginine (L-NNA)group (n = 21) group, indomethacin (INDO) group (n = 22) and high-dose heparin group (n = 24). The rats were administrated 1mL of saline, L-NNA (3.3 mg/kg·d) and INDO (5 mg/kg·d) respectively through gastric tubes for one week,then heparin (200 IU/Kg/min) was given to rats by intravenous injection for an hour. Splanchnic and systemic hemodynamics were measured using radioactive microsphere techniques. The serum nitrate/nitrite(NO2-/NO3-) levels as a marker of production of NO were assessed by a colorimetric method, and concentration of 6-keto-PGF1α, a stable hydrolytic product of PGI2, was determined by radioimmunoassay.
RESULTS: The concentrations of plasma 6-keto-PGF1α (pg/mL) and serum NO2-/NO3- (μmol/L) in IHPH rats (1123.85±153.64, 73.34±4.31) and PHPH rats (891.88±83.11, 75.21±6.89) were significantly higher than those in SO rats(725.53±105.54, 58.79±8.47) (P<0.05). Compared with SO rats, total peripheral vascular resistance (TPR) and splanchnic vascular resistance (SVR) decreased but cardiac index (CI) and portal venous inflow (PVI) increased obviously in IHPH and PHPH rats (P<0.05). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGF1α and serum NO2-/NO3-in IHPH and PHPH rats (P<0.05) .Meanwhile, CI, FPP and PVI lowered but MAP,TPR and SVR increased(P<0.05). After deduction of the action of NO, there was no significant correlation between plasma PGI2 level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of the action of PGI2, NO still correlated highly with the hemodynamic parameters, indicating that there was a close correlation between NO and the hemodynamic parameters. After administration of high-dose heparin, plasma 6-keto-PGF1α concentrations in IHPH, PHPH and SO rats were significantly higher than those in rats administrated vehicle (P<0.05). On the contrary, levels of serum NO2-/NO3- in IHPH, PHPH and SO rats were significantly lower than those in rats administrated Vehicle (P<0.05). Compared with those rats administrated vehicle, the hemodynamic parameters of portal hypertensive rats, such as CI and PVI, declined significantly after administration of high-dose heparin (P<0.05), while TPR and SVR increased significantly (P<0.05).
CONCLUSION: It is NO rather than PGI2 that is a mediator in the formation and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.
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Affiliation(s)
- Zhi-Yong Wu
- Department of General Surgery, Renji Hospital, 1630 Dongfang Road, Shanghai 200127, China.
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Moreira AJ, Fraga C, Alonso M, Collado PS, Zetller C, Marroni C, Marroni N, González-Gallego J. Quercetin prevents oxidative stress and NF-kappaB activation in gastric mucosa of portal hypertensive rats. Biochem Pharmacol 2005; 68:1939-46. [PMID: 15476665 DOI: 10.1016/j.bcp.2004.07.016] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2004] [Accepted: 07/12/2004] [Indexed: 02/07/2023]
Abstract
The present study was designed to investigate the effects of quercetin on oxidative stress and activation of nuclear factor kappa B (NF-kappaB) in an experimental model of portal hypertensive gastropathy induced by partial portal vein ligation (PPVL). Portal pressure was significantly elevated in PPVL rats. Transaminase and alkaline phosphatase activities were not significantly modified, indicating absence of liver injury. Histological analysis of gastric sections showed a lost of normal architecture, with edema and vasodilatation. The cytosolic concentration of thiobarbituric acid reactive substances and the lipoperoxidation measurement by chemiluminiscence were significantly increased. Superoxide dismutase activity in gastric mucosa was significantly reduced. Portal hypertensive gastropathy induced a marked activation of NF-kappaB, accompanied by a decrease in IkappaB protein levels and a significant induction of nitric oxide synthase (iNOS) protein. Administration of quercetin markedly alleviated histological abnormalities and inhibited oxidative stress and NF-kappaB activation. IkappaB decrease and induction of iNOS protein were partially prevented by quercetin. Quercetin treatment, by abolishing the NF-kappaB signal transduction pathway, may block the production of noxious mediators involved in the pathogenesis of portal hypertensive gastropathy.
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Affiliation(s)
- Andrea J Moreira
- Universidade Federal de Rio Grande do Sul and Universidade Luterana do Brasil, Brazil
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Wei CL, Hon WM, Lee KH, Khoo HE. Temporal expression of hepatic inducible nitric oxide synthase in liver cirrhosis. World J Gastroenterol 2005; 11:362-7. [PMID: 15637745 PMCID: PMC4205338 DOI: 10.3748/wjg.v11.i3.362] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Nitric oxide (NO) has been implicated in the pathogenesis of liver cirrhosis. We have found inducible nitric oxide synthase (iNOS) can be induced in hepatocytes of cirrhotic liver. This study further investigated the temporal expression and activity of hepatic iNOS in cirrhosis development.
METHODS: Cirrhosis was induced in rats by chronic bile duct ligation (BDL). At different time points after the operation, samples were collected to examine NO concentration, liver function, and morphological changes. Hepatocytes were isolated for determination of iNOS mRNA, protein and enzymatic activity.
RESULTS: Histological examination showed early cirrhosis 1-2 wk after BDL, with advanced cirrhosis at 3-4 wk. Bilirubin increased dramatically 3 d after BDL, but decreased by 47% on d 14. Three weeks after BDL, it elevated again. Systemic NO concentration did not increase significantly until 4 wk after BDL, when ascites developed. Hepatocyte iNOS mRNA expression was identified 3 d after BDL, and enhanced with time to 3 wk, but reduced thereafter. iNOS protein showed a similar pattern to mRNA expression. iNOS activity decreased from d 3 to d 7, but increased again thereafter till d 21.
CONCLUSION: Hepatic iNOS can be induced in the early stage, which increases with time as cirrhosis develops. Its enzymatic activity is significantly correlated with protein expression and histological alterations of the liver, but not with systemic NO levels, nor with absolute values of liver function markers.
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Affiliation(s)
- Chang-Li Wei
- Department of Biochemistry, Faculty of Medicine, National University of Singapore, 119260, Singapore
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Finley DS, Lugo B, Ridgway J, Teng W, Imagawa DK. Fatal variceal rupture after sildenafil use: Report of a case. ACTA ACUST UNITED AC 2005; 62:55-6. [PMID: 15708146 DOI: 10.1016/j.cursur.2004.06.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Sildenafil may increase the risk of variceal bleeding in portal hyptertension by increasing splanchnic blood flow. We report herein the second case of variceal rupture after sildenafil use.
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Affiliation(s)
- David S Finley
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, University of California, Irvine, Orange, California 92868, USA.
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44
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Biecker E, Neef M, Sägesser H, Shaw S, Koshy A, Reichen J. Nitric oxide synthase 1 is partly compensating for nitric oxide synthase 3 deficiency in nitric oxide synthase 3 knock-out mice and is elevated in murine and human cirrhosis. Liver Int 2004; 24:345-53. [PMID: 15287858 DOI: 10.1111/j.1478-3231.2004.0933.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND The role of endothelial nitric oxide synthase 3 (NOS-3) in the hyperdynamic circulation associated with cirrhosis is established but not that of the neuronal (NOS-1) isoform. We therefore investigated aortic NOS-1 levels in NOS-3 knock-out (KO) and wildtype (WT) mice and in hepatic arteries of patients. METHODS Mice rendered cirrhotic by bile duct ligation (BDL) were compared with sham-operated controls. Hepatic arteries of cirrhotic patients were collected during liver transplantation; donor vessels served as controls. mRNA levels were quantified by real-time PCR, protein levels by Western blotting and NO production by Nomega-nitro-L-arginine methyl ester inhibitable arginine-citrulline assay. RESULTS Aortae of NOS-3 KO mice exhibited higher NOS-1mRNA (5.6-fold, P < 0.004) and protein levels (8.8-fold) compared with WT. NO production in aortae of NOS-3 KO mice was 52% compared with WT (P = 0.002). BDL increased NOS-1 mRNA (2.4-fold, P = 0.01) and protein (7.1-fold) levels in aortae of WT, but no further in the NOS-3 KO mice. Hepatic artery NOS-1 mRNA levels in cirrhotic patients were markedly increased compared with controls (24.5-fold, P = 0.0007). CONCLUSIONS Increased NOS-1 mRNA and protein levels and partially maintained in vitro NO-production in aortae of NOS-3 KO mice suggest that NOS-1 may partially compensate for NOS-3 deficiency. BDL-induced increase in aortic NOS-1 mRNA and protein levels hint that not only NOS-3, but also NOS-1 may be involved in the regulation of systemic hyperdynamic circulation and portal hypertension. Upregulation of NOS-1 mRNA levels in hepatic arteries of portal hypertensive patients suggests possible clinical significance for these experimental findings.
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Affiliation(s)
- Erwin Biecker
- Department of Clinical Pharmacology, University of Berne, Murtenstrasse, Switzerland
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Abstract
AIM: To determine the role and effect of nitric oxide synthase type II (NOS II) in cirrhotic rats.
METHODS: Expression of NOS II mRNA was detected by real time RT-PCR. The activity of nitric oxide synthase and serum levels of NO, systemic and portal hemodynamics and degrees of cirrhosis were measured with high sensitive methods. Chinese traditional medicine tetrandrine was used to treat cirrhotic rats and to evaluate the function of NO. Double-blind method was applied during the experiment.
RESULTS: The concentration of NO and the activity of NOS were increased markedly at all stages of cirrhosis, and iNOSmRNA was greatly expressed. Meanwhile the portal-venous-pressure (PVP), and portal-venous-flow (PVF) were significantly increased. NO, NOS and iNOSmRNA were positively correlated to the quantity of hepatic fibrosis. Tetrandrine significantly inhibited NO production and the expression of iNOSmRNA.
CONCLUSION: Increased hepatic expression of NOS II is one of the important causes of hepatic cirrhosis and portal hypertension.
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Affiliation(s)
- Hai Wang
- Liver Center of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Abstract
Hepatopulmonary syndrome is defined by oxygenation impairment due to abnormal intrapulmonary vascular dilatations in patients with liver disease. The implication of enhanced pulmonary production of nitric oxide in the pathogenesis of intrapulmonary vascular dilatations has been demonstrated both in murine models and in human hepatopulmonary syndrome. The diagnosis of hepatopulmonary syndrome in chronic liver disease is of paramount importance, considering the fact that severe hypoxemia related to hepatopulmonary syndrome may occur in patients with well compensated liver disease and that survival is reduced in patients with hepatopulmonary syndrome relative to non hepatopulmonary syndrome patients. Priority for liver transplantation, which is presently the only cure, has been recently increased in patients with advanced hepatopulmonary syndrome.
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Affiliation(s)
- G Rolla
- Allergology and Clinical Immunology, Department of Human Oncology, University of Torino, Mauriziano Umberto I Hospital, Largo Turati 62, Turin 10128, Italy.
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Biecker E, Sägesser H, Reichen J. Vasodilator mRNA levels are increased in the livers of portal hypertensive NO-synthase 3-deficient mice. Eur J Clin Invest 2004; 34:283-9. [PMID: 15086360 DOI: 10.1111/j.1365-2362.2004.01331.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND/AIMS Nitric oxide synthase (NOS) 3-deficient (NOS-3 KO) mice have an increased systemic arterial pressure but develop portal hypertension to the same extent as wildtype (WT) mice. We hypothesized that other vasodilators in the portal circulation compensate for the lack in NOS-3 activity. We used quantitative PCR as a screening method to identify mediators that possibly compensate for NOS-3 in NOS-3 KO mice. METHODS Mean arterial pressure (MAP) and portal venous pressure (PVP) were measured in the anaesthetized animal. mRNA levels in whole liver tissue were determined by quantitative RT-PCR. RESULTS NOS-3 KO mice had a significantly higher mean arterial pressure than WT mice, but portal venous pressure did not differ. Bile duct ligation (BDL) induced a drop in MAP and a rise in PVP in both groups. Bile duct ligation induced a significant increase in mRNA levels of the cannabinoid receptor (CB)-1, adrenomedullin and NOS-2 in the liver of NOS-3 KO and WT mice. Nitric oxide synthase-1 and NOS-3 mRNA levels were elevated in BDL WT mice compared with sham-operated WT mice. Higher mRNA levels of CB-1, NOS-1 and the adrenomedullin receptor were found in sham-operated NOS-3 KO mice compared with sham-operated WT mice. CONCLUSIONS We used quantitative PCR as a screening method to identify vasodilative mediators that might be involved in the compensation for the lack of NOS-3 activity in NOS-3 KO mice. Elevated mRNA levels in sham-operated NOS-3 KO mice compared with sham-operated WT mice were demonstrated for CB-1, NOS-1 and the adrenomedullin receptor.
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Affiliation(s)
- E Biecker
- Department of Clinical Pharmacology, University of Berne, Berne, Switzerland.
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Cárdenas A, Arroyo V. Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites. Best Pract Res Clin Endocrinol Metab 2003; 17:607-22. [PMID: 14687592 DOI: 10.1016/s1521-690x(03)00052-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Patients with advanced cirrhosis and portal hypertension often show an abnormal regulation of extracellular fluid volume, resulting in the accumulation of fluid as ascites, pleural effusion or oedema. The mechanisms responsible for ascites formation include alterations in the splanchnic circulation as well as renal functional abnormalities that favour sodium and water retention. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increase cardiac output, a reduction in total vascular resistance and an activation of neurohormonal vasoactive systems. This circulatory dysfunction, due mainly to intense arterial vasodilation in the splanchnic circulation, is considered to be a primary feature in the pathogenesis of ascites. A major factor involved in the development of splanchnic arterial vasodilation is nitric oxide (NO), a potent vasodilator that is elevated in the splanchnic circulation of patients with cirrhosis. This event decreases effective arterial blood volume and leads to fluid accumulation and renal function abnormalities which are a consequence of the homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction. The mechanisms of sodium and water retention and ascites formation in patients with cirrhosis are discussed in this review.
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Affiliation(s)
- Andrés Cárdenas
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Dana 501, Boston, MA 02215, USA
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Ai JH, Yang Z, Qiu FZ, Zhu T. Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats. World J Gastroenterol 2003; 9:2544-7. [PMID: 14606093 PMCID: PMC4656537 DOI: 10.3748/wjg.v9.i11.2544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the participation of HSP90 in portal hypertensive rat mesentery in vitro.
METHODS: immunohistochemistry and Western-blot were used to examine the expression of HSP90 in mesenteric vasculature. HSP90 mRNA was detected by RT-PCR, and the role of HSP90 in hyperdynamic circulation was examined by in vitro mesenteric perfusion studies.
RESULTS: HSP90 was overexpressed in endothelium of mesentery vasculature in animals with experimental portal hypertension induced by partial portal vein ligation (PVL) compared with normal animals. Geldanamycin (GA), a special inhibitor of HSP90 signaling, attenuated ACh-dependent vasodilation but did not affect vasodilation in response to sodium nitroprusside in normal rats. In PVL animals, the perfused mesentery was hyporesponsive to vasoconstrictor methoxamine. GA significantly potentiated methoxamine-induced vasoconstrictor after PVL.
CONCLUSION: HSP90 plays a key role in NO-dependent hyperdynamic circulation in portal hypertension and provides a novel method for future treatment of portal hypertension.
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Affiliation(s)
- Jian-Hua Ai
- Center for Hepatic Surgery, Tongi Hospital, Tongi Medical College, Huazhong Science and Technological University, Wuhan, Hubei Province, China.
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Tsai MH, Iwakiri Y, Cadelina G, Sessa WC, Groszmann RJ. Mesenteric vasoconstriction triggers nitric oxide overproduction in the superior mesenteric artery of portal hypertensive rats. Gastroenterology 2003; 125:1452-61. [PMID: 14598261 DOI: 10.1016/j.gastro.2003.07.014] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Vasoconstriction of the superior mesenteric artery (SMA) is the earliest hemodynamic event occurring after partial portal vein ligation (PVL). We tested the hypothesis that this early vasoconstriction of the SMA may initiate eNOS up-regulation in PVL. METHODS Portal hypertension with or without mesenteric vasoconstriction was induced by differentially calibrated stenosis of the portal vein (PVL-20G and PVL-18G, respectively). In a separate group of rats, mesenteric vasoconstriction was achieved by renal artery ligation. Sham-operated rats were used as controls. Effects of vasoconstriction of the SMA in PVL and RAL rats were evaluated by measuring perfusion pressure changes in isolated SMA beds in response to methoxamine, nitric oxide synthase activity, and eNOS protein expression. Mean arterial pressure, portal pressure, and SMA blood flow were measured by catheterization and Doppler flowmetry. SMA vascular resistance was calculated from arterial pressure, portal pressure, and SMA flow. RESULTS There was a significant increase in SMA vascular resistance in PVL-20G (2.33 +/- 0.13 vs. 1.22 +/- 0.03 mm Hg/% flow; P < 0.05) and RAL (2.32 +/- 0.18 vs. 1.18 +/- 0.02 mm Hg/% flow; P < 0.05) but not in PVL-18G, showing mesenteric vasoconstriction in both PVL-20G and RAL groups. The mesenteric vasculature of PVL-20G and RAL animals showed hyporeactivity to methoxamine (P < 0.01). Whereas both PVL groups were portal hypertensive (P < 0.01), RAL rats were not. The SMA hyporeactivity of PVL-20G and RAL rats was corrected by N(G)()-monomethyl-L-arginine, and nitric oxide synthase enzyme activity was significantly higher in PVL-20G and RAL rats (P < 0.05). CONCLUSIONS Mesenteric arterial vasoconstriction plays a triggering role in up-regulation of eNOS catalytic activity in the SMA of portal hypertensive rats.
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Affiliation(s)
- Ming-Hung Tsai
- Hepatic Hemodynamic Laboratory, Veterans Administration Medical Center, 950 Campbell Avenue, West Haven, CT 06516, USA
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