|
1
|
Ramkissoon R, Cao S, Shah VH. The Pathophysiology of Portal Hypertension. Clin Liver Dis 2024; 28:369-381. [PMID: 38945632 DOI: 10.1016/j.cld.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
This article reviews the pathophysiology of portal hypertension that includes multiple mechanisms internal and external to the liver. This article starts with a review of literature describing the cellular and molecular mechanisms of portal hypertension, microvascular thrombosis, sinusoidal venous congestion, portal angiogenesis, vascular hypocontractility, and hyperdynamic circulation. Mechanotransduction and the gut-liver axis, which are newer areas of research, are reviewed. Dysfunction of this axis contributes to chronic liver injury, inflammation, fibrosis, and portal hypertension. Sequelae of portal hypertension are discussed in subsequent studies.
Collapse
Affiliation(s)
- Resham Ramkissoon
- Department of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA
| | - Sheng Cao
- Mayo College of Medicine, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA
| | - Vijay H Shah
- Department of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA; Department of Internal Medicine, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA.
| |
Collapse
|
|
2
|
Sauerbruch T, Hennenberg M, Trebicka J, Schierwagen R. Beta-blockers in patients with liver cirrhosis: Pragmatism or perfection? Front Med (Lausanne) 2023; 9:1100966. [PMID: 36743678 PMCID: PMC9891090 DOI: 10.3389/fmed.2022.1100966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/12/2022] [Indexed: 01/11/2023] Open
Abstract
With increasing decompensation, hyperdynamic circulatory disturbance occurs in liver cirrhosis despite activation of vasoconstrictors. Here, the concept of a therapy with non-selective beta-blockers was established decades ago. They lower elevated portal pressure, protect against variceal hemorrhage, and may also have pleiotropic immunomodulatory effects. Recently, the beneficial effect of carvedilol, which blocks alpha and beta receptors, has been highlighted. Carvedilol leads to "biased-signaling" via recruitment of beta-arrestin. This effect and its consequences have not been sufficiently investigated in patients with liver cirrhosis. Also, a number of questions remain open regarding the expression of beta-receptors and its intracellular signaling and the respective consequences in the intra- and extrahepatic tissue compartments. Despite the undisputed role of non-selective beta-blockers in the treatment of liver cirrhosis, we still can improve the knowledge as to when and how beta-blockers should be used in which patients.
Collapse
Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
| |
Collapse
|
|
3
|
Wong F, Sauerbruch T. Terlipressin in Liver Cirrhosis. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:149-166. [DOI: 10.1007/978-981-19-2615-0_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
4
|
Sauerbruch T, Hennenberg M, Trebicka J, Beuers U. Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction. Front Physiol 2021; 12:718783. [PMID: 34393832 PMCID: PMC8358446 DOI: 10.3389/fphys.2021.718783] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
Collapse
Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology I, University Hospital, LMU Munich, Munich, Germany
| | - Jonel Trebicka
- Translational Hepatology, Medical Department, University of Frankfurt, Frankfurt, Germany
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
| |
Collapse
|
|
5
|
Abstract
Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.
Collapse
Affiliation(s)
- Joseph J. Alukal
- Institute of Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, Maryland, USA
| | - Savio John
- Division of Gastroenterology, Department of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Paul J. Thuluvath
- Institute of Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, Maryland, USA
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
6
|
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: 41] [Impact Index Per Article: 8.2] [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.
Collapse
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
| |
Collapse
|
|
7
|
Fais P, Leopizzi M, Di Maio V, Longo L, Della Rocca C, Tagliaro F, Bortolotti F, Lo Vasco VR. Phosphoinositide-specific phospholipase C in normal human liver and in alcohol abuse. J Cell Biochem 2019; 120:7907-7917. [PMID: 30426534 DOI: 10.1002/jcb.28067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 10/22/2018] [Indexed: 01/24/2023]
Abstract
The phosphoinositide (PI) signal transduction pathway participates in liver metabolism. Abnormal activity or expression of PI-specific phospholipase C (PLC) enzymes has been described in different liver diseases. We resume the role of the PI metabolism in liver and PLC abnormalities in different liver diseases. Moreover, we present the results of PLC analyses in a normal human liver and an alcohol-damaged liver. PLC enzymes and the expression of the corresponding genes in liver biopsies from individuals deceased for complications of the alcoholic liver disease (ALD) at different stages compared with normal controls (deceased individuals with histologically normal livers without alcohol addiction anamnesis) were analyzed by using immunohistochemistry and molecular biology techniques. The expression panel of PLCs was described in normal and alcohol abuse liver. Our observations suggest that the regulation of PLC expression might be due to posttranscriptional events and that alcohol affects the epigenetic control of PLC expression belonging to PI signaling. We also describe the alternate expression of PLCB1 and PLCH1 genes in liver. Our results corroborate literature data suggesting that PLC enzymes are differently expressed in normal versus pathological liver, playing a role in the histopathogenesis of liver tissue damage. The expression and/or localization of selected PLC isoforms is especially affected in alcohol-related liver tissue histopathology. Our present observations confirm that the modulation of protein synthesis plays a role in the regulation of PLC enzymes. We also suggest that this modulation might act at the transcription level. Further studies are required to investigate related epigenetic mechanisms.
Collapse
Affiliation(s)
- Paolo Fais
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Bologna, Italy
| | - Martina Leopizzi
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University, Latina, Italy
| | - Valeria Di Maio
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University, Latina, Italy
| | - Lucia Longo
- Department of Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Carlo Della Rocca
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University, Latina, Italy
| | - Franco Tagliaro
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Bologna, Italy.,Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University, Latina, Italy.,Department of Sensory Organs, Sapienza University of Rome, Rome, Italy.,Department of Diagnostics and Public Health, Unit of Forensic Medicine, University of Verona, Verona, Italy
| | - Federica Bortolotti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Bologna, Italy.,Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University, Latina, Italy.,Department of Sensory Organs, Sapienza University of Rome, Rome, Italy.,Department of Diagnostics and Public Health, Unit of Forensic Medicine, University of Verona, Verona, Italy
| | | |
Collapse
|
|
8
|
Annicchiarico BE, Santonocito C, Siciliano M, Scapaticci M, Guarino D, Di Stasi C, Riccioni ME, Di Stasio E, Capoluongo E, Gasbarrini A. ACE I allele is associated with more severe portal hypertension in patients with liver cirrhosis: A pilot study. Dig Liver Dis 2019; 51:293-296. [PMID: 30236768 DOI: 10.1016/j.dld.2018.08.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 08/03/2018] [Accepted: 08/04/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND In liver cirrhosis, the renin-angiotensin-aldosterone system is involved in the pathogenesis of portal hypertension. Its effector, angiotensin II, is generated by angiotensin-converting enzyme (ACE). Serum ACE levels are affected by I/D polymorphism of its gene, with alleles I and D being associated, respectively, with lesser and greater activity of the enzyme. In cirrhotic patients carrying the ACE I allele, an increased risk for gastro-oesophageal varices was observed. AIM The aim of our study was to evaluate whether ACE I/D polymorphism influenced portal pressure. METHODS Fifty-one consecutive cirrhotic patients were divided based on ACE genotype (DD, ID, and II). Kidney and liver function tests, upper endoscopy, and hepatic venous pressure gradient measurement (HVPG) were performed in all patients. RESULTS The presence of the ACE I allele was associated with a higher HVPG value (18.7±6.4 vs 10.3±6.3mmHg; P<.001), higher frequency of large gastrooesophageal varices (59.3% vs 25.0%; P<.05), and higher frequency of variceal bleeding (63.0% vs 29.2%; P<.05). No significant differences were found between patients with and those without the ACE I allele regarding Child-Pugh score, MELD score, ascites, and hepatic encephalopathy. CONCLUSION ACE I/D polymorphism seems to influence the severity of portal hypertension and the risk of variceal bleeding in liver cirrhosis, regardless of the severity of liver disease.
Collapse
Affiliation(s)
- Brigida E Annicchiarico
- Department of Internal Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Concetta Santonocito
- Laboratory of Clinical Molecular Biology, Department of Biochemistry & Clinical Biochemistry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy.
| | - Massimo Siciliano
- Department of Internal Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Margherita Scapaticci
- Laboratory of Clinical Molecular Biology, Department of Biochemistry & Clinical Biochemistry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy; Laboratory Medicine Department, San Camillo Hospital, Treviso, Italy
| | - Donatella Guarino
- Laboratory of Clinical Molecular Biology, Department of Biochemistry & Clinical Biochemistry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Carmine Di Stasi
- Department of Bioimaging and Radiological Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Maria E Riccioni
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Enrico Di Stasio
- Laboratory of Clinical Molecular Biology, Department of Biochemistry & Clinical Biochemistry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Ettore Capoluongo
- Laboratory of Clinical Molecular Biology, Department of Biochemistry & Clinical Biochemistry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of the Sacred Heart, Rome, Italy
| |
Collapse
|
|
9
|
Casey S, Herath C, Rajapaksha I, Jones R, Angus P. Effects of angiotensin-(1-7) and angiotensin II on vascular tone in human cirrhotic splanchnic vessels. Peptides 2018; 108:25-33. [PMID: 30179652 DOI: 10.1016/j.peptides.2018.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/14/2018] [Accepted: 08/14/2018] [Indexed: 12/12/2022]
Abstract
Evidence suggests that the renin angiotensin system (RAS) may play a role in the pathological splanchnic vasodilatation that leads to a hyperdynamic circulation in cirrhosis. An impaired contractile response to the angiotensin II peptide of the classical RAS system has been described in animal models of cirrhosis and in vivo in cirrhotic subjects. Furthermore, in experimental cirrhosis, the so-called alternate arm of the RAS was found to be upregulated and its effector peptide, angiotensin-(1-7) was shown to attenuate splanchnic vascular tone. The aim of this study was to explore the relevance of these findings to human disease. Omental arteries from cirrhotic and controls subjects were studied in isolation using a wire myograph. Varied protocols to evaluate the vasoactivity of RAS mediators were enacted. The contractile response to angiotensin II was comparable in cirrhotic vs control splanchnic arteries (61 ± 9 vs 68 ± 11% KPSS, respectively). Despite this, however, arterial contractility of the cirrhotic vessels correlated negatively with Child Pugh score (p = 0.0003, r=-0.83) and there was evidence that angiotensin II-induced contractility was increased in early cirrhosis. Angiotensin II-induced contractility was attenuated by angiotensin-(1-7) in cirrhotic and control arteries, however, adrenergic responses were not affected by angiotensin-(1-7). Contractile responses to angiotensin II are preserved in narrow lumen human cirrhotic splanchnic arteries and are comparatively augmented in early disease. Angiotensin-(1-7) had no vasodilatory effect on adrenergic tone, however, attenuated angiotensin II-induced contractility, possibly through an Ang-(1-7)-AT1R interaction, and thus may contribute to pathological vasodilatation in human cirrhosis.
Collapse
Affiliation(s)
- Stephen Casey
- Liver Unit, Austin Health, Melbourne, Australia; Department of Medicine, Austin Health, University of Melbourne, Australia.
| | - Chandana Herath
- Department of Medicine, Austin Health, University of Melbourne, Australia
| | - Indu Rajapaksha
- Department of Medicine, Austin Health, University of Melbourne, Australia
| | | | - Peter Angus
- Liver Unit, Austin Health, Melbourne, Australia; Department of Medicine, Austin Health, University of Melbourne, Australia
| |
Collapse
|
|
10
|
Kuroda S, Tashiro H, Kimura Y, Hirata K, Tsutada M, Mikuriya Y, Kobayashi T, Amano H, Tanaka Y, Ohdan H. Rho-kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats. Liver Transpl 2015; 21:123-31. [PMID: 25307969 DOI: 10.1002/lt.24020] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 09/22/2014] [Accepted: 10/04/2014] [Indexed: 02/07/2023]
Abstract
Rho-kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver-specific ROCK inhibition is required. Here, we tested vitamin A (VA)-coupled liposomes carrying the ROCK inhibitor Y-27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline-deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y-27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA-coupled liposome accumulation in livers. Liposomal Y-27632 was 100-fold more effective in inhibiting HSC activation than free Y-27632. Liposomal Y-27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y-27632 elicited severe systemic hypotension. We conclude that VA-coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity.
Collapse
Affiliation(s)
- Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Abstract
BACKGROUND Prostacyclin has been shown to increase portal hypertension, but the mechanism is unclear. This study aimed to investigate whether the overproduction of prostacyclin (PGI2) in cirrhosis participates in the splanchnic vascular hyporesponsiveness to vasoconstrictors in cirrhotic rats. METHODS Cirrhotic model was created by subcutaneous injection of 60% carbon tetrachloride (CCl4) corn oil solution combined with intermittent drinking of 5% alcohol, and age-matched rats served as controls. The isolated third-generation mesenteric arterioles were used to examine the contractile response to norepinephrine. The changes in vascular diameter were observed under a microscope imaging device. The plasma concentration of 6-ketone-prostaglandin F1alpha (6-keto-PGF1alpha, a stable metabolite of PGI2) was tested via enzyme immunoassays and the expression of cyclooxygenase (COX) in mesenteric arteries was detected by Western blotting. RESULTS In parallel with the increase of plasma 6-keto-PGF1alpha, the contractile response of arterioles from cirrhotic rats to norepinephrine was significantly impaired compared with that from controls. Inhibition of PGI2 or protein kinase A with indomethacin or Rp-adenosine 3', 5'-cyclic monophosphothioate (Rp-cAMPS) partially reversed the vascular hypo-contractile response to norepinephrine in arterioles from cirrhotic rats. Indomethacin significantly decreased the plasma 6-keto-PGF1alpha. Furthermore, indomethacin significantly attenuated the effect of Rp-cAMPS on arterioles from cirrhotic rats. COX-1 expression was up-regulated in mesenteric arteries from cirrhotic rats, whereas COX-2 was not detectable in the mesenteric arteries from both cirrhotic and control rats. CONCLUSION Enhanced COX-1 expression in cirrhotic rats resulted in elevated PGI2 production which partially contributed to the splanchnic vascular hyporesponsiveness to a vasoconstrictor via the protein kinase A pathway.
Collapse
|
|
12
|
Zhang B, Zhang CG, Zhou QB, Chen W, Wu ZY. Estrogen improves the hyperdynamic circulation and hyporeactivity of mesenteric arteries by alleviating oxidative stress in partial portal vein ligated rats. World J Gastroenterol 2013; 19:6863-6868. [PMID: 24187462 PMCID: PMC3812486 DOI: 10.3748/wjg.v19.i40.6863] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 08/18/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of estrogen (E2) on systemic and splanchnic hyperdynamic circulation in portal hypertensive rats.
METHODS: Fifty castrated female Sprague-Dawley rats were divided into five groups: sham operation (SO), partial portal vein ligation (PPVL) + placebo (PLAC), PPVL + E2, PPVL + ICI and PPVL + E2 + ICI. Hemodynamic measurements were performed using ultrasonography. Mesenteric arteriole contractility in response to norepinephrine was determined using a vessel perfusion system. Oxidative stress in the mesenteric artery was investigated by in situ detection of the superoxide anion (O2•−) and hydrogen peroxide (H2O2) concentrations.
RESULTS: Treatment with E2 resulted in a significant decrease of portal pressure (P < 0.01) and portal venous inflow (P < 0.05), and higher systemic vascular resistance (P < 0.05) and splanchnic arteriolar resistance (P < 0.01) in PPVL + E2 rats compared to PPVL + PLAC rats. In the mesenteric arterioles of PPVL + E2 rats, the dose-response curve was shifted left, and the EC50 was decreased (P < 0.01). E2 reduced O2•− production and H2O2 concentration in the mesenteric artery. However, ICI182, 780 reversed the beneficial effects of E2, therefore, the systemic and splanchnic hyperdynamic circulation were more deteriorated in ICI182, 780-treated rats.
CONCLUSION: Treatment with estrogen improved the systemic and splanchnic hyperdynamic circulation in PPVL rats, in part due to the alleviation of oxidative stress.
Collapse
|
|
13
|
Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N, Walther T, Sauerbruch T, Burrell LM, Angus PW, Trebicka J. Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 2013; 145:874-884.e5. [PMID: 23796456 DOI: 10.1053/j.gastro.2013.06.036] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 06/13/2013] [Accepted: 06/18/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis. METHODS We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response. RESULTS Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance. CONCLUSIONS In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.
Collapse
Affiliation(s)
- Josephine A Grace
- Department of Medicine, The University of Melbourne, Heidelberg Repatriation Hospital, Heidelberg, Melbourne, Victoria, Australia; Austin Health, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Chen W, Sang JY, Liu DJ, Qin J, Huo YM, Xu J, Wu ZY. Desensitization of G-protein-coupled receptors induces vascular hypocontractility in response to norepinephrine in the mesenteric arteries of cirrhotic patients and rats. Hepatobiliary Pancreat Dis Int 2013; 12:295-304. [PMID: 23742775 DOI: 10.1016/s1499-3872(13)60047-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The increased beta-arrestin-2 and its combination with G-protein-coupled receptors (GPCRs) lead to GPCRs desensitization. The latter may be responsible for decreased contractile reactivity in the mesenteric arteries of cirrhotic patients and rats. The present study is to investigate the machinery changes of alpha-adrenergic receptors and G proteins and their roles in the contractility of mesenteric arteries of cirrhotic patients and animal models. METHODS Patients with cirrhosis due to hepatitis B and cirrhotic rats induced by CCl4 were studied. Mesenteric artery contractility in response to norepinephrine was determined by a vessel perfusion system. The contractile effect of G protein-coupled receptor kinase-2 (GRK-2) inhibitor on the mesenteric artery was evaluated. The protein expression of the alpha1 adrenergic receptor, G proteins, beta-arrestin-2, GRK-2 as well as the activity of Rho associated coiled-coil forming protein kinase-1 (ROCK-1) were measured by Western blot. In addition, the interaction of alpha1 adrenergic receptor with beta-arrestin-2 was assessed by co-immunoprecipitation. RESULTS The portal vein pressure of cirrhotic patients and rats was significantly higher than that of controls. The dose-response curve to norepinephrine in mesenteric arteriole was shifted to the right, and EC50 was significantly increased in cirrhotic patients and rats. There were no significant differences in the expressions of the alpha1 adrenergic receptor and G proteins in the cirrhotic group compared with the controls. However, the protein expressions of GRK-2 and beta-arrestin-2 were significantly elevated in cirrhotic patients and rats compared with those of the controls. The interaction of the alpha1 adrenergic receptor and beta-arrestin-2 was significantly aggravated. This interaction was significantly reversed by GRK-2 inhibitor. Both the protein expression and activity of ROCK-1 were significantly decreased in the mesenteric artery in patients with cirrhosis compared with those of the controls, and this phenomenon was not shown in the cirrhotic rats. Norepinephrine significantly increased the activity of ROCK-1 in normal rats but not in cirrhotic ones. Norepinephrine significantly increased ROCK-1 activity in cirrhotic rats when GRK-2 inhibitor was used. CONCLUSIONS beta-arrestin-2 expression and its interaction with GPCRs are significantly upregulated in the mesenteric arteries in patients and rats with cirrhosis. These upregulations result in GPCR desensitization, G-protein dysfunction and ROCK inhibition. These may explain the decreased contractility of the mesenteric artery in response to vasoconstrictors.
Collapse
Affiliation(s)
- Wei Chen
- Department of Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | | | | | | | | | | | | |
Collapse
|
|
15
|
HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol 2012; 57:1220-7. [PMID: 22878469 DOI: 10.1016/j.jhep.2012.07.033] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 07/24/2012] [Accepted: 07/27/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Rho-kinase activation mediates cell contraction and increases intrahepatic resistance and consequently portal pressure in liver cirrhosis. Systemic Rho-kinase inhibition decreases portal pressure in cirrhosis, but also arterial pressure. Thus, liver-specific Rho-kinase inhibition is needed. The delivery of Rho-kinase inhibitor to activated hepatic stellate cells reduces fibrosis. It might also relax these contractile cells and therewith decrease intrahepatic resistance. We tested this hypothesis by performing acute experiments in cirrhotic rats. METHODS Cirrhosis models were CCl(4)-intoxication and bile duct ligation. Three hours after injection of the Rho-kinase inhibitor (Y26732) coupled with a carrier (mannose-6-phosphate modified human serum albumin), which targets activated hepatic stellate cells, hemodynamics were analyzed by the colored microsphere technique and direct pressure measurements. The delivery site and effect of Rho-kinase inhibitor were investigated by immunohistochemical stainings, as well as Western blot. Experiments with Rho-kinase inhibitor coupled with unmodified human serum albumin served as untargeted control. RESULTS In both models of cirrhosis, the carrier coupled Rho-kinase inhibitor lowered the portal pressure and decreased the hepatic-portal resistance. Immunohistochemical desmin-staining showed the carrier in hepatic stellate cells. The targeted therapy decreased the expression of the phosphorylated substrate of Rho-kinase (moesin) and abolished myosin light chains phosphorylation in fibrotic septae (collagen-staining). The targeted Rho-kinase inhibitor showed no major extrahepatic effects. By contrast, the untargeted Rho-kinase inhibitor elicited severe systemic hypotension. CONCLUSIONS Activated hepatic stellate cells are crucially involved in portal hypertension in cirrhosis. Targeting of Rho-kinase in hepatic stellate cells not only decreased fibrosis, as previously shown, but also lowers portal pressure acutely without major systemic effects as demonstrated in this study.
Collapse
|
|
16
|
Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Clin Sci (Lond) 2012; 123:225-39. [PMID: 22548407 DOI: 10.1042/cs20120030] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.
Collapse
|
|
17
|
Huang HC, Chang CC, Wang SS, Lee FY, Teng TH, Lee JY, Lin HC, Chuang CL, Lee SD. The roles of angiotensin II receptors in the portosystemic collaterals of portal hypertensive and cirrhotic rats. J Vasc Res 2012; 49:160-8. [PMID: 22285953 DOI: 10.1159/000332347] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 08/19/2011] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS In liver cirrhosis/portal hypertension, collaterals as varices may bleed and are influenced by vasoresponsiveness. An angiotensin blockade ameliorates portal hypertension but the influence on collaterals is unknown. METHODS Portal hypertension and cirrhosis were induced by portal vein (PVL) and common bile duct ligation (BDL). Hemodynamics, real-time PCR of angiotensin II receptors (AT(1)R, AT(2)R) in the left adrenal vein (LAV, sham) and splenorenal shunt derived from LAV (PVL, BDL) were performed. With an in situcollateral perfusion model, angiotensin II vasoresponsiveness with different preincubations was evaluated: (1) vehicle; (2) AT(1)R blocker losartan; (3) losartan plus nonselective nitric oxide synthase (NOS) inhibitor (N(ω)-nitro-L-arginine); (4) AT(2)R blocker PD123319; (5) PD123319 plus N(ω)-nitro-L-arginine; (6) N(ω)-nitro-L-arginine, and (7) losartan plus inducible NOS inhibitor aminoguanidine. RESULTS LAV AT(1)R and AT(2)R expression decreased in PVL and BDL rats. Losartan attenuated angiotensin II-elicited vasoconstriction but PD123319 had no effect. N(ω)-nitro-L-arginine but not aminoguanidine reversed the losartan effect. CONCLUSIONS Angiotensin receptors are downregulated in the collateral vessel of portal hypertensive and cirrhotic rats. The AT(1)R blockade attenuates the angiotensin II vasoconstrictive effect, suggesting AT(1)R mediates collateral vasoconstriction and the influence of AT(2)R is negligible. The lack of aminoguanidine influence indicates that endothelial NOS participates in the losartan effect.
Collapse
Affiliation(s)
- Hui-Chun Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Vascular Smooth Muscle Dysfunction and Remodeling Induced by Ginsenoside Rg3, a Bioactive Component of Ginseng. Toxicol Sci 2010; 117:505-14. [DOI: 10.1093/toxsci/kfq201] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
|
|
19
|
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.
Collapse
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
| | | | | | | | | |
Collapse
|
|
20
|
Hennenberg M, Trebicka J, Kohistani AZ, Heller J, Sauerbruch T. Vascular hyporesponsiveness to angiotensin II in rats with CCl(4)-induced liver cirrhosis. Eur J Clin Invest 2009; 39:906-13. [PMID: 19522833 DOI: 10.1111/j.1365-2362.2009.02181.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: 12/12/2022]
Abstract
BACKGROUND Portal hypertension is triggered by vasodilation due to impaired contraction of extrahepatic vessels. Angiotensin II type 1 (AT(1)) receptor-induced vasocontraction is mediated by G proteins and may be desensitized by recruitment of beta-arrestin-2 to the receptor. In this study, we analysed the interaction of AT(1) receptors with beta-arrestin-2 in the context of vascular hypocontractility in rats with CCl(4)-induced cirrhosis. METHODS Micronodular liver cirrhosis in rats (n = 15) was induced by regular CCl(4) exposure. Age-matched rats (n = 15) served as controls. Contractility of aortic rings was measured by myography. Protein expressions and phosphorylations were assessed by Western blot analysis, and AT(1) receptor interaction with beta-arrestin-2 by co-immunoprecipitation. RESULTS Aortic rings from CCl(4) rats were hypocontractile to angiotensin II independent of nitric oxide synthases (Nomega-nitro-l-arginine methyl ester 200 microM). Expression of the AT(1) receptor, Galpha(q/11) and the contraction-mediating effector Rho kinase was similar in aortas from both groups. Expression and AT(1) receptor binding of beta-arrestin-2 were up-regulated in aortas from CCl(4) rats. Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats, but no further interaction of AT(1) receptors with beta-arrestin-2 was found in aortas from CCl(4) rats. While angiotensin II stimulation resulted in Rho kinase activation in aortas from noncirrhotic rats but not in aortas from CCl(4) rats, extracellular signal-regulated kinase activation in response to angiotensin II was observed in aortas from both groups. CONCLUSIONS Vascular hyporesponsiveness to angiotensin II in CCl(4) rats is due to enhanced interaction of the AT(1) receptor with beta-arrestin-2 and consecutively changed receptor function.
Collapse
Affiliation(s)
- M Hennenberg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
| | | | | | | | | |
Collapse
|
|
21
|
Hennenberg M, Trebicka J, Buecher D, Heller J, Sauerbruch T. Lack of effect of norfloxacin on hyperdynamic circulation in bile duct-ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho-kinase? Liver Int 2009; 29:933-41. [PMID: 19490424 DOI: 10.1111/j.1478-3231.2009.02010.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS In cirrhosis, portal hypertension is maintained by splanchnic vasodilation owing to overproduction of the vasodilator nitric oxide (NO) and defective contractile signalling by Rho-kinase. NO overproduction is partially caused by bacterial translocation from the gut to mesenteric lymph nodes. However, the effects of intestinal bacterial decontamination on hyperdynamic circulation or vascular contractility are unknown. We investigated the haemodynamic and vascular effects of norfloxacin in rats with secondary biliary cirrhosis. METHODS Cirrhosis was induced by bile duct ligation (BDL). One group was treated with norfloxacin (20 mg/kg/day, 5 days, orally). Bacterial growth in the lymph nodes was determined on blood agar plates. Invasive haemodynamic measurements were combined with coloured microspheres. Aortic contractility was assessed myographically. Protein expression/phosphorylation was examined by Western blot analysis. RESULTS Norfloxacin treatment of BDL rats abolished bacterial translocation to mesenteric lymph nodes. BDL rats had hyperdynamic circulation, including portal hypertension and splanchnic vasodilation. None of these parameters was changed by norfloxacin, although norfloxacin reduced endothelial NO synthase expression and phosphorylation. The latter was associated with a diminished activity of protein kinase G (PKG), which mediates NO-induced vasodilation. However, norfloxacin had no effect on aortic contractility to methoxamine or Ca2+, or the aortic expression of RhoA, Rho-kinase and beta-arrestin 2, or the phosphorylation of the Rho-kinase substrate moesin. CONCLUSIONS Short-term treatment of BDL rats with norfloxacin does not change hyperdynamic circulation or vascular contractility, despite reduction of PKG activity.
Collapse
Affiliation(s)
- Martin Hennenberg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
| | | | | | | | | |
Collapse
|
|
22
|
Colle I, Geerts AM, Van Steenkiste C, Van Vlierberghe H. Hemodynamic changes in splanchnic blood vessels in portal hypertension. Anat Rec (Hoboken) 2008; 291:699-713. [PMID: 18484617 DOI: 10.1002/ar.20667] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Portal hypertension (PHT) is associated with a hyperdynamic state characterized by a high cardiac output, increased total blood volume, and a decreased splanchnic vascular resistance. This splanchnic vasodilation is a result of an important increase in local and systemic vasodilators (nitric oxide, carbon monoxide, prostacyclin, endocannabinoids, and so on), the presence of a splanchnic vascular hyporesponsiveness toward vasoconstrictors, and the development of mesenteric angiogenesis. All these mechanisms will be discussed in this review. To decompress the portal circulation in PHT, portosystemic collaterals will develop. The presence of these portosystemic shunts are responsible for major complications of PHT, namely bleeding from gastrointestinal varices, encephalopathy, and sepsis. Until recently, it was accepted that the formation of collaterals was due to opening of preexisting vascular channels, however, recent data suggest also the role of vascular remodeling and angiogenesis. These points are also discussed in detail.
Collapse
Affiliation(s)
- Isabelle Colle
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.
| | | | | | | |
Collapse
|
|
23
|
Hennenberg M, Trebicka J, Biecker E, Schepke M, Sauerbruch T, Heller J. Vascular dysfunction in human and rat cirrhosis: role of receptor-desensitizing and calcium-sensitizing proteins. Hepatology 2007; 45:495-506. [PMID: 17256744 DOI: 10.1002/hep.21502] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED In cirrhosis, vascular hypocontractility leads to vasodilation and contributes to portal hypertension. Impaired activation of contractile pathways contributes to vascular hypocontractility. Angiotensin II type 1 receptors (AT1-Rs) are coupled to the contraction-mediating RhoA/Rho-kinase pathway and may be desensitized by phosphorylation through G-protein-coupled receptor kinases (GRKs) and binding of beta-arrestin-2. In the present study, we analyzed vascular hypocontractility to angiotensin II in cirrhosis. Human hepatic arteries were obtained during liver transplantation. In rats, cirrhosis was induced by bile duct ligation (BDL). Contractility of rat aortic rings was measured myographically. Protein expression and phosphorylation were analyzed by Western blot analysis. Immunoprecipitation was performed with protein A-coupled Sepharose beads. Myosin light chain (MLC) phosphatase activity was assessed as dephosphorylation of MLCs. Aortas from BDL rats were hyporeactive to angiotensin II and extracellular Ca2+. Expression of AT1-R and Galphaq/11,12,13 remained unchanged in hypocontractile rat and human vessels, whereas GRK-2 and beta-arrestin-2 were up-regulated. The binding of beta-arrestin-2 to the AT1-R was increased in hypocontractile rat and human vessels. Inhibition of angiotensin II-induced aortic contraction by the Rho-kinase inhibitor Y-27632 was pronounced in BDL rats. Basal phosphorylation of the ROK-2 substrate moesin was reduced in vessels from rats and patients with cirrhosis. Analysis of the expression and phosphorylation of Ca(2+)-sensitizing proteins (MYPT1 and CPI-17) in vessels from rats and patients with cirrhosis suggested decreased Ca2+ sensitivity. Angiotensin II-stimulated moesin phosphorylation was decreased in aortas from BDL rats. MLC phosphatase activity was elevated in aortas from BDL rats. CONCLUSION Vascular hypocontractility to angiotensin II in cirrhosis does not result from changes in expression of AT1-Rs or G-proteins. Our data suggest that in cirrhosis-induced vasodilation, the AT1-R is desensitized by GRK-2 and beta-arrestin-2 and that changed patterns of phosphorylated Ca(2+) sensitizing proteins decrease Ca(2+) sensitivity.
Collapse
Affiliation(s)
- Martin Hennenberg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
| | | | | | | | | | | |
Collapse
|
|
24
|
Hennenberg M, Biecker E, Trebicka J, Jochem K, Zhou Q, Schmidt M, Jakobs KH, Sauerbruch T, Heller J. Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats. Gastroenterology 2006; 130:838-54. [PMID: 16530523 DOI: 10.1053/j.gastro.2005.11.029] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2005] [Accepted: 11/16/2005] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Portal hypertension is associated with arterial hypotension and vascular hypocontractility, which persists despite elevated plasma levels of vasoconstrictors. We investigated the role of the RhoA/Rho-kinase pathway in vascular smooth muscle hypocontractility of rats with secondary biliary cirrhosis. METHODS Aortic expressions of RhoA and Rho-kinase were analyzed in sham-operated and BDL rats by reverse-transcription polymerase chain reaction (RT-PCR) and immunoblots. Activation of aortic RhoA was examined by pull down of guanosine triphosphate (GTP)-RhoA and membrane translocation of RhoA. Rho-kinase activity was assessed as phosphorylation of its substrate, moesin. Contractility of isolated aortic rings was determined myographically. The hemodynamic effect of the Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) was determined in vivo by measuring changes in mean arterial pressure and systemic vascular resistance (SVR) (microspheres). RESULTS Contraction of aortic rings from BDL rats was impaired in response to the alpha(1)-adrenergic receptor agonist methoxamine but not to high molar KCl. Aortic expression of RhoA was unchanged in cirrhotic rats, whereas Rho-kinase was down-regulated posttranscriptionally. Methoxamine-induced activation of RhoA as well as basal and methoxamine-induced phosphorylation of moesin were strongly reduced in aortas from cirrhotic rats. Aortic rings from cirrhotic rats precontracted with methoxamine showed an increased sensitivity to relaxation with Y-27632. The drop in SVR induced by Y-27632 was larger in cirrhotic rats than in sham-operated rats. CONCLUSIONS An impaired vascular activation of RhoA and a down-regulation of Rho-kinase might contribute to vasodilation and vascular hypocontractility in BDL-induced cirrhosis.
Collapse
Affiliation(s)
- Martin Hennenberg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Vaughan RB, Angus JA, Angus PW. Vasoconstrictor responses are normal but prostanoid-mediated vasodilatation is enhanced in human cirrhotic mesenteric arteries. J Gastroenterol Hepatol 2005; 20:1158-64. [PMID: 16048562 DOI: 10.1111/j.1440-1746.2005.03946.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS The mechanisms responsible for mesenteric vasodilatation in cirrhosis have not been fully elucidated. The aim of the present study was to examine whether there is altered intrinsic vascular reactivity of human mesenteric vessels in cirrhosis, which might contribute to vasodilatation in vivo. METHODS Ten mesenteric arteries from six cirrhosis patients undergoing liver transplantation were compared with 11 arteries from six control patients. Vasoconstrictor responses to potassium, norepinephrine and methoxamine were determined. Endothelium-dependent vasodilatation responses to acetylcholine and substance P were determined both before and after inhibition of nitric oxide (NO) and prostanoid synthesis. RESULTS Cirrhotic vessels responded normally to potassium depolarization and did not differ to control vessels with respect to sensitivity and maximal response to norepinephrine. In cirrhotic vessels, inhibition of NO synthesis had significantly less effect on substance P-induced vasorelaxation than in controls (% Relaxation: cirrhosis 70.3 +/- 9.6; control 34.9 +/- 9.5; P = 0.03). However, after inhibition of both NO and prostanoid synthesis, vasodilatory responses were eliminated in both groups. CONCLUSIONS The findings of the present study indicate that intrinsic hyporesponsiveness to vasoconstrictors does not play a pathogenetic role in the mesenteric vasodilatation in human cirrhosis. Furthermore, vasodilator prostanoids might make a significant contribution in mediating enhanced endothelium-dependent vasorelaxation in the mesenteric circulation.
Collapse
Affiliation(s)
- Rhys B Vaughan
- Victorian Liver Transplant Unit, Department of Gastroenterology, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia
| | | | | |
Collapse
|
|
26
|
Heller J, Trebicka J, Shiozawa T, Schepke M, Neef M, Hennenberg M, Sauerbruch T. Vascular, hemodynamic and renal effects of low-dose losartan in rats with secondary biliary cirrhosis. Liver Int 2005; 25:657-66. [PMID: 15910503 DOI: 10.1111/j.1478-3231.2005.01053.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
BACKGROUND In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to alpha1-adrenoceptor agonists. Recently, the angiotensin II type 1-receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to alpha1-adrenoceptor agonists. METHODS We studied, in rats with secondary biliary cirrhosis and sham-operated rats, the effect of 0.5 and 10 mg losartan/kg x day on aortic responsiveness to alpha1-adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function. RESULTS In cirrhotic rats, 10 mg losartan/kg x day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg x day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis. CONCLUSIONS In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to alpha1-adrenoceptor agonists.
Collapse
Affiliation(s)
- Jörg Heller
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Lin HC, Yang YY, Huang YT, Lee TY, Hou MC, Lee FY, Lee SD. Vascular contractile response and signal transduction in endothelium-denuded aorta from cirrhotic rats. World J Gastroenterol 2005; 11:2306-12. [PMID: 15818743 PMCID: PMC4305816 DOI: 10.3748/wjg.v11.i15.2306] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [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: The mechanism of decreased vascular reactivity to vasoconstrictors in portal hypertension is still unclear. In addition to nitric oxide, defects in post-receptor signal transduction pathway have been suggested to play a role. However, substantial evidences observed equivocal changes of vascular reactivity following different agonists that challenged the hypothesis of the post-receptor defect. The current study was to evaluate the vascular reactivity to different agonists and the inositol trisphosphate (IP3) changes in signal transduction cascade from cirrhotic rats with portal hypertension.
METHODS: The endothelial denuded aortic rings from cirrhotic and sham-operated rats were obtained for ex vivo tension study and measurement of the corresponding [3H] IP3 formation following different receptor and nonreceptor-mediated agonists’ stimulation. Additionally, iNOS protein expression was measured in thoracic aorta. The contractile response curves to phenylephrine were performed in endothelial denuded aortic rings with and without preincubation with a specific iNOS inhibitor (L-N(6)-(1-iminoethyl)-lysine, L-NIL).
RESULTS: In endothelial denuded aortic rings of cirrhotic rats, the vascular responses were reduced with phenylephrine and arginine vasopressin (AVP) stimulation but were normal with U-46619, NaF/AlCl3, and phorbol esterdibutyrate (PdBU) stimulation. Compared to the corresponding control groups, the degree of the increment of [3H] IP3 formation from basal level was also decreased with phenylephrine and AVP stimulation, but was normal with U-46619 and NaF/AlCl3 stimulation. The preincubation with L-NIL did not modify the hyporesponsiveness to phenylephrine. Additionally, the iNOS protein expression in thoracic aorta was not different in cirrhotic and sham-operated rats.
CONCLUSION: Without the influence of nitric oxide, vascular hyporeactivity to vasoconstrictors persisted in cirrhotic rats with portal hypertension. However, the decreased vascular reactivity is an agonist-specific phenomenon. In addition, G-protein and phospholipase C pathway associated with the IP3 productions may be intact in cirrhotic rats with portal hypertension.
Collapse
Affiliation(s)
- Han-Chieh Lin
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan, China.
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Ytrebø LM, Ekse S, Sen S, Rose C, Nedredal GI, Fuskevåg OM, Jalan R, Revhaug A. Contractile response of femoral arteries in pigs with acute liver failure. Scand J Gastroenterol 2004; 39:1000-4. [PMID: 15513341 DOI: 10.1080/00365520410003254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. METHODS Norwegian Landrace pigs weighing 27.1 +/- 0.5 kg (mean +/- sx (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10(-13) - 10(-5) mol/L) or norepinephrine (10(-13) - 10(-3) mol/L). RESULTS Pigs suffering from ALF developed a hyperdynamic circulation with an increased cardiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 +/- 7 versus 56 +/- 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 +/- 8 versus 93 +/- 16 mN, P = 0.55). CONCLUSIONS This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.
Collapse
Affiliation(s)
- L M Ytrebø
- Department of Digestive Surgery, University Hospital Northern Norway, Tromsø.
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Vashist Y, Semela D, Dufour JF. Hyperdynamic circulation in liver cirrhosis: desensitization of vasoconstrictive receptors by G protein-coupled receptor kinases. Med Hypotheses 2004; 62:82-5. [PMID: 14729009 DOI: 10.1016/s0306-9877(03)00311-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Liver cirrhosis is complicated by a hyperdynamic circulation characterized by a generalized arterial vasodilatation. This vasodilatation occurs despite high plasma concentration of several potent vasoconstrictive substances like angiotensin, vasopressin, endothelin and norepinephrine. The experimental evidence available shows that compensatory adrenergic and vasoconstrictive signals are not normally transmitted intracellularly. G protein-coupled receptor kinases phosporylate plasma membrane receptors and block the transmission of the signal intracellularly. We hypothesize that these kinases are responsible for the desensitization to vasoconstrictors observed in patients with liver cirrhosis. Pharmacological intervention at this level might be beneficial to treat complications like ascites and variceal bleeding.
Collapse
Affiliation(s)
- Yogesh Vashist
- Department of Clinical Pharmacology, University of Bern, Murtenstrasse 35, Bern 3010, Switzerland
| | | | | |
Collapse
|
|
30
|
Abstract
OBJECTIVE To review the characteristic features of patients with advanced liver disease that may lead to increased perioperative morbidity and mortality rates. DESIGN Literature review. RESULTS Patients with end-stage liver disease are at high risk of major complications and death following surgery. The most common complications are secondary to acute liver failure and include severe coagulopathy, encephalopathy, adult respiratory distress syndrome, acute renal failure, and sepsis. The degree of malnutrition, control of ascites, level of encephalopathy, prothrombin time, concentration of serum albumin, and concentration of serum bilirubin predict the risk of complications and death following surgery. Other determinants of adverse outcome include emergency surgery, advanced age, and cardiovascular disease. Portal hypertension is a prominent feature of advanced liver disease, and it predisposes the patient to variceal hemorrhage, hepatorenal syndrome, hepatopulmonary syndrome, and uncontrolled ascites. Portal hypertension can be ameliorated by percutaneous or surgical portasystemic shunting procedures. If well-defined contraindications are not present, patients with advanced liver disease should be evaluated for orthotopic liver transplantation from a cadaver donor or possible living-related liver transplantation. CONCLUSIONS Optimal preparation, which addresses the common features of advanced liver disease, may decrease the risk of complications or death following surgery. Preparation should include correcting coagulopathy, minimizing preexisting encephalopathy, preventing sepsis, and optimizing renal function.
Collapse
Affiliation(s)
- Richard A Wiklund
- Department of Anesthesia and Critical Care, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
31
|
Neef M, Biecker E, Heller J, Schepke M, Nischalke HD, Wolff M, Spengler U, Reichen J, Sauerbruch T. Portal hypertension is associated with increased mRNA levels of vasopressor G-protein-coupled receptors in human hepatic arteries. Eur J Clin Invest 2003; 33:249-55. [PMID: 12641544 DOI: 10.1046/j.1365-2362.2003.01131.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The contractile response of human splanchnic vessels to different vasoconstrictors is attenuated in cirrhosis. Functional studies indicate a cellular signalling defect upstream of the G-protein level. The aim of the present study was to analyze expression and mRNA levels of the following most relevant vasopressor receptors in the smooth musculature of human hepatic arteries: alpha1 adrenoceptor (AR) subtypes a, b and d, angiotensin II type 1 receptor (AT1), arginine vasopressin receptor type 1a (V1a), endothelin receptor type A (ETA) and B (ETB). MATERIALS AND METHODS Hepatic arteries were collected from 10 donors (noncirrhotic) and 14 recipients (cirrhotic) at liver transplantations. Real-time-PCR was performed to quantify steady-state levels of receptor mRNAs. RESULTS alpha 1aAR mRNA levels showed no significant difference between the cirrhotic arteries and the controls while the mRNA levels of the other vasoactive receptors were significantly higher in the cirrhotic hepatic arteries (alpha 1bAR: 4-fold, P = 0.013; AT1: 16-fold, P = 0.024; V1a: 23-fold, P = 0.001; ETA: 4-fold, P = 0.02; ETB: 8-fold, P = 0.008). No mRNA for the alpha 1dAR was detected either in the donor or recipient hepatic arteries. CONCLUSION We conclude that vascular hyporeactivity to the most relevant endogenous vasoconstrictors of cirrhotic hepatic arteries is not caused by a receptor down-regulation at mRNA levels. In contrast they were up-regulated.
Collapse
MESH Headings
- Adult
- Female
- Hepatic Artery/metabolism
- Humans
- Hypertension, Portal/metabolism
- Male
- Middle Aged
- Polymerase Chain Reaction/methods
- RNA, Messenger/isolation & purification
- RNA, Messenger/metabolism
- Receptors, Adrenergic, alpha/metabolism
- Receptors, Angiotensin/metabolism
- Receptors, Cell Surface/metabolism
- Receptors, Endothelin/metabolism
- Receptors, Vasopressin/metabolism
- Transcription, Genetic
Collapse
Affiliation(s)
- M Neef
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|