Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats

Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg−1·day−1), sorafenib (1 mg·kg−1·day−1), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant ( P < 0.001) and similar reduction in PP (−19 and −15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (−35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (−30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (−39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (−25 and −33%, respectively), splanchnic vascularization (−37 and −41%, respectively), liver fibrosis (38%), and hepatic neovascularization (−42 and −51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.

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Interaction of flow and resistance in maintenance of portal hypertension in a rat model

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1986.250.2.g205 ◽

1986 ◽

Vol 250 (2) ◽

pp. G205-G212 ◽

Cited By ~ 4

Author(s):

E. Sikuler ◽

R. J. Groszmann

Keyword(s):

Portal Hypertension ◽

Portal Vein ◽

Rat Model ◽

Portal Pressure ◽

Flow Theory ◽

Sham Operation ◽

Portal Flow ◽

Hemodynamic Changes ◽

Forward Flow ◽

Arteriolar Resistance

To clarify the roles that portocollateral resistance ("backward-flow" theory) and portal flow ("forward-flow" theory) play in maintaining chronic portal hypertension, we studied, in a rat model with prehepatic portal hypertension, the hemodynamic changes that occur when portocollateral resistance is reduced and high portal venous inflow is maintained. In 30 portal-hypertensive rats the constriction around the portal vein was removed 4 days after induction of portal hypertension, 30 rats were used as portal vein-constricted controls, and 30 additional rats were subjected to a sham operation. The removal of the ligature constricting the portal vein was followed by an immediate decrease in portal pressure (from 16.3 +/- 0.8 to 9.6 +/- 0.8 mmHg, P less than 0.001). Two days after the ligature removal, hyperdynamic circulation was still evident and was characterized by a decreased splanchnic arteriolar resistance and an increased portal venous inflow. The coexistence of high portal venous inflow and normal portal pressure indicates that high portal venous inflow per se is not sufficient to produce an increase in portal pressure when it faces a low-resistance vascular bed. We conclude that portal hypertension is induced by the interaction of an abnormally high portal venous inflow and high resistance offered to the flow by the portocollateral vessels. Neither the forward-flow theory nor the backward-flow theory can be applied solely to explain the increased portal pressure.

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Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22147662 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7662

Author(s):

Chon Kit Pun ◽

Hui-Chun Huang ◽

Ching-Chih Chang ◽

Chiao-Lin Chuang ◽

Chun-Hsien Yen ◽

...

Keyword(s):

Liver Cirrhosis ◽

Portal Hypertension ◽

Liver Fibrosis ◽

Statistical Significance ◽

Portal Pressure ◽

Sham Operation ◽

Sprague Dawley ◽

Beneficial Effects ◽

Duct Ligation ◽

The Impact

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.

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Portal hyperflow in patients with hepatosplenic mansonic schistosomiasis

Revista do Hospital das Clínicas ◽

10.1590/s0041-87812004000100003 ◽

2004 ◽

Vol 59 (1) ◽

pp. 10-14 ◽

Cited By ~ 5

Author(s):

Roberto de Cleva ◽

William Abrão Saad ◽

Paulo Herman ◽

Vincenzo Pugliese ◽

Bruno Zilberstein ◽

...

Keyword(s):

Portal Hypertension ◽

Esophageal Varices ◽

Portal Pressure ◽

Previous History ◽

Portal Flow ◽

Portal Hemodynamics ◽

Significant Drop ◽

Hemodynamic Assessment ◽

History Of ◽

Hepatosplenic Schistosomiasis

PURPOSE: The purpose of this study was to assess portal hemodynamics in patients with portal hypertension due to hepatosplenic schistosomiasis as well as to assess the contribution of splanchnic hyperflow to the pathophysiology of the portal hypertension. METHODS: Sixteen patients with schistosomal portal hypertension and previous history of upper digestive bleeding due to esophageal varices rupture underwent elective esophagogastric devascularization and splenectomy and were prospectively studied. All patients underwent intraoperative invasive hemodynamic portal monitoring with a 4F-thermodilution catheter. The intraoperative portal hemodynamic assessment was conducted after laparotomy (initial) and after esophagogastric devascularization (final). RESULTS: The initial portal pressure was elevated (mean 28.5 ± 4.5 mm Hg), and a significant drop of 25% was observed at the end of the surgery (21.9 ± 4.9 mm Hg). The initial portal flow was elevated (mean 1766.9 ± 686.6 mL/min). A significant fall (42%) occurred at the end of the surgical procedure (1025.62 ± 338.7 mL/min). Fourteen patients (87.5%) presented a portal flow of more than 1200 mL/min, and in 5 cases, values greater than 2000 mL/min were observed. CONCLUSIONS: Esophagogastric devascularization and splenectomy promote a significant reduction of the elevated portal pressure and flow in schistosomal portal hypertension. These data favor the hypothesis of portal hyperflow in the physiopathology of portal hypertension of schistosomiasis.

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Role of thromboxane A2 in early BDL-induced portal hypertension

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00315.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. G453-G460 ◽

Cited By ~ 44

Author(s):

Yukihiro Yokoyama ◽

Hongzhi Xu ◽

Nicole Kresge ◽

Steve Keller ◽

Amir H. Sarmadi ◽

...

Keyword(s):

Portal Hypertension ◽

Portal Pressure ◽

Sham Operation ◽

Sprague Dawley ◽

Bicarbonate Buffer ◽

Constant Flow Rate ◽

Sprague Dawley Rats ◽

Duct Ligation ◽

Cox 2

Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A2 (TXA2) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TXA2 in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane B2(TXB2), the stable metabolite of TXA2. Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TXB2 in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 ± 803 vs. 10,210 ± 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TXB2 release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TXA2 release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TXA2 in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TXA2, which is associated with upregulation of the COX-2 enzyme.

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Protection of estrogen in portal hypertension gastropathy: an experimental model

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032011000300011 ◽

2011 ◽

Vol 48 (3) ◽

pp. 211-216 ◽

Cited By ~ 4

Author(s):

Maria Isabel Morgan-Martins ◽

Simone Iahnig Jacques ◽

Renata Minuzzo Hartmann ◽

Camila Moraes Marques ◽

Cláudio Augusto Marroni ◽

...

Keyword(s):

Antioxidant Enzymes ◽

Portal Hypertension ◽

Portal Vein ◽

Experimental Model ◽

Portal Pressure ◽

The Other ◽

Portal System ◽

Sham Operation ◽

Portal Vein Ligation ◽

Significant Difference

CONTEXT: Portal hypertension is a complication secondary to cirrhosis that is characterized by increased blood flow and/or vascular resistance in the portal system, causing the appearance of a hyperdynamic collateral circulation. Partial portal vein ligation is an experimental model used in rats to study the pathophysiological mechanisms involved in pre-hepatic portal hypertension. Estrogen E2 is an antioxidant molecule with various physiological actions. OBJECTIVES: To evaluate the antioxidant activity of endogenous estrogen in an experimental model of partial portal vein ligation by comparing intact with castrated rats. METHODS: Twenty Wistar rats, weighing on average 250 g were used and divided into four groups: sham-operated (SO); intact (I) with partial portal vein ligation (I + PPVL), castrated (C) and castrated with partial ligation of the vein (C + PPVL). Day 1: castration or sham-operation; day 7, PPVL surgery; on day 15 post-PPVL, portal pressure in the mesenteric vein of rats was measured on polygraph Letica. Lipid peroxidation in the stomach was assessed using the technique of thiobarbituric acid reactive substances and activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase. Statistical analysis was done with ANOVA - Student-Newman-Keuls (mean ± SE), and P<0.05 was considered as significant. RESULTS: Portal pressure was significantly increased in C + PPVL as compared to the other groups. There was no significant difference in the group of intact rats. TBARS showed significant damage in C and C + PPVL in relation to others. Antioxidant enzymes were significantly increased in the castrated rats with subsequent PPVL as compared to the other groups. CONCLUSION: We suggest that estrogen E2 plays a protective role in intact compared with castrated rats because it presents hydrophenolic radicals in its molecule, thus acting as an antioxidant in this experimental model.

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Update on new aspects of the renin–angiotensin system in liver disease: clinical implications and new therapeutic options

Clinical Science ◽

10.1042/cs20120030 ◽

2012 ◽

Vol 123 (4) ◽

pp. 225-239 ◽

Cited By ~ 49

Author(s):

Josephine A. Grace ◽

Chandana B. Herath ◽

Kai Yan Mak ◽

Louise M. Burrell ◽

Peter W. Angus

Keyword(s):

Portal Hypertension ◽

Liver Fibrosis ◽

Portal Pressure ◽

Renin Angiotensin System ◽

Active Role ◽

Angiotensin System ◽

Renin Angiotensin ◽

Hepatic Expression ◽

Important Regulator

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 AT1 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.

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Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00336.2012 ◽

2013 ◽

Vol 305 (7) ◽

pp. G496-G502 ◽

Cited By ~ 14

Author(s):

María Gabriela Delgado ◽

Jordi Gracia-Sancho ◽

Giusi Marrone ◽

Aina Rodríguez-Vilarrupla ◽

Ramon Deulofeu ◽

...

Keyword(s):

Nitric Oxide ◽

Portal Hypertension ◽

Liver Fibrosis ◽

Vascular Resistance ◽

Vascular Tone ◽

Leptin Receptor ◽

Portal Pressure ◽

Systemic Hemodynamics ◽

Receptor Blockade ◽

Nitric Oxide Bioavailability

Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O2− levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.

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Brief Review of Portal Hypertension Related Complications

10.5772/intechopen.96646 ◽

2021 ◽

Author(s):

Achyut Bikram Hamal

Keyword(s):

Portal Hypertension ◽

Pressure Gradient ◽

Beta Blockers ◽

Venous Pressure ◽

Portal Pressure ◽

Hepatopulmonary Syndrome ◽

Portal Blood Flow ◽

Variceal Hemorrhage ◽

The Difference ◽

Clinically Significant

The pathologic increase in the pressure gradient between portal vein and inferior venacava is called portal hypertension. Increased portal blood flow and increased resistance in the portal venous system cause portal hypertension. The structural components and the functional components contribute to the resistance. Hepatic venous pressure gradient (HVPG) reflects the degree of portal pressure in liver disease. HVPG is calculated as the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP). Clinically significant portal hypertension (CSPH) is defined as HVPG ≥10. Different values of HVPG have been defined as threshold for different consequences of portal hypertension. Variceal hemorrhage, portal hypertensive gastropathy, ascites, colopathy, biliopathy and hepatopulmonary syndrome are main complications of portal hypertension. Besides nonselective beta blockers, other drugs like statins, antioxidants, antidiabetic, anti-inflammatory and antiapoptotic drugs have also been seen to be effective in reducing portal pressure.

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The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Biomedicines ◽

10.3390/biomedicines9010060 ◽

2021 ◽

Vol 9 (1) ◽

pp. 60

Author(s):

Philipp Schwabl ◽

Eva Hambruch ◽

Grant R. Budas ◽

Paul Supper ◽

Michael Burnet ◽

...

Keyword(s):

Blood Flow ◽

Portal Hypertension ◽

Liver Fibrosis ◽

Target Genes ◽

Portal Pressure ◽

Farnesoid X Receptor ◽

Systemic Hemodynamics ◽

Splanchnic Blood Flow ◽

Hydroxyproline Content ◽

Sirius Red

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.

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Glucobrassicin Metabolites Ameliorate the Development of Portal Hypertension and Cirrhosis in Bile Duct-Ligated Rats

International Journal of Molecular Sciences ◽

10.3390/ijms20174161 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4161

Author(s):

Ting Chang ◽

Hsin-Ling Ho ◽

Shao-Jung Hsu ◽

Ching-Chih Chang ◽

Ming-Hung Tsai ◽

...

Keyword(s):

Liver Cirrhosis ◽

Portal Hypertension ◽

Bile Duct ◽

Portal Pressure ◽

Sham Operation ◽

Duct Ligation ◽

Phosphorylated Akt ◽

Protein Expressions ◽

Portosystemic Shunting ◽

Portosystemic Collaterals

Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3′-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.

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