Insulin reverses major portal hypertension-related derangements in rats with liver cirrhosis and diabetes

2018 ◽  
Vol 132 (22) ◽  
pp. 2391-2405
Author(s):  
I-Fang Hsin ◽  
Hui-Chun Huang ◽  
Ching-Chih Chang ◽  
Shao-Jung Hsu ◽  
Fa-Yauh Lee ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Perfusion ◽  
Diabetic Rats ◽  
Vascular Density ◽  
Diabetic Patients ◽  
Common Bile Duct Ligation ◽  
Portal Hemodynamics ◽  
Duct Ligation ◽  
Protein Expressions ◽  
Portosystemic Collaterals

Liver cirrhosis is accompanied by increased intrahepatic resistance and angiogenesis-related portosystemic collaterals formation. Diabetic patients suffer from abnormal vasoresponsiveness and angiogenesis that can be ameliorated by glucose control. However, the relevant presentation is not clear in those with cirrhosis and diabetes, in whom insulin is the treatment of choice. Liver cirrhosis was induced in Sprague–Dawley rats with common bile duct ligation (BDL) and sham rats were used as controls. Streptozotocin 60 mg/kg (STZ, i.p., to induce diabetes) or vehicle was injected. The rats received BDL and STZ injections were injected with insulin or vehicle. On the 29th day after the procedure, the groups were surveyed for (1) systemic and portal hemodynamics; (2) mesenteric vascular density; (3) severity of portosystemic collaterals; (4) hepatic resistance using in situ liver perfusion; (5) histology survey of mesentery and liver; and (6) mesentery angiogenesis- and liver fibrogenesis-related protein expressions. Compared with the cirrhotic rats, the cirrhotic diabetic rats had lower body weight, cardiac output, superior mesenteric arterial (SMA) resistance and portal venous (PV) resistance, and higher SMA and PV flow, which were mostly reversed by insulin. The cirrhotic diabetic rats also had increased mesenteric vascular density, and enhanced pERK, pAkt, VEGF, VEGFR2 protein expressions that were reversed by insulin. Insulin decreased the degree of shunting in the diabetic cirrhotic rats. Hepatic perfusion pressure and severity of liver fibrosis were not significantly influenced by diabetes and insulin treatment in the cirrhotic rats. In conclusion, diabetes aggravated hemodynamic derangements, mesenteric angiogenesis and collaterals in the cirrhotic rats, which were mostly ameliorated by insulin. Further clinical investigations are warranted.

scholarly journals Microbiota transplants from feces or gut content attenuated portal hypertension and portosystemic collaterals in cirrhotic rats

2021 ◽  
Author(s):  
Hui-Chun Huang ◽  
Ming-Hung Tsai ◽  
Ching-Chih Chang ◽  
Chon Kit Pun ◽  
Yi-Hsiang Huang ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Liver Injury ◽  
Portal Pressure ◽  
Vascular Density ◽  
Variceal Hemorrhage ◽  
Distribution Method ◽  
Portosystemic Shunts ◽  
Duct Ligation ◽  
Portosystemic Collaterals

Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P = .010, .044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated eNOS was downregulated. Portosystemic shunts determined by splenorenal shunt flow decreased in both transplantation groups (P = .037, .032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared to sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.

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

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.

scholarly journals The beneficial effects of curcumin in cirrhotic rats with portal hypertension

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Shao-Jung Hsu ◽  
Jing-Yi Lee ◽  
Te-Yueh Lin ◽  
Yu-Hsin Hsieh ◽  
Hui-Chun Huang ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Vascular Resistance ◽  
Portal Pressure ◽  
Acute Administration ◽  
Vegf Receptor ◽  
Variceal Hemorrhage ◽  
Common Bile Duct Ligation ◽  
Duct Ligation ◽  
Portosystemic Collaterals

In liver cirrhosis with portal hypertension, the uneven distribution of vasoactive substances leads to increased intrahepatic vascular resistance and splanchnic vasodilatation. Angiogenesis also induces increased portal inflow and portosystemic collaterals. The collaterals may induce lethal complications such as gastroesophageal variceal hemorrhage, but the therapeutic effect of vasoconstrictors is still suboptimal due to poor collateral vasoresponsivenss. Curcumin has aroused much attention for its antifibrosis, vasoactive, and anti-angiogenesis actions. However, whether it affects the aforementioned aspects is unknown. Liver cirrhosis was induced by common bile duct ligation (CBDL) in Sprague–Dawley rats. Sham-operated rats were controls. CBDL and sham rats were randomly allocated to receive curcumin (600 mg/kg per day) or vehicle since the 15th day after BDL. On the 29th day, portal hypertension related parameters were surveyed. Portosystemic collateral in situ perfusion was performed to evaluate vascular activity. Chronic curcumin treatment decreased portal pressure (PP), cardiac index (CI) and increased systemic vascular resistance (SVR) in cirrhotic rats. In splanchnic system, curcumin decreased superior mesenteric artery (SMA) flow and increased SMA resistance. Mesenteric angiogenesis was attenuated by curcumin. Acute administration of curcumin significantly induced splanchnic vasoconstriction. The mesenteric protein expressions of p-endothelial nitric oxide synthase (eNOS), cyclooxygenase (COX) 2 (COX2), vascular endothelial growth factor (VEGF), p-VEGF receptor 2 (VEGFR2), and p-Erk were down-regulated. In collateral system, curcumin decreased portosystemic shunting and induced vasoconstriction. In conclusion, chronic curcumin administration in cirrhotic rats ameliorated portal hypertension related hemodynamic derangements and portosystemic collaterals. Curcumin also attenuated splanchnic hyperdynamic circulation by inducing vasoconstriction through inhibition of eNOS activation and by decreasing mesenteric angiogenesis via VEGF pathway blockade.

scholarly journals Effects of Caffeine Treatment on Hepatopulmonary Syndrome in Biliary Cirrhotic Rats

2019 ◽  
Vol 20 (7) ◽  
pp. 1566
Author(s):  
Ching-Chih Chang ◽  
Chiao-Lin Chuang ◽  
Ming-Hung Tsai ◽  
I.-Fang Hsin ◽  
Shao-Jung Hsu ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Liver Fibrosis ◽  
Portal Pressure ◽  
Hepatopulmonary Syndrome ◽  
Gas Analysis ◽  
Common Bile Duct Ligation ◽  
Arterial Blood ◽  
Duct Ligation ◽  
Intrapulmonary Shunting ◽  
Protein Expressions

Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to receive caffeine or vehicle for 14 days. On the 28th day after CBDL, mortality rate, hemodynamics, liver, and renal biochemistry parameters and arterial blood gas analysis were evaluated. Lung and liver were dissected for the evaluation of inflammation, angiogenesis and protein expressions. In another series with parallel groups, the intrapulmonary shunting was determined. Caffeine significantly reduced portal pressure (caffeine vs. control: 10.0 ± 3.7 vs. 17.0 ± 8.1 mmHg, p < 0.05) in CBDL rats. The mortality rate, mean arterial pressure, biochemistry data and hypoxia were similar between caffeine-treated and control groups. Caffeine alleviated liver fibrosis and intrahepatic angiogenesis but intrapulmonary inflammation and angiogenesis were not ameliorated. The hepatic VEGF/Rho-A protein expressions were down-regulated but the pulmonary inflammation- and angiogenesis-related protein expressions were not significantly altered by caffeine. Caffeine did not reduce the intrapulmonary shunting, either. Caffeine has been shown to significantly improve liver fibrosis, intrahepatic angiogenesis and portal hypertension in cirrhotic rats, however, it does not ameliorate HPS.

Effects of renal denervation on tubular sodium handling in rats with CBL-induced liver cirrhosis

2003 ◽  
Vol 284 (3) ◽  
pp. F555-F563 ◽  
Author(s):  
Thomas E. N. Jonassen ◽  
Lone Brønd ◽  
Malene Torp ◽  
Martin Græbe ◽  
Søren Nielsen ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Renal Denervation ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Sodium Retention ◽  
Common Bile Duct Ligation ◽  
Duct Ligation ◽  
Natriuretic Effect

This study was designed to examine the effect of bilateral renal denervation (DNX) on thick ascending limb of Henle's loop (TAL) function in rats with liver cirrhosis induced by common bile duct ligation (CBL). The CBL rats had, as previously shown, sodium retention associated with hypertrophy of the inner stripe of the outer medulla (ISOM) and increased natriuretic effect of furosemide in vivo, and semiquantitative immunoblotting showed increased expression of the furosemide-sensitive Na-K-2Cl cotransporter type 2 (NKCC2) in ISOM from CBL rats. DNX significantly attenuated the sodium retention in the CBL rats, which was associated with normalization of the natriuretic effect of furosemide, as well as a significant reduction in the expression of NKCC2 in the ISOM. However, the marked hypertrophy of the ISOM found in CBL rats was not reversed by DNX. Together, these data indicate that increased renal sympathetic nerve activity known to be present in CBL rats plays a significant role in the formation of sodium retention by stimulating sodium reabsorption in the TAL via increased renal abundance of NKCC2.

Hypoxic pulmonary hypertension is prevented in rats with common bile duct ligation

2005 ◽  
Vol 98 (2) ◽  
pp. 739-747 ◽  
Author(s):  
Masatoshi Imamura ◽  
Bao Luo ◽  
Jennifer Limbird ◽  
Andrea Vitello ◽  
Masahiko Oka ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Liver Cirrhosis ◽  
Bile Duct ◽  
Chronic Hypoxia ◽  
Bile Duct Ligation ◽  
Heme Oxygenase 1 ◽  
Common Bile Duct Ligation ◽  
Hypoxic Pulmonary Hypertension ◽  
Vascular Responses ◽  
Duct Ligation

Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas-exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial NO synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Importantly, during cirrhosis, the pulmonary vascular responses to acute hypoxia are blunted. The purpose of this work was to examine the pulmonary vascular responses and adaptations to the combination of liver cirrhosis and chronic hypoxia (CH). In addition to hemodynamic measurements, we investigated whether pulmonary expression changes of eNOS, ET-1 and its receptors (endothelin A and B), or heme oxygenase 1 in experimental cirrhosis affect the development of hypoxic pulmonary hypertension. We induced cirrhosis in male Sprague-Dawley rats using common bile duct ligation (CBDL) and exposed them to CH (inspired Po2 ≈ 76 Torr) or maintained them in Denver (Den, inspired Po2 ≈ 122 Torr) for 3 wk. Our data show 1) CBDL-CH rats had a persistent blunted hypoxic pulmonary vasoconstriction similar to CBDL-Den; 2) the development of hypoxic pulmonary hypertension was completely prevented in the CBDL-CH rats, as indicated by normal pulmonary arterial pressure and lack of right ventricular hypertrophy and pulmonary arteriole remodeling; and 3) selective increases in expression of ET-1, pulmonary endothelin B receptor, eNOS, and heme oxygenase 1 are potential mechanisms of protection against hypoxic pulmonary hypertension in the CBDL-CH rats. These data demonstrate that unique and undefined hepatic-pulmonary interactions occur during liver cirrhosis and chronic hypoxia. Understanding these interactions may provide important information for the prevention and treatment of pulmonary hypertension.

scholarly journals Jiao Tai Wan Attenuates Hepatic Lipid Accumulation in Type 2 Diabetes Mellitus

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Zhaoyi Huang ◽  
Xiaohu Xu ◽  
Fuer Lu ◽  
Nan Wang ◽  
Guang Chen ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Hepatic Triglyceride ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Lipogenic Gene Expression ◽  
Protein Expressions ◽  
Triglyceride Content ◽  
Main Components

Jiao Tai Wan (JTW), a Chinese herbal formula containing Rhizoma Coptidis and Cortex Cinnamomi, has been used for diabetic treatment for many years. The aim of this study was to determine the main components in JTW and to investigate the effects of JTW on hepatic lipid accumulation in diabetic rats and humans. JTW extract was prepared and the main components were assayed by HPLC. An animal model of diabetes mellitus was established and JTW was administered intragastrically. In the clinical study, diabetic patients with poor glycemic control were treated with JTW. Blood glucose and lipid parameters, liver histology, hepatic triglyceride content and lipogenic gene expression were examined. Our data demonstrated that JTW significantly improved hyperglycemia, hyperlipidemia and hepatic lipid accumulation in diabetic rats. This was accompanied by the down-regulation of acetyl coenzyme A carboxylase (ACC) and fatty acid synthase (FAS) protein expressions, and the up-regulation of AMP-activated protein kinase (AMPK) and phosphorylated-ACC (pACC) protein expressions in the liver tissues. Diabetic patients also exhibited decreases in their hepatic triglyceride content. The results suggest that JTW attenuates hepatic lipid accumulation in diabetic rats and humans. These beneficial effects are possibly associated with the inhibition of lipogenic gene expression in the liver.

Inhibition of KCa channels restores blunted hypoxic pulmonary vasoconstriction in rats with cirrhosis

2000 ◽  
Vol 279 (5) ◽  
pp. L903-L910 ◽  
Author(s):  
Ethan P. Carter ◽  
Koichi Sato ◽  
Yoshiteru Morio ◽  
Ivan F. McMurtry
Keyword(s):  
Liver Cirrhosis ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Soluble Guanylyl Cyclase ◽  
Hepatopulmonary Syndrome ◽  
Channel Blockers ◽  
Common Bile Duct Ligation ◽  
Pulmonary Vasoconstriction ◽  
Duct Ligation ◽  
Peptide Expression

Rats with liver cirrhosis exhibit the hepatopulmonary syndrome composed of blunted hypoxic pulmonary vasoconstriction and arterial hypoxemia. The purpose of this study was to investigate the roles of nitric oxide (NO) and endothelin-1 (ET-1) in the blunted hypoxic pressor response (HPR) in rats with common bile duct ligation (CBDL). Lungs from CBDL rats exhibited markedly blunted HPR, increased endothelial NO synthase (NOS) protein expression, and decreased ET-1 mRNA and peptide expression. The blunted HPR was not reversed by sequential NOS and soluble guanylyl cyclase inhibition by nitro-l-arginine and 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxaline-1-one (ODQ), respectively, or by NOS inhibition combined with ET-1 addition. The blunted HPR was not due to a generalized inability to vasoconstrict because perfusion pressure was equally elevated by increased perfusate KCl in CBDL and sham lungs. After KCl vasoconstriction, HPR was potentiated and did not differ between CBDL and sham lungs. Blunted HPR was also completely restored in CBDL lungs treated with nitro-l-arginine, ODQ, and the Ca2+-activated K+ channel blockers apamin and charybdotoxin. These results indicate that although CBDL-induced liver cirrhosis is associated with increased NO and decreased ET-1 in the lung, the blunted HPR is a result of additional factors and appears to involve Ca2+-activated K+ channel activation.

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