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

2013 ◽  
Vol 305 (7) ◽  
pp. G496-G502 ◽  
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.

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

Biomedicines ◽  
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.

Endothelial modulation of neural sympathetic vascular tone in canine skeletal muscle

1998 ◽  
Vol 85 (4) ◽  
pp. 1362-1367 ◽  
Author(s):  
C. E. King-VanVlack ◽  
S. E. Curtis ◽  
J. D. Mewburn ◽  
S. M. Cain ◽  
C. K. Chapler
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Vascular Resistance ◽  
Nerve Stimulation ◽  
Sympathetic Nerve ◽  
Vascular Tone ◽  
Control Period ◽  
Receptor Blockade ◽  
Before And After ◽  
Group 2

The effect of nitric oxide synthase (NOS) inhibition and endothelin-A (ETA)-receptor blockade on neural sympathetic control of vascular tone in the gastrocnemius muscle was examined in anesthetized dogs under conditions of constant flow. Muscle perfusion pressure (MPP) was measured before and after NOS inhibition ( N ω-nitro-l-arginine methyl ester; l-NAME) and ETA-receptor blockade [ cyclo-(d-Trp- d-Asp-Pro-d-Val-Leu); BQ-123]. Zero and maximum sympathetic nerve activities were achieved by sciatic nerve cold block and stimulation, respectively. In group 1( n = 6), MPP was measured 1) before nerve cold block, 2) during nerve cold block, and 3) during nerve stimulation. Measurements under these conditions were repeated afterl-NAME and then BQ-123. The same protocol was followed in group 2( n = 6) except that the order ofl-NAME and BQ-123 was reversed. MPP and muscle vascular resistance (MVR) increased afterl-NAME and then decreased to control values after BQ-123. MVR decreased after BQ-123 alone and, with the addition of l-NAME, increased to a level not different from that observed during the control period. MVR fell during nerve cold block. This response was not affected by administration ofl-NAME followed by BQ-123, but it was attenuated by administration of BQ-123 beforel-NAME. The constrictor response during sympathetic nerve stimulation was enhanced byl-NAME; no further effect was observed with BQ-123, nor was the response affected when BQ-123 was given first. These findings indicate that endothelin contributes to 1) basal vascular tone in skeletal muscle and 2) the increase in skeletal muscle vascular resistance after NOS inhibition. Finally, nitric oxide “buffers” the degree of constriction in skeletal muscle vasculature during maximal sympathetic stimulation.

Splanchnic and systemic haemodynamic response to volume changes in patients with cirrhosis and portal hypertension

1999 ◽  
Vol 96 (5) ◽  
pp. 475-481 ◽  
Author(s):  
Panagiotis VLAVIANOS ◽  
Padraik MAC MATHUNA ◽  
Roger WILLIAMS ◽  
David WESTABY
Keyword(s):  
Cardiac Output ◽  
Portal Hypertension ◽  
Systemic Vascular Resistance ◽  
Blood Volume ◽  
Vascular Resistance ◽  
Venous Pressure ◽  
Portal Pressure ◽  
Haemodynamic Response ◽  
Volume Depletion ◽  
Compensated Cirrhosis

We investigated the haemodynamic response to volume depletion and subsequent repletion in patients with cirrhosis and portal hypertension. Twelve patients with compensated cirrhosis and portal hypertension were included in the study. The haemodynamic changes occurring after removal of approx. 15% of the blood volume, and subsequently after isovolume repletion with colloid, were assessed. Baseline haemodynamic measurements showed increased cardiac output and a systemic vascular resistance at the lower limit of normal. The hepatic venous pressure gradient (HVPG) was increased, at 18 mmHg. After depletion, arterial pressure, cardiac output and all right-heart-sided pressures decreased, and systemic vascular resistance increased. HVPG decreased to 16.0 mmHg. All the above changes were statistically significant. After blood volume restitution, the haemodynamic values returned to baseline. In particular, an increase in HVPG was shown in four out of the twelve patients (two with ascites and two without), which was small in three of them. However, HVPG remained the same as or lower than the baseline in the other eight patients. Patients with cirrhosis and portal hypertension exhibit an abnormal haemodynamic response to blood volume depletion. After volume repletion, no increase in the portal pressure was noted in this group of patients as a whole, although four out of the twelve patients did show an increase, possibly due to extensive collateral circulation.

Cirrhosis regression: extrahepatic angiogenesis and liver hyperarterialization persist

2018 ◽  
Vol 132 (12) ◽  
pp. 1341-1343
Author(s):  
Audrey Payancé ◽  
Pierre-Emmanuel Rautou
Keyword(s):  
Vascular Resistance ◽  
Antiviral Treatment ◽  
Venous Pressure ◽  
Portal Pressure ◽  
Systemic Hemodynamics ◽  
Marginal Effect ◽  
Hemodynamic Changes ◽  
Systemic Hemodynamic ◽  
Duct Ligation ◽  
Intrahepatic Vascular Resistance

Data on the consequences of cirrhosis regression on portal hypertension and on splanchnic and systemic hemodynamic are scarce. Previous studies have reported a decrease in hepatic venous pressure gradient following antiviral treatment in patients with hepatitis B or C related cirrhosis. However, these studies did not investigate splanchnic and systemic hemodynamic changes associated with virus control. To fill this gap in knowledge, in a recent issue of Clinical Science, Hsu et al. (vol. 132, issue 6, 669-683) used rat models of cirrhosis induced by thioacetamide and by bile duct ligation and provided a comprehensive analysis of the effects of cirrhosis regression on splanchnic and systemic hemodynamics. They observed a significant reduction in portal pressure accompanied by a normalization of systemic hemodynamic (normal cardiac index and systemic vascular resistance) and a decrease in intrahepatic vascular resistance. No change in extrahepatic vascular structures were observed despite normalization of collateral shunting, meaning that portosystemic collaterals persist but are not perfused. One intriguing part of their results is the only marginal effect of cirrhosis regression on liver hyperarterialisation. This result suggests that changes in splanchnic hemodynamic features induced by cirrhosis remain when hepatic vascular resistance decreases, raising the hypothesis of an autonomous mechanism persisting despite regression of intrahepatic vascular resistance. Microbiota changes and bacterial translocation might account for this effect. In conclusion cirrhosis regression normalizes systemic hemodynamics, but some splanchnic hemodynamic changes persist including extrahepatic angiogenesis and liver hyperarterialization.

Nitric oxide modulates hepatic vascular tone in normal rat liver

1994 ◽  
Vol 267 (3) ◽  
pp. G416-G422 ◽  
Author(s):  
M. K. Mittal ◽  
T. K. Gupta ◽  
F. Y. Lee ◽  
C. C. Sieber ◽  
R. J. Groszmann
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Portal Pressure ◽  
Portal Circulation ◽  
Perfusate Flow ◽  
Normal Rat ◽  
Rat Livers

This study investigated whether nitric oxide (NO) plays a role in the intrahepatic portal circulation in normal rat livers perfused in situ. N omega-nitro-L-arginine (NNA), a specific NO biosynthesis inhibitor, significantly increased baseline portal pressure compared with controls (P < 0.05). Concentration-effect curves to norepinephrine (NE) were performed. Perfusate flow was maintained as constant, and perfusion pressure was continuously measured. NNA markedly enhanced the responsiveness to NE. This effect was abolished by the addition of L-arginine, a specific NO substrate. Presence of indomethacin did not alter the response to NE. The response to NE in the presence of indomethacin and NNA was significantly more than the response to NE in the presence of NNA alone. In vivo, intraportal infusion of NNA significantly enhanced the portal pressure compared with vehicle. This study demonstrates that NO contributes to the basal vascular tone and attenuates the response to NE in intrahepatic portal vascular bed of normal rats. These results support a functional role of NO in the regulation of the intrahepatic portal circulation in normal rats. This study also suggests a synergistic, albeit limited, role of prostacyclin in the intrahepatic circulation.

Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state

2006 ◽  
Vol 290 (5) ◽  
pp. G980-G987 ◽  
Author(s):  
Juan G. Abraldes ◽  
Yasuko Iwakiri ◽  
Mauricio Loureiro-Silva ◽  
Omar Haq ◽  
William C. Sessa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Portal Pressure ◽  
No Production ◽  
Portal Vein Ligation ◽  
Vegf Expression ◽  
Enos Expression ◽  
Hyperdynamic Circulation ◽  
Intestinal Microcirculation ◽  
Hypertension Portal

Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation.

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