Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats

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• 作者：Federica Cerini¹ ; ^&dagger ; ; Marina Vilaseca¹ ; ³ ; ⁵ ; ^&dagger ; ; Erica Lafoz¹ ; ⁵ ; Oihane Garcí ; a-Irigoyen² ; ³ ; Hé ; ctor Garcí ; a-Calderó ; ¹ ; ³ ; ⁵ ; Dinesh M. Tripathi¹ ; ⁵ ; Matias Avila² ; ³ ; Juan Carlos Reverter⁴ ; ⁵ ; Jaime Bosch¹ ; ³ ; ⁵ ; Jordi Gracia-Sancho¹ ; ³ ; ⁵ ; Juan Carlos Garcí ; a-Pagá ; n¹ ; ³ ; ⁵ ; ^{jcgarcia@clinic.cat" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HSC ; hepatic stellate cells ; PAR ; protease activated receptor ; LMWH ; low molecular weight heparin ; PVT ; portal vein thrombosis ; NO ; nitric oxide ; CCl4 ; carbon tetrachloride ; MAP ; mean arterial pressure ; PP ; portal pressure ; PBF ; portal blood flow ; SMABF ; superior mesenteric artery blood flow ; HVR ; hepatic vascular resistance ; cGMP ; cyclic guanosine monophosphate ; O2&minus ; superoxide ; α-SMA ; alpha-smooth muscle actin ; PDGFRb ; platelet derived growth factor receptor b ; eNOS ; endothelial NO synth
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：64
• 期：4
• 页码：834-842
• 全文大小：1885 K

文摘

Increased hepatic vascular resistance due to fibrosis and elevated hepatic vascular tone is the primary factor in the development of portal hypertension. Heparin may decrease fibrosis by inhibiting intrahepatic microthrombosis and thrombin-mediated hepatic stellate cell activation. In addition, heparin enhances eNOS activity, which may reduce hepatic vascular tone. Our study aimed at evaluating the effects of acute, short-, long-term and preventive enoxaparin administration on hepatic and systemic hemodynamics, liver fibrosis and nitric oxide availability in cirrhotic rats.

Methods

Enoxaparin (1.8 mg/kg subcutaneously), or its vehicle, was administered to CCl₄-cirrhotic rats 24 h and 1 h before the study (acute), daily for 1 week (short-term) or daily for 3 weeks (long-term) and to thioacetamide-cirrhotic rats daily for 3 weeks with/without thioacetamide (preventive/long-term, respectively). Mean arterial pressure, portal pressure, portal blood flow, hepatic vascular resistance and molecular/cellular mechanisms were evaluated.

Results

No significant changes in hemodynamic parameters were observed in acute administration. However, one-week, three-week and preventive treatments significantly decreased portal pressure mainly due to a decrease in hepatic vascular resistance without significant changes in mean arterial pressure. These findings were associated with significant reductions in liver fibrosis, hepatic stellate cell activation, and desmin expression. Moreover, a reduction in fibrin deposition was observed in enoxaparin-treated rats, suggesting reduced intrahepatic microthrombosis.

Conclusion

Enoxaparin reduces portal pressure in cirrhotic rats by improving the structural component of increased liver resistance. These findings describe the potentially beneficial effects of enoxaparin beyond the treatment/prevention of portal vein thrombosis in cirrhosis, which deserve further investigation.