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Droxidopa, an oral norepinephrine precursor, improves hemodynamic and renal alterations of portal hypertensive rats

Authors

  • Mar Coll,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Sarai Rodriguez,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Imma Raurell,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Nahia Ezkurdia,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Astrid Brull,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Salvador Augustin,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Jaime Guardia,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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  • Rafael Esteban,

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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  • María Martell,

    Corresponding author
    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
    • Liver Diseases Laboratory, Hospital Vall d'Hebron Institut de Recerca (VHIR), Pg Vall d'Hebron 119-127, 08035 Barcelona, Spain
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    • fax: +34-934894032

  • Joan Genescà

    1. Laboratory of Liver Diseases, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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  • Potential conflict of interest: Nothing to report.

  • Nahia Ezcurdia and Sarai Rodríguez are recipients of a predoctoral fellowship grant from the VHIR and enrolled in the postgraduate program of the Department of Medicine of the Universitat Autònoma de Barcelona. Imma Raurell is a recipient of a fellowship grant from the Instituto de Salud Carlos III. Salvador Augustin is a recipient of a “Rio Hortega” fellowship grant from the Instituto de Salud Carlos III. CIBERehd is supported by Instituto de Salud Carlos III. The study was funded by a grant from Ministerio de Ciencia e Innovación (MICINN) SAF2009-08354. Chelsea Therapeutics Inc. has not contributed financially to this work.

Abstract

We aimed to evaluate the effects of droxidopa (an oral synthetic precursor of norepinephrine) on the hemodynamic and renal alterations of portal hypertensive rats. Sham, portal vein-ligated (PVL), and 4-week biliary duct-ligated (BDL) rats received a single oral dose of droxidopa (25-50 mg/kg) or vehicle and hemodynamic parameters were monitored for 2 hours. Two groups of BDL and cirrhotic rats induced by carbon tetrachloride (CCl4) were treated for 5 days with droxidopa (15 mg/kg, twice daily, orally); hemodynamic parameters and blood and urinary parameters were assessed. The droxidopa effect on the Rho kinase (RhoK) / protein kinase B (AKT) / endothelial nitric oxide synthase (eNOS) pathways was analyzed by western blot in superior mesenteric artery (SMA). The acute administration of droxidopa in PVL and BDL rats caused a significant and maintained increase in arterial pressure and mesenteric arterial resistance, with a significant decrease of mesenteric arterial and portal blood flow, without changing portal pressure and renal blood flow. Two-hour diuresis greatly increased. Carbidopa (DOPA decarboxylase inhibitor) blunted all effects of droxidopa. Chronic droxidopa therapy in BDL rats produced the same beneficial hemodynamic effects observed in the acute study, did not alter liver function parameters, and caused a 50% increase in 24-hour diuresis volume (7.4 ± 0.9 mL/100g in BDL vehicle versus 11.8 ± 2.5 mL/100g in BDL droxidopa; P = 0.01). Droxidopa-treated rats also showed a decreased ratio of p-eNOS/eNOS and p-AKT/AKT and increased activity of RhoK in SMA. The same chronic treatment in CCl4 rats caused similar hemodynamic effects and produced significant increases in diuresis volume and 24-hour natriuresis (0.08 ± 0.02 mmol/100g in CCl4 vehicle versus 0.23 ± 0.03 mmol/100g in CCl4 droxidopa; P = 0.014). Conclusion: Droxidopa might be an effective therapeutic agent for hemodynamic and renal alterations of liver cirrhosis and should be tested in cirrhosis patients. (HEPATOLOGY 2012;56:1849–1860)

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