Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats

Authors

  • Eugenio Rosado,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Aina Rodríguez-Vilarrupla,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Jorge Gracia-Sancho,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Dinesh Tripathi,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Héctor García-Calderó,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Jaume Bosch,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Juan Carlos García-Pagán

    Corresponding author
    • Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the Ministerio de Economía y Competitividad (SAF 2010/17043 and ACI2009-0938) and from Instituto de Salud Carlos III (FIS PS09/01261 and FIS PI11/00235). Ciberehd is funded by Instituto de Salud Carlos III. Jorge Gracia-Sancho has a Ramón y Cajal contract from the Ministerio de Economía y Competitividad.

Address reprint requests to: Juan Carlos García-Pagán, Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. E-mail: jcgarcia@clinic.ub.es; fax: +34-93-2279856.

Abstract

Increased production of vasoconstrictive prostanoids, such as thromboxane A2 (TXA2), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA2 induces vasoconstriction by way of activation of the thromboxane-A2/prostaglandin-endoperoxide (TP) receptor. This study investigated whether terutroban, a specific TP receptor blocker, decreases hepatic vascular tone and portal pressure in rats with cirrhosis due to carbon tetrachloride (CCl4) or bile duct ligation (BDL). Hepatic and systemic hemodynamics, endothelial dysfunction, liver fibrosis, hepatic Rho-kinase activity (a marker of hepatic stellate cell contraction), and the endothelial nitric oxide synthase (eNOS) signaling pathway were measured in CCl4 and BDL cirrhotic rats treated with terutroban (30 mg/kg/day) or its vehicle for 2 weeks. Terutroban reduced portal pressure in both models without producing significant changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. Terutroban did not significantly change arterial pressure in CCl4-cirrhotic rats but decreased it significantly in BDL-cirrhotic rats. In livers from CCl4 and BDL-cirrhotic terutroban-treated rats, endothelial dysfunction was improved and Rho-kinase activity was significantly reduced. In CCl4-cirrhotic rats, terutroban reduced liver fibrosis and decreased alpha smooth muscle actin (α-SMA), collagen-I, and transforming growth factor beta messenger RNA (mRNA) expression without significant changes in the eNOS pathway. In contrast, no change in liver fibrosis was observed in BDL-cirrhotic rats but an increase in the eNOS pathway. Conclusion: Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl4-cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation. (Hepatology 2013;58:1424–1435)

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