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Terutroban, a TP‐receptor antagonist, reduces portal pressure in cirrhotic rats
Author(s) -
Rosado Eugenio,
RodríguezVilarrupla Aina,
GraciaSancho Jorge,
Tripathi Dinesh,
GarcíaCalderó Héctor,
Bosch Jaume,
GarcíaPagán Juan Carlos
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26520
Subject(s) - medicine , endocrinology , portal venous pressure , portal hypertension , cirrhosis , thromboxane a2 , enos , thromboxane , hepatic stellate cell , hepatic fibrosis , nitric oxide synthase , nitric oxide , receptor , platelet
Increased production of vasoconstrictive prostanoids, such as thromboxane A 2 (TXA 2 ), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA 2 induces vasoconstriction by way of activation of the thromboxane‐A 2 /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 (CCl 4 ) 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 CCl 4 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 CCl 4 ‐cirrhotic rats but decreased it significantly in BDL‐cirrhotic rats. In livers from CCl 4 and BDL‐cirrhotic terutroban‐treated rats, endothelial dysfunction was improved and Rho‐kinase activity was significantly reduced. In CCl 4 ‐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 CCl 4 ‐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. (H epatology 2013;58:1424–1435)