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Title: Terutroban, A TP-receptor antagonist, reduces portal pressure in cirrhotic rats
Author: Rosado Mateo, Eugenio
Rodríguez-Vilarrupla, Aina
Gracia-Sancho, Jorge
Tripathi, Dinesh
García-Calderó, Héctor
Bosch i Genover, Jaume
García Pagán, Juan Carlos
Keywords: Cirrosi hepàtica
Hipertensió portal
Fibrosi pulmonar
Òxid nítric
Animals de laboratori
Hepatic cirrhosis
Portal hypertension
Pulmonary fibrosis
Nitric oxide
Laboratory animals
Issue Date: 7-Aug-2013
Publisher: Wiley
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.
Note: Versió postprint del document publicat a:
It is part of: Hepatology, 2013, vol. 58, num. 4, p. 1424-1435
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ISSN: 0270-9139
Appears in Collections:Articles publicats en revistes (Medicina)

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