title: Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Rosado
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Jorge
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: Dinesh
authors.initials: D
authors.lastname: Tripathi
authors.forename: Héctor
authors.initials: H
authors.lastname: García-Calderó
authors.forename: Jaume
authors.initials: J
authors.lastname: Bosch
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000503:physiopathology; D002251:Carbon Tetrachloride / Q000009:adverse effects; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008026:Ligation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D017082:Portal Pressure / Q000187:drug effects* / Q000502:physiology; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D054460:rho-Associated Kinases / Q000502:physiology
chemical_list: D009281:Naphthalenes; D011422:Propionates; D017482:Receptors, Thromboxane; C501362:terutroban; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases