Liver, spleen, and body weight were not different between groups (Table 1B). Livers from cirrhotic rats treated with vehicle
exhibited an impaired vasodilatory response to Ach. Terutroban Ribociclib research buy treatment significantly improved vasorelaxation in response to Ach (Fig. 6A). An increase in the hepatic production of the vasoconstrictor prostanoid TXA2 has been shown to increase hepatic resistance in cirrhotic livers, contributing to increased portal pressure.[3, 20, 30-32] Up to now, in vivo efforts to reduce this increased hepatic resistance by reducing TXA2 levels have been based on treatments with nonselective COX inhibitors.[32, 33] However, the strategy to block TXA2 production by nonselective COX inhibition is not acceptable in cirrhosis due to its demonstrated deleterious effects on sodium and water retention and renal function.[34, 35] There are no previous reports of the effects of TP-receptor blockade in vivo in cirrhotic animals. We hereby report the effects of terutroban, a specific TP-receptor blocker, in cirrhotic rats. Terutroban has been extensively used in clinical trials in vascular diseases and proven to be safe.[14, 36, 37] Our study demonstrates selleck compound that in vivo chronic TP-receptor blockade with terutroban produced a similar reduction in portal pressure in two different
models, CCl4 and BDL. The decrease in portal pressure was not associated with changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. This beneficial effect of terutroban on hepatic resistance could be attributed,
in part, to the blockade of the vasoconstrictor effect of TXA2.[3, 32] Indeed, the blunted increase in portal pressure after the infusion of the TXA2 agonist U46619 in terutroban-treated rats suggests an adequate TP-receptor blockade and inhibition of TXA2-derived vasoconstriction of HSC and/or vascular smooth muscle cells in the hepatic vasculature. We also characterized the effects of terutroban on Rho-kinase activity. Non-specific serine/threonine protein kinase Rho-kinase, which is activated among other factors by the TP-receptor, is a well-known mechanism of HSC contraction[18, 38, 39] and it has been recently shown that its inhibition reduces hepatic vascular resistance.[40, 41] Our results showing that terutroban reduces hepatic Rho-kinase activity in both experimental models suggest that this may be an additional mechanism by which terutroban decreases hepatic vascular resistance. However, other effects of terutroban were different according to the cirrhotic rat model. In CCl4-cirrhotic rats, terutroban ameliorated the architectural abnormalities of the liver, as shown by the reduction in liver fibrosis area on Sirius red staining. This was associated with a decrease in collagen I mRNA expression, suggesting a reduced collagen synthesis as a consequence of TP-receptor blockade, as it was not observed in vehicle-treated rats.