Role of Endothelin 3 (ET3) in Estradiol 17B-glucuronide (E217G)-induced Cholestasis in the Rat

RODRIGUEZ M; MARTINEFSKI M; TRIPPODI V; VATTA MS; BIANCIOTTI LG

Boston

Congreso; Experimental Biology; 2015

Federation of American Societies for Experimental Biology

Wepreviously reported that ET3 induces choleresis through ETB receptors coupledto nitric oxide (NO). It enhances, independently of hemodynamic changes, bileacid dependent and independent bile flows and promotes plasma membraneinsertion of the main hepatic transporters involved in bile genesis andincreases their mRNA expression (Clin Sci., 125:531, 2013). In this workwe aimed to determine whether ET3 played a beneficial role in E217G-inducedcholestasis. Sprague-Dawley rats were infused with ET3 (5 ng/kg/min) or vehiclefor 30 min followed by E217G administration to induce cholestasis. Bile sampleswere collected every 5 min for 120 min. Bile acids were assessed in bile bycapillary electrophoresis. Other set of animals were also pretreated withL-NAME (NO synthases inhibitor) or BQ788 (ETB receptor antagonist) before ET3and E217G administration. ET3 prevented E217G-induced cholestasis and theresponse was abolished by BQ788 or L-NAME. Furthermore ET3 also modified bileacid excretion, particularly ursodeoxycholic acid and lithocholic acid ascompared with control and E217G. ET3 induced no changes in plasmatransaminases, bilirubin, alkaline phosphatase or 5´nucleotidase or in thehepatic histology assessed by light microscopy in stained hematoxylin and eosinliver samples. Present findings show that ET3 through ETB receptorscoupled to NO prevents E217G-induced cholestasis and modifies bile acid profileexcretion in the rat. Results further suggest that the ETB receptormay represent a promising therapeutic target in pathophysiological situationswhere bile flow is impaired.