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

Abstract

We previously reported that ET3 induces choleresis through ETB receptors coupled to nitric oxide (NO). It enhances, independently of hemodynamic changes, bile acid dependent and independent bile flows and promotes plasma membrane insertion of the main hepatic transporters involved in bile genesis and increases their mRNA expression (Clin Sci., 125:531, 2013). In this work we aimed to determine whether ET3 played a beneficial role in E217G‐induced cholestasis. Sprague‐Dawley rats were infused with ET3 (5 ng/kg/min) or vehicle for 30 min followed by E217G administration to induce cholestasis. Bile samples were collected every 5 min for 120 min. Bile acids were assessed in bile by capillary electrophoresis. Other set of animals were also pretreated with L‐NAME (NO synthases inhibitor) or BQ788 (ETB receptor antagonist) before ET3 and E217G administration. ET3 prevented E217G‐induced cholestasis and the response was abolished by BQ788 or L‐NAME. Furthermore ET3 also modified bile acid excretion, particularly ursodeoxycholic acid and lithocholic acid as compared with control and E217G. ET3 induced no changes in plasma transaminases, bilirubin, alkaline phosphatase or 5´nucleotidase or in the hepatic histology assessed by light microscopy in stained hematoxylin and eosin liver samples. Present findings show that ET3 through ETB receptors coupled to NO prevents E217G‐induced cholestasis and modifies bile acid profile excretion in the rat. Results further suggest that the ETB receptor may represent a promising therapeutic target in pathophysiological situations where bile flow is impaired.