Mechanism of ethacrynic acid-induced choleresis in the rat

Ethacrynic acid (EA) was injected to rats with functional nephrectomy after a control period of steady-state bile flow sustained by taurocholate infusion. Biliary clearance of [14C]mannitol was measured in order to estimate canalicular bile flow and bile salt-independent fraction (BSIF). After EA infusion, bile flow increased by 56%; bile salt excretion rate decreased by 10%; electrolyte excretion rates all increased, principally Na+ and K+. Mannitol clearance increased in parallel with bile flow. The BSIF increased. EA was excreted into bile as a metabolite identified as the cysteine adduct of EA; its excretion rate was linearly correlated with the increment in bile flow. The results are consistent with the hypothesis that the biliary excretion of an EA derivative results in an osmotic water flow increasing the canalicular BSIF. Since EA ia a Na+-K+-ATPase inhibitor, it is necessary to reconsider the relationship between secretion of canalicular BSIF and active Na+ transport mediated by the Na+-K+-ATPase system.