title: Endothelin-1 and -3 induce choleresis in the rat through ETB receptors coupled to nitric oxide and vagovagal reflexes.
abstract: We have reported previously that centrally applied ET (endothelin)-1 and ET-3 induce either choleresis or cholestasis depending on the dose. In the present study, we sought to establish the role of these endothelins in the short-term peripheral regulation of bile secretion in the rat. Intravenously infused endothelins induced significant choleresis in a dose-dependent fashion, ET-1 being more potent than ET-3. Endothelins (with the exception of a higher dose of ET-1) did not affect BP (blood pressure), portal venous pressure or portal blood flow. ET-1 and ET-3 augmented the biliary excretion of bile salts, glutathione and electrolytes, suggesting enhanced bile acid-dependent and -independent bile flows. ET-induced choleresis was mediated by ET(B) receptors coupled to NO and inhibited by truncal vagotomy, atropine administration and capsaicin perivagal application, supporting the participation of vagovagal reflexes. RT (reverse transcription)-PCR and Western blot analysis revealed ETA and ET(B) receptor expression in the vagus nerve. Endothelins, through ET(B) receptors, augmented the hepatocyte plasma membrane expression of Ntcp (Na⁺/taurocholate co-transporting polypeptide; Slc10a1), Bsep (bile-salt export pump; Abcb11), Mrp2 (multidrug resistance protein-2; Abcc2) and Aqp8 (aquaporin 8). Endothelins also increased the mRNAs of these transporters. ET-1 and ET-3 induced choleresis mediated by ET(B) receptors coupled to NO release and vagovagal reflexes without involving haemodynamic changes. Endothelin-induced choleresis seems to be caused by increased plasma membrane translocation and transcriptional expression of key bile transporters. These findings indicate that endothelins are able to elicit haemodynamic-independent biological effects in the liver and suggest that these peptides may play a beneficial role in pathophysiological situations where bile secretion is impaired.
authors: Cátedras de Fisiopatología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Myrian R
authors: MR
authors: Rodriguez
authors: Leandro R
authors: LR
authors: Soria
authors: María S
authors: MS
authors: Ventimiglia
authors: Ana C
authors: AC
authors: Najenson
authors: Adrián
authors: A
authors: Di María
authors: Paula
authors: P
authors: Dabas
authors: Andrea
authors: A
authors: Fellet
authors: Raúl A
authors: RA
authors: Marinelli
authors: Marcelo S
authors: MS
authors: Vatta
authors: Liliana G
authors: LG
authors: Bianciotti
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D002779:Cholestasis / Q000139:chemically induced* / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000378:metabolism / Q000502:physiology*; D012018:Reflex / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D002756:Cholagogues and Choleretics; D019332:Endothelin-1; D019334:Endothelin-3; D044023:Receptor, Endothelin B; D009569:Nitric Oxide