Influence of indomethacin on effects of endothelin-1 on guinea pig isolated rings of common bile duct and sphincter of Oddi

The effects of endothelin-1 on motility of guinea pig extra-hepatic biliary tract portions were studied. Endothelin-1 (less than or equal to 100 nM) failed to contract rings of hepatic, cystic, proximal or distal common bile ducts, or choledochal or papillary halves of sphincter of Oddi. At 100 nM, endothelin-1 or sarafotoxin S6c (selective endothelin ETB receptor agonist) inhibited contractions of choledochal (but not papillary) sphincter of Oddi to carbachol (1 muM) by 63 +/- 5 and 45 +/- 9%, respectively. In distal common bile duct, indomethacin (5.6 muM) unmasked potent contractile effects of endothelin-1 [EC50 7.8 (5.5 - 11.1) nM; E-MAX 80 +/- 6% of response to 80 mM KCl] and enhanced the contractile potency of carbachol (585-fold at EC50 level), but not cholecystokinin C-terminal octapeptide. Inhibition of cholinergic responsiveness of the choledochal sphincter of Oddi by endothelin-1 was reduced by BQ-123 (1 muM; endothelin ETA receptor antagonist; cyclo[DTrp-DAsp-Pro-DVal-Leu]) and abolished by either BQ-123 plus BQ-788 (1 muM; endothelin ETB receptor antagonist; N-cis-2,6-methylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-D-norleucine) or indomethacin. Thus, eicosanoids of the cyclo-oxygenase pathway (i.e. prostanoids) suppress endothelin-1-induced contractions of distal common bile duct and mediate endothelin ETA and ETB receptor-dependent inhibition of cholinergic responsiveness of the choledochal portion of the sphincter of Oddi. (C) 2002 Elsevier Science B.V. All rights reserved.