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

Abstract

The effects of endothelin-1 on motility of guinea pig extra-hepatic biliary tract portions were studied. Endothelin-1 (≤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 ET B receptor agonist) inhibited contractions of choledochal (but not papillary) sphincter of Oddi to carbachol (1 μM) by 63±5 and 45±9%, respectively. In distal common bile duct, indomethacin (5.6 μM) unmasked potent contractile effects of endothelin-1 [EC 50 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 EC 50 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 μM; endothelin ET A receptor antagonist; cyclo[DTrp-DAsp-Pro-DVal-Leu]) and abolished by either BQ-123 plus BQ-788 (1 μM; endothelin ET B receptor antagonist; N- cis-2,6-dimethylpiperidinocarbonyl- l-γ-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 ET A and ET B receptor-dependent inhibition of cholinergic responsiveness of the choledochal portion of the sphincter of Oddi.