Endothelins induce gallbladder contraction independent of elevated blood pressure in vivo in the Australian possum

Endothelin levels are elevated in shock, sepsis, and cholestatic jaundice, and an effect on biliary motility may be postulated. The aim of this study was to determine whether (1) endothelin-1 and endothelin-3 induce gallbladder contraction in vivo, (2) the response is caused by changes in blood pressure, and (3) the response is nerve mediated. Gallbladder pressure and blood pressure were measured in 38 anesthetized possums. Endothelin-1 or endothelin-3 (5 to 200 pmol/kg) was administered by close intra-arterial injection. Tetrodotoxin (9 mug/kg) or the mixed endothelin antagonist tezosentan was infused at a rate of 10 or 100 nmol/kg/min (close intra-arterial injection). Maximum changes in gallbladder pressure (% of carbachol-induced contraction) and blood pressure (mm Hg) were determined. Statistical analysis was carried out by means of repeated-measures analysis of variance and Kruskal-Wallis test. Both endothelin-1 and endothelin-3 induced dose-dependent increases in gallbladder pressure and blood pressure (P<0.05), which were unaffected by pretreatment with tetrodotoxin. The endothelin-1-induced gallbladder pressure but not blood pressure was reduced by the higher dose of tezosentan (P<0.03). The lower dose of tezosentan also produced a decrease in the endothelin-3-induced gallbladder pressure (P<0.02) but not in blood pressure, whereas the higher dose reduced the blood pressure with no further reduction in gallbladder pressure (P<0.05). Endothelins increase gallbladder motility in vivo, acting directly on the smooth muscle and independent of changes in blood pressure.