Receptors mediating endothelin-1-induced contractions of rabbit gallbladder

We have examined the responsiveness of strips of rabbit gallbladder (RGB) t o endothelin (ET) receptor agonists, and its susceptibility to blockade by selective antagonists. Endothelin-1 (ET-1; 0.1-100.0 nM) caused graded toni c contractions with a CK50 (concentration causing response equivalent to 50 % of KCI 80 mM) of 3.4 nM and E-H (response to highest concentration) of 18 6 +/- 22, being 40-fold less potent than cholecystokinin-8 (CCK-8), 103-fol d more potent than carbachol, but equipotent to ET-3, sarafotoxin S6c (S6c) and IRL 1620. The selective ETA receptor antagonists BQ-123 (3 muM) and A- 127722-5 (0.3 muM) did not block responses to ET-1, but BQ-123 depressed re sponses to 30-100 nM ET-3 by about 35%. The ETB receptor antagonist BQ-788 (1 muM) shifted the curve to S6c by only fivefold. In rabbit aorta and at t hese same concentrations, BQ-123 and A-127722-5 markedly shifted (greater t han or equal to 100-fold) the curve for ET-1-induced contraction, whereas B Q-788 shifted that for S6c 40-fold. Higher concentrations of all three anta gonists contracted the RGB. Thus, although RGB responses to ETs and selecti ve ETB receptor agonists seem to be largely mediated via ETB receptors, the y are remarkably insensitive to blockade by both selective ETA and ETB rece ptor antagonists, as previously reported in the guinea pig gallbladder. Fin ally, through yet unknown mechanisms, high concentrations of ET receptor an tagonists induce marked RGB contractions. It remains to be seen whether thi s finding is predictive of adverse biliary tract side-effects of such drugs in the clinic.