We have examined the responsiveness of strips of rabbit gallbladder (RGB) to endothelin (ET) receptor agonists, and its susceptibility to blockade by selective antagonists. Endothelin-1 (ET-1; 0.1-100.0 nM) caused graded tonic contractions with a CK50 (concentration causing response equivalent to 50% of KCI 80 mM) of 3.4 nM and EH (response to highest concentration) of 186 ± 22, being 40-fold less potent than cholecystokinin-8 (CCK-8), 103-fold more potent than carbachol, but equipotent to ET-3, sarafotoxin S6c (S6c) and IRL 1620. The selective ETA receptor antagonists BQ-123 (3 μM) and A-127722-5 (0.3 μM) did not block responses to ET-1, but BQ-123 depressed responses to 30-100 nM ET-3 by about 35%. The ETB receptor antagonist BQ-788 (1 μM) shifted the curve to S6c by only fivefold. In rabbit aorta and at these same concentrations, BQ-123 and A-127722-5 markedly shifted (≥ 100-fold) the curve for ET-1-induced contraction, whereas BQ-788 shifted that for S6c 40-fold. Higher concentrations of all three antagonists contracted the RGB. Thus, although RGB responses to ETs and selective ETB receptor agonists seem to be largely mediated via ETB receptors, they are remarkably insensitive to blockade by both selective ETA and ETB receptor antagonists, as previously reported in the guinea pig gallbladder. Finally, through yet unknown mechanisms, high concentrations of ET receptor antagonists induce marked RGB contractions. It remains to be seen whether this finding is predictive of adverse biliary tract side-effects of such drugs in the clinic.
Department of Pharmacology, CCB, Federal University of Santa Catarina, Florianópolis, SC, Brazil and*Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada
Address correspondence and reprint requests to Dr Giles A. Rae, Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, Rua Ferreira Lima, 82, 88015-420, Florianópolis SC, Brazil. E-mail: [email protected]
© 2000 Lippincott Williams & Wilkins, Inc.