Endothelins (ETs) potently contract guinea pig gallbladder (GPGB) via endothelin-A and -B (ETA and ETB) receptors. This study assesses the possible participation of eicosanoids in the mediation of responses of the GPGB (Krebs' solution, 37°C, 0.5 g load) triggered through each receptor type. Indomethacin (INDO; 5.6 μM) shifted the curve to endothelin-1 (ET-1) (0.1-100 nM) to the right, enhancing the CK50 (concentration causing 50% of response to KC1 80 mM) from 0.9 to 6.8 nM and reducing its EH (response to 100 nM) from 170 ± 13 to 123 ± 9 (% of response to 80 mM KC1). INDO strongly depressed responses to sarafotoxin S6c (S6c; control CK50 0.9 nM), reducing its EH from 108 ± 5 to 21 ± 4. Neither BQ-123 nor BQ-788 (1 μM) changed responses to ET-1, but each markedly reduced responsiveness to ET-3 (control: CK50 of 9.7 nM and EH of 153 ± 14; BQ-123: ≅ 100 nM and 44 ± 12; BQ-788 ≅ 100 nM and 65 ± 18). In the presence of BQ-123, INDO further depressed responses to ET-3 (EH 26 ± 6), whereas in the presence of BQ-788, such responses were strongly enhanced (EH 126 ± 9). These findings strongly suggest that contractions of GPGB caused via ETB receptors are mediated to a large extent by contractile eicosanoids, whereas those caused (at least by ET-3) via ETA receptors are limited by relaxant eicosanoids. The cellular sources and nature of the eicosanoids released by ETs remain to be established.
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.