Atypical antagonism observed with BQ-123 in human saphenous vein.

At present, endothelin (ET) receptor classification remains controversial. We investigated the presence of atypical ET A receptors in human saphenous veins (SV). Human SV was obtained from 24 patients undergoing coronary artery bypass grafting. Vessels were set up in organ baths, stretched to a tension of 6 g, and left to relax before being challenged with 90 mM KCl. After KCl challenge, tissues were incubated with 2.8 μM indomethacin and 100 μM L-NMMA for 30 min followed by 30 min in the presence of antagonist before a concentration-response curve to ET-1 or sarafotoxin 6b (S6b) (10 -10 -10 -7 M) was constructed. In endothelium-intact vessels, incubated with indomethacin and L-NMMA, BQ-123 (1 μM) caused nonparallel shifts. with lower concentrations of ET-I being antagonized more than higher concentrations. This antagonism with BQ-123 was unaffected by BQ-788 (0.1 μM; n = 6) or by desensitization of ET B receptors with S6c (0.1 μM; n = 8). Blocking the Ca 2+ channels with nifedipine (1 μM; n = 5) did not affect the antagonism, nor did denuding the endothelium or leaving the endothelium intact (n = 5). When S6b was used as an agonist, BQ-123 (0.3-3 μM) caused concentration-dependent biphasic shifts, with low concentrations of S6b not being antagonized. In conclusion, the antagonism observed with BQ-123 is not due to the action of ET-1 at ET B receptors, changes in Ca 2+ handling, or endothelium. This unusual action of BQ- 123 suggests subtypes of the ET A receptor.