Comparative effects of the two endothelin ETA receptor antagonists, BQ-123 and FR139317, on endothelin-1-induced contraction in guinea-pig iliac artery.

The effects of two recently introduced endothelin ETA receptor antagonists, BQ-123 and FR139317, were investigated and compared in guinea-pig isolated iliac artery. Endothelins and sarafotoxins induced contraction of guinea-pig iliac artery with a pharmacological profile characteristic of the ETA receptor. The rank order of agonist potency was (mean EC50 values, nM): endothelin-1 (11.7) > or = endothelin-2 (14.9) > or = vasoactive intestinal contractor (19.5) > sarafotoxin S6b (49.8) > or = [Ala3,11]endothelin-1 (55.0) > sarafotoxin S6a (> 100) > endothelin-3 (> or = 1000). The C-terminal hexapeptide, endothelin-(16-21), sarafotoxin S6c and sarafotoxin S6d were neither agonists nor antagonists at concentrations up to 10, 3 and 1 microM, respectively. Both FR139317 (1-10 microM) and BQ-123 (0.1-1 microM) surmountably antagonized the effects of endothelin-1. Schild analysis suggested competitive antagonism for FR139317 (Schild slope 1.32 +/- 0.21, pA2 5.82 +/- 0.16, n = 5), but not for BQ-123 (Schild slope 0.28 +/- 0.08, n = 5), which was however more potent (apparent pKB 6.6-7.2) than FR139317. The potency of FR139317 was particularly low with respect to the reported affinity for ETA receptors, suggesting heterogeneity among ETA receptors. Thus, the endothelin receptor present in guinea-pig iliac artery has the following features: (1) rank order of agonist potencies of the ETA type; (2) low potency of FR139317 and (3) non-competitive antagonism by BQ-123.