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) ≥ endothelin-2(14.9) ≥ vasoactive intestinal contractor (19.5) > sarafotoxin S6b (49.8) ≥ [Ala3,11]endothelin-1 (55.0) > sarafotoxin S6a (>100) > endothelin-3 (≥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 μM, respectively. Both FR139317 (1–10 μM) and BQ-123 (0.1–1 μM) 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.