Differential modulation of endothelin ligand-induced contraction in isolated tracheae from endothelin B (ETB) receptor knockout mice

1 The role of endothelin B (ETB) receptors in mediating ET ligand-induced contractions in mouse trachea was examined in ETB receptor knockout animals. 2 Autoradiographic binding studies, using [I-125]-ET-1, confirmed the presence of ETA receptors in tracheal and bronchial airway smooth muscle from wild-type (+/+) and homozygous recessive (-/-) ETB receptor knockout mice. In contrast, ETB receptors were not detected in airway tissues from (-/-) mice. 3 In tracheas from (+/+) mice, the rank order of potencies of the ET ligands was sarafotoxin (Stx) S6c > ET-1 > ET-3; Stx S6c had a lower efficacy than ET-1 or ET-3. In tissues from (-/-) mice there was no response to Stx S6c (up to 0.1 muM), whereas the maximum responses and potencies of ET-1 and ET-3 were similar to those in (+/+) tracheae. ET-3 concentration-response curve was biphasic in (+/+) tissues (via ETA and ETB receptor activation), and monophasic in (-/-) preparations (via stimulation of only ETA receptors). 4 In (+/+) preparations SE 234551 (1 nM), an ETA receptor-selective antagonist, inhibited the secondary phase, but not the first phase, of the ET-3 concentration-response curve, whereas A192621 (100 nM), an ETB receptor-selective antagonist, had the opposite effect. In (-/-) tissues SE 234551 (1 nM), but not A192621 (100 nM), produced a rightward shift in ET-3 concentration-response curves. 5 The results confirm the significant influence of both ETA and ETB receptors in mediating ET-1-induced contractions in mouse trachea. Furthermore, the data do not support the hypothesis of atypical ETB receptors. In this preparation ET-3 is not an ETB receptor-selective ligand, producing contractions via activation of both ETA and ETB receptors.