TY - JOUR
T1 - Differential modulation of endothelin ligand-induced contraction in isolated tracheae from endothelin B (ETB) receptor knockout mice
AU - Hay, D.W.P.
AU - Douglas, S.A.
AU - Zhao, A.
AU - Ohlstein, E.A.
AU - Moesker, R.M.
AU - Self, G.J.
AU - Rigby, Paul
AU - Luttman, M.A.
AU - Goldie, Roy
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
U2 - 10.1038/sj.bjp.0703957
DO - 10.1038/sj.bjp.0703957
M3 - Article
SN - 0007-1188
VL - 132
SP - 1905
EP - 1915
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
ER -