Premium
Mechanical and electrophysiological effects of endothelin‐1 on guinea‐pig isolated lower oesophageal sphincter circular smooth muscle
Author(s) -
Imaeda Kenro,
Trout Stephen J,
Cunnane Thomas C
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704426
Subject(s) - apamin , tetrodotoxin , chemistry , muscle contraction , contraction (grammar) , membrane potential , endocrinology , medicine , biophysics , potassium channel , biology , biochemistry
The effects of endothelin‐1 (ET‐1) on guinea‐pig lower oesophageal sphincter (LOS) circular smooth muscle were investigated by using intracellular microelectrodes and isometric tension recording techniques. ET‐1 produced biphasic mechanical responses; an initial transient relaxation followed by a sustained contraction. The initial relaxation was not inhibited by either tetrodotoxin (TTX, 1 μ M ) or L ‐N G ‐nitroarginine ( L ‐NOARG, 100 μ M ). The sustained contraction was greatly attenuated by nifedipine (1 μ M ). ET‐1 (1 – 30 n M ) induced a concentration‐dependent hyperpolarisation that was unaffected by TTX or L ‐NOARG. The ET A receptor antagonist, BQ123 (0.3 μ M ) abolished the ET‐1‐induced hyperpolarisation, whereas the ET B receptor antagonist, BQ788 (0.3 μ M ) had no detectable effect. Sarafotoxin S6c (10 n M ) did not change the membrane potential. The ET‐1‐induced hyperpolarisation was abolished by apamin (0.1 μ M ). Interestingly, apamin abolished the ET‐1‐induced transient relaxation but potentiated the sustained contraction. In Ca 2+ ‐free Krebs solution, the ET‐1‐induced hyperpolarisation was greatly attenuated and returned to the control value when the tissue was reperfused with Krebs solution containing Ca 2+ . The ET‐1‐induced hyperpolarisation was insensitive to nifedipine but was attenuated by SK&F 96365 (1 ‐ {β‐[3‐(4 ‐ methoxy ‐ phenyl)propoxy] ‐ 4 ‐ methoxyphenethyl} ‐ 1H‐imidazole hydrochloride, 50 μ M ), an inhibitor of receptor‐mediated Ca 2+ entry. The residual component of the ET‐1‐induced hyperpolarisation was sensitive to thapsigargin (1 μ M ). These results demonstrate that, in guinea‐pig LOS circular smooth muscle, ET‐1 hyperpolarizes the membrane by activating apamin‐sensitive K + channels, mainly as a result of receptor‐mediated Ca 2+ entry and partly by Ca 2+ release from intracellular stores. The hyperpolarisation triggers the initial transient relaxation, which acts to oppose the sustained contraction.British Journal of Pharmacology (2002) 135 , 197–205; doi: 10.1038/sj.bjp.0704426