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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 μM) or L-NG-nitroarginine (L-NOARG, 100 μM). The sustained contraction was greatly attenuated by nifedipine (1 μM). ET-1 (1 – 30 nM) induced a concentration-dependent hyperpolarisation that was unaffected by TTX or L-NOARG. The ETA receptor antagonist, BQ123 (0.3 μM) abolished the ET-1-induced hyperpolarisation, whereas the ETB receptor antagonist, BQ788 (0.3 μM) had no detectable effect. Sarafotoxin S6c (10 nM) did not change the membrane potential. The ET-1-induced hyperpolarisation was abolished by apamin (0.1 μM). Interestingly, apamin abolished the ET-1-induced transient relaxation but potentiated the sustained contraction. In Ca2+-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 Ca2+. 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 μM), an inhibitor of receptor-mediated Ca2+ entry. The residual component of the ET-1-induced hyperpolarisation was sensitive to thapsigargin (1 μM). 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 Ca2+ entry and partly by Ca2+ 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 |
