Hilal-Dandan R, Urasawa K, Brunton L L
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093-0636.
J Biol Chem. 1992 May 25;267(15):10620-4.
We have assessed the effects of endothelin-1 (ET-1) on transmembrane signaling in adult rat ventricular myocytes. ET-1 stimulates phosphoinositide hydrolysis with an EC50 of 0.3-0.8 nM. This stimulation is linear for up to 30 min in the presence of a protease inhibitor, is additive with the effects of other stimulators of phosphoinositide hydrolysis, is not inhibited by the Ca2+ entry blocker, nifedipine, and is insensitive to pertussis toxin. ET-1 also reduces cyclic AMP production in myocytes in response to isoproterenol and forskolin (EC50, 1 nM). This cyclic AMP-lowering effect of ET-1 is sensitive to pertussis toxin, can be demonstrated directly in assays of adenylate cyclase activity of myocyte membranes, and seems to be mediated by Gi. These data indicate that the effects of endothelin on adult cardiac myocytes involve multiple signaling pathways, including enhanced activity of the inositol phosphate pathway and a decrease in cyclic AMP-mediated responses, neither of which seems likely to account for the positive contractile effects of endothelin.
我们评估了内皮素-1（ET-1）对成年大鼠心室肌细胞跨膜信号传导的影响。ET-1刺激磷酸肌醇水解，其半数有效浓度（EC50）为0.3 - 0.8 nM。在存在蛋白酶抑制剂的情况下，这种刺激在长达30分钟内呈线性，与其他磷酸肌醇水解刺激剂的作用具有加和性，不受钙离子通道阻滞剂硝苯地平的抑制，且对百日咳毒素不敏感。ET-1还可降低心肌细胞中异丙肾上腺素和福斯高林（EC50，1 nM）刺激引起的环磷酸腺苷（cAMP）生成。ET-1的这种降低cAMP的作用对百日咳毒素敏感，可在心肌细胞膜腺苷酸环化酶活性测定中直接证明，且似乎由Gi介导。这些数据表明，内皮素对成年心肌细胞的作用涉及多种信号通路，包括肌醇磷酸途径活性增强和cAMP介导反应的降低，而这两者似乎都不太可能解释内皮素的正性收缩作用。
