Pollock D M, Divish B J, Milicic I, Novosad E I, Burres N S, Opgenorth T J
Abbott Laboratories, Abbott Park, IL 60064.
Eur J Pharmacol. 1993 Feb 16;231(3):459-64. doi: 10.1016/0014-2999(93)90124-z.
Experiments were conducted to characterize the nature of a phosphoramidon-sensitive endothelin-converting enzyme in vivo by evaluating the pressor response to a bolus intravenous (i.v.) injection of endothelin family peptides following administration of phosphoramidon in anesthetized Sprague-Dawley rats. Phosphoramidon given i.v. at 10 mg/kg completely prevented the pressor response to human big endothelin-1-(1-38) (big ET-1). The EC50 for phosphoramidon was determined to be in the range of 1 to 3 mg/kg. The pressor response to big ET-1 60 min after phosphoramidon injection was attenuated by roughly 60% indicating a long inhibitory half-life. Very high doses of big ET-1 (> 20 mg/kg) were capable of over-riding the effect of phosphoramidon and produced characteristic pressor responses suggesting that the inhibition by phosphoramidon can be considered competitive in nature. Human big endothelin-3-(1-41) (big ET-3) produced significant increases in arterial pressure although with less potency and efficacy compared to big ET-1. The pressor response to big ET-3 was also inhibited by phosphoramidon. Phosphoramidon does not act indirectly by interfering with ET-1 receptor-mediated actions since the inhibitor has no effect on the in vivo pressor response to ET-1 and does not antagonize [125I]ET-1 receptor binding or constrictor responses in vitro. These results are consistent with the idea that a phosphoramidon-sensitive endothelin-converting enzyme is capable of cleaving both big ET-1 and big ET-3 to the active peptides in the rat.
通过评估在麻醉的Sprague-Dawley大鼠中给予磷酰胺后静脉推注内皮素家族肽的升压反应，进行实验以在体内表征磷酰胺敏感的内皮素转化酶的性质。以10mg/kg静脉注射磷酰胺可完全阻止对人big内皮素-1-(1-38)(big ET-1)的升压反应。磷酰胺的EC50确定在1至3mg/kg范围内。磷酰胺注射60分钟后对big ET-1的升压反应减弱约60%，表明抑制半衰期长。非常高剂量的big ET-1(>20mg/kg)能够克服磷酰胺的作用并产生特征性升压反应，这表明磷酰胺的抑制作用在性质上可被认为是竞争性的。人big内皮素-3-(1-41)(big ET-3)使动脉压显著升高，尽管与big ET-1相比效力和效能较低。对big ET-3的升压反应也被磷酰胺抑制。磷酰胺不会通过干扰ET-1受体介导的作用而间接起作用，因为该抑制剂对ET-1的体内升压反应没有影响，并且在体外不拮抗[125I]ET-1受体结合或收缩反应。这些结果与以下观点一致，即磷酰胺敏感的内皮素转化酶能够在大鼠中将big ET-1和big ET-3都切割成活性肽。
