D'Orléans-Juste P, Lidbury P S, Telemaque S, Warner T D, Vane J R
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
J Cardiovasc Pharmacol. 1991;17 Suppl 7:S251-5. doi: 10.1097/00005344-199100177-00072.
Human big endothelin (big ET) and endothelin-1 (ET-1) induce similar increases in left ventricular systolic pressure in the anesthetized rabbit. Unlike ET-1, human big ET does not induce an initial transient hypotension. Human big ET (3 nmol/kg) inhibits ADP-induced platelet aggregation ex vivo by 60% whereas ET-1 at 1 nmol/kg inhibits platelet aggregation by more than 80%. The C-terminal fragment, big ET[22-38] (3 nmol/kg), has no antiaggregatory properties. Inhibition of ex vivo platelet aggregation by human big ET and ET-1 was not seen in rabbits pretreated with indomethacin (5 mg/kg). Human big ET (10(-7) M) or ET-1 (2.5 x 10(-9)-10(-8) M) induced the release of prostacyclin (PGI2) from rabbit, guinea pig, and rat lungs. Phosphoramidon (50 microM, infused 45 min prior to and during administration of peptides) inhibited the prostanoid-releasing properties of human big ET without affecting the release induced by ET-1. Intravascular administration of human big ET (1 nmol/kg) significantly increased the circulating levels of immunoreactive ET-1 (ir-ET-1) for 30 min whereas administration of ET-1 at the same concentration increased the plasma level of ir-ET-1 for 5 min only. Our results suggest that human big ET is converted to ET-1 in the rabbit in vivo. We further suggest that to induce the release of prostanoids in perfused lungs, human big ET needs to be converted to ET-1 by a phosphoramidon-sensitive endothelin-converting enzyme (ECE).
人 big 内皮素（big ET）和内皮素 -1（ET -1）可使麻醉兔的左心室收缩压产生相似程度的升高。与 ET -1 不同，人 big ET 不会引发初始的短暂性低血压。人 big ET（3 nmol/kg）可在体外抑制 ADP 诱导的血小板聚集达 60%，而 1 nmol/kg 的 ET -1 对血小板聚集的抑制率超过 80%。C 末端片段 big ET[22 - 38]（3 nmol/kg）不具有抗聚集特性。在预先用吲哚美辛（5 mg/kg）处理的兔子中，未观察到人 big ET 和 ET -1 对体外血小板聚集的抑制作用。人 big ET（10⁻⁷ M）或 ET -1（2.5×10⁻⁹ - 10⁻⁸ M）可诱导兔、豚鼠和大鼠肺组织释放前列环素（PGI2）。磷酰胺脒（50 μM，在肽给药前 45 分钟及给药期间输注）抑制了人 big ET 的前列腺素释放特性，但不影响 ET -1 诱导的释放。血管内注射人 big ET（1 nmol/kg）可使免疫反应性 ET -1（ir -ET -1）的循环水平在 30 分钟内显著升高，而相同浓度的 ET -1 注射仅使 ir -ET -1 的血浆水平在 5 分钟内升高。我们的结果表明人 big ET 在兔体内可转化为 ET -1。我们进一步表明，为了在灌注肺中诱导前列腺素释放，人 big ET 需要通过磷酰胺脒敏感的内皮素转化酶（ECE）转化为 ET -1。
