Pollock D M, Opgenorth T J
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064.
Am J Physiol. 1991 Jul;261(1 Pt 2):R257-63. doi: 10.1152/ajpregu.1991.261.1.R257.
The potent vasoconstrictor endothelin 1 (ET-1) is thought to arise from the proteolytic processing of big endothelin 1 (Big ET) by a unique endothelin-converting enzyme, possibly a metalloprotease. Experiments were conducted to determine the effects of Big ET on cardiovascular and renal functions during inhibition of metalloprotease activity in vivo. Intravenous infusion of Big ET (0.1 nmol.kg-1.min-1) in anesthetized euvolemic rats produced a significant increase in mean arterial pressure (MAP; 39 +/- 8%) and a decrease in effective renal plasma flow (ERPF; -39 +/- 2%), whereas glomerular filtration rate (GFR) remained unchanged (-8 +/- 8%). Simultaneous intravenous infusion of phosphoramidon (0.25 mg.kg-1.min-1), an inhibitor of metalloprotease activity including neutral endopeptidase EC 3.4.24.11 (NEP), completely prevented these effects of Big ET. Thiorphan (0.1 mg.kg-1.min-1), also an inhibitor of NEP, had absolutely no effect on either the renal or cardiovascular response to Big ET. Similarly, the response to Big ET was unaffected by infusion of enalaprilat (0.1 mg.kg-1.min-1), an inhibitor of the angiotensin-converting enzyme, which is also a metalloprotease. To determine whether the effect of phosphoramidon was due to antagonism of ET-1, an identical series of experiments was performed using ET-1 infusion (0.02 nmol.kg-1.min-1). Although the increase in MAP (24 +/- 5%) produced by ET-1 was less than that observed for the given dose of Big ET, the renal vasoconstriction was much more severe; the smaller peptide changed ERPF and GFR by -66 +/- 7 and -54 +/- 9%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
强效血管收缩剂内皮素1（ET-1）被认为是由大内皮素1（Big ET）经一种独特的内皮素转换酶（可能是一种金属蛋白酶）进行蛋白水解加工产生的。进行实验以确定在体内抑制金属蛋白酶活性期间Big ET对心血管和肾功能的影响。在麻醉的血容量正常的大鼠中静脉输注Big ET（0.1 nmol·kg⁻¹·min⁻¹）导致平均动脉压（MAP）显著升高（39±8%），有效肾血浆流量（ERPF）降低（-39±2%），而肾小球滤过率（GFR）保持不变（-8±8%）。同时静脉输注磷酰胺素（0.25 mg·kg⁻¹·min⁻¹），一种包括中性内肽酶EC 3.4.24.11（NEP）在内的金属蛋白酶活性抑制剂，完全阻止了Big ET的这些作用。硫丙脯酸（0.1 mg·kg⁻¹·min⁻¹），也是一种NEP抑制剂，对Big ET引起的肾脏或心血管反应完全没有影响。同样，对Big ET的反应不受血管紧张素转换酶抑制剂依那普利拉（0.1 mg·kg⁻¹·min⁻¹）输注的影响，血管紧张素转换酶也是一种金属蛋白酶。为了确定磷酰胺素的作用是否是由于对ET-1的拮抗作用，使用ET-1输注（0.02 nmol·kg⁻¹·min⁻¹）进行了一系列相同的实验。尽管ET-1引起的MAP升高（24±5%）小于给定剂量的Big ET所观察到的升高，但肾血管收缩更为严重；较小的肽分别使ERPF和GFR改变了-66±7%和-54±9%。（摘要截断于250字）
