Leckie B, Szelke M, Hallett A, Hughes M, Lever A F, McIntyre G, Morton J J, Tree M
Clin Exp Hypertens A. 1983;5(7-8):1221-36. doi: 10.3109/10641968309048853.
Three experiments are described using new substrate analogue inhibitors of renin. The first experiment shows that introduction of a reduced isostere in the scissile peptide bond of an analogue greatly increases its ability to inhibit renin of a particular species. However, different species of renin substrate have different amino acids in their scissile bond and variation here also greatly influences the affinity of renin and substrate and hence of renin and substrate analogues. Finally, substitution of amino acids in the C-terminal adjacent to the scissile bond influences the affinity and efficacy of substrate analogues as inhibitors. In our second experiment a peptide inhibitor of dog renin, H.77, was used in an affinity column to produce a one-stage, 2000-fold, and complete purification of human renin. In our third experiment infusion of H.77 was used to lower circulating concentrations of angiotensin I and angiotensin II in conscious sodium-deplete dogs. Captopril was then given in addition to H.77 but blood pressure did not fall further, suggesting that captopril lowers blood pressure wholly or partly by reducing angiotensin II within the circulation and in extravascular sites.
本文描述了三项使用肾素新型底物类似物抑制剂的实验。第一项实验表明，在类似物的可裂解肽键中引入还原等排体可大大提高其抑制特定物种肾素的能力。然而，不同物种的肾素底物在其可裂解键中的氨基酸不同，此处的变化也极大地影响肾素与底物以及肾素与底物类似物之间的亲和力。最后，在紧邻可裂解键的C末端进行氨基酸取代会影响底物类似物作为抑制剂的亲和力和效力。在我们的第二项实验中，将犬肾素的肽抑制剂H.77用于亲和柱，以一步法对人肾素进行2000倍的完全纯化。在我们的第三项实验中，对清醒的缺钠犬输注H.77以降低循环中血管紧张素I和血管紧张素II的浓度。然后在给予H.77的基础上再加用卡托普利，但血压并未进一步下降，这表明卡托普利降低血压全部或部分是通过降低循环中和血管外部位的血管紧张素II实现的。
