Szelke M, Leckie B J, Tree M, Brown A, Grant J, Hallett A, Hughes M, Jones D M, Lever A F
Hypertension. 1982 May-Jun;4(3 Pt 2):59-69.
Chemical modification of the backbone at the cleavage site in the (6-13)-octapeptide of equine angiotensinogen resulted in greatly increased binding affinity and resistance to cleavage by renin. The D-His6-Tyr13 octapeptide analog containing the reduced bond -CH2-NH-instead of a peptide bond -CO-NH- at the Leu10-Leu11 linkage (H-77) was a powerful in vitro inhibitor of canine renin (IC50 = 24nM). It gave an IC50 of 1 microM against human renin and 0.6 microM against rat renin. In sodium-depleted conscious dogs, infusion of H-77 caused dose-related falls of plasma angiotensin I plasma angiotensin II concentration and mean arterial pressure; the minimum effective dose was 0.1 mg . kg-1 hr-1. Similar infusions of H-77 in chronically catheterized rats have no effect on blood pressure or plasma angiotensin II concentration. Thus, the in vitro effect of H-77 as an inhibitor of renin in dog, human, and rat plasma was paralleled by its action in the whole animal.
对马血管紧张素原（6-13）八肽裂解位点处的主链进行化学修饰，可显著提高其与肾素的结合亲和力并增强对肾素裂解的抗性。在Leu10-Leu11连接位点含有还原键-CH2-NH-而非肽键-CO-NH-的D-His6-Tyr13八肽类似物（H-77）是犬肾素强大的体外抑制剂（IC50 = 24nM）。它对人肾素的IC50为1μM，对大鼠肾素的IC50为0.6μM。在钠缺乏的清醒犬中，输注H-77可导致血浆血管紧张素I、血浆血管紧张素II浓度和平均动脉压呈剂量依赖性下降；最小有效剂量为0.1mg·kg-1·hr-1。在长期插管的大鼠中进行类似的H-77输注，对血压或血浆血管紧张素II浓度无影响。因此，H-77在犬、人及大鼠血浆中作为肾素抑制剂的体外作用与其在整个动物体内的作用相似。
