Campbell D J, Lawrence A C, Towrie A, Kladis A, Valentijn A J
St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Hypertension. 1991 Dec;18(6):763-73. doi: 10.1161/01.hyp.18.6.763.
We compared the effects of the converting enzyme inhibitor perindopril on components of the renin-angiotensin system in plasma and kidney of male Sprague-Dawley rats administered perindopril in their drinking water at two doses (1.4 and 4.2 mg/kg) over 7 days. Eight angiotensin peptides were measured in plasma and kidney: angiotensin-(1-7), angiotensin II, angiotensin-(1-9), angiotensin I, angiotensin-(2-7), angiotensin III, angiotensin-(2-9), and angiotensin-(2-10). In addition, angiotensin converting enzyme activity, renin, and angiotensinogen were measured in plasma, and renin, angiotensinogen, and their respective messenger RNAs were measured in kidney; angiotensinogen messenger RNA was also measured in liver. In plasma, the highest dose of perindopril reduced angiotensin converting enzyme activity to 11% of control, increased renin 200-fold, reduced angiotensinogen to 11% of control, increased angiotensin-(1-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels 25-, 9-, 10-, and 13-fold, respectively; angiotensin II levels were not significantly different from control. By contrast, for the kidney, angiotensin-(1-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels did not increase; angiotensin II levels fell to 14% of control, and angiotensinogen fell to 12% of control. Kidney renin messenger RNA levels increased 12-fold, but renal renin content and angiotensinogen messenger RNA levels in kidney and liver were not influenced by perindopril treatment. These results demonstrate a differential regulation of angiotensin peptides in plasma and kidney and provide direct support for the proposal that the cardiovascular effects of converting enzyme inhibitors depend on modulation of tissue angiotensin systems. Moreover, the failure of kidney angiotensin I levels to increase with perindopril treatment, taken together with the fall in kidney angiotensinogen levels, suggests that angiotensinogen may be a major rate-limiting determinant of angiotensin peptide levels in the kidney.
我们比较了转化酶抑制剂培哚普利对雄性斯普拉格 - 道利大鼠血浆和肾脏中肾素 - 血管紧张素系统各组分的影响。这些大鼠连续7天饮用含两种剂量（1.4和4.2毫克/千克）培哚普利的水。检测了血浆和肾脏中的八种血管紧张素肽：血管紧张素 -（1 - 7）、血管紧张素II、血管紧张素 -（1 - 9）、血管紧张素I、血管紧张素 -（2 - 7）、血管紧张素III、血管紧张素 -（2 - 9）和血管紧张素 -（2 - 10）。此外，还检测了血浆中的血管紧张素转换酶活性、肾素和血管紧张素原，以及肾脏中的肾素、血管紧张素原及其各自的信使核糖核酸；同时也检测了肝脏中的血管紧张素原信使核糖核酸。在血浆中，培哚普利的最高剂量将血管紧张素转换酶活性降至对照的11%，使肾素增加200倍，将血管紧张素原降至对照的11%，使血管紧张素 -（1 - 7）、血管紧张素I、血管紧张素 -（2 - 7）和血管紧张素 -（2 - 10）水平分别升高25倍、9倍、10倍和13倍；血管紧张素II水平与对照无显著差异。相比之下，在肾脏中，血管紧张素 -（1 - 7）、血管紧张素I、血管紧张素 -（2 - 7）和血管紧张素 -（2 - 10）水平没有升高；血管紧张素II水平降至对照的14%，血管紧张素原降至对照的12%。肾脏肾素信使核糖核酸水平升高了12倍，但肾脏肾素含量以及肾脏和肝脏中的血管紧张素原信使核糖核酸水平不受培哚普利治疗的影响。这些结果表明血浆和肾脏中血管紧张素肽存在差异调节，并为转化酶抑制剂的心血管效应取决于组织血管紧张素系统的调节这一观点提供了直接支持。此外，培哚普利治疗后肾脏血管紧张素I水平未升高，再加上肾脏血管紧张素原水平下降，提示血管紧张素原可能是肾脏中血管紧张素肽水平的主要限速决定因素。
