Yamada K, Iyer S N, Chappell M C, Ganten D, Ferrario C M
From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, and Max Delbruck Center for Molecular Medicine, Berlin-Buch, Germany.
Hypertension. 1998 Sep;32(3):496-502. doi: 10.1161/01.hyp.32.3.496.
We determined the mechanism accounting for the removal and metabolism of angiotensin-(1-7) [Ang-(1-7)] in 21 anesthetized spontaneously hypertensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 36 mRen-2 transgenic (TG+) rats. Animals of all 3 strains were provided with tap water or tap water containing losartan, lisinopril, or a combination of lisinopril and losartan for 2 weeks. On the day of the experiment, Ang-(1-7) was infused for a period of 15 minutes at a rate of 278 nmol . kg-1 . min-1. After this time, samples of arterial blood were collected rapidly at regular intervals for the assay of plasma Ang-(1-7) levels by radioimmunoassay. Infusion of Ang-(1-7) had a minimal effect on vehicle-treated SD rats but elicited a biphasic pressor/depressor response in vehicle-treated SHR and TG+ rats. In lisinopril-treated rats, Ang-(1-7) infusion increased blood pressure, whereas losartan treatment abolished the pressor component of the response without altering the secondary fall in arterial pressure. Combined treatment with lisinopril and losartan abolished the cardiovascular response to Ang-(1-7) in all 3 strains. In vehicle-treated SD, SHR and TG+ the half-life (t1/2) of Ang-(1-7) averaged 10+/-1, 10+/-1, and 9+/-1 seconds, respectively. Lisinopril alone or in combination with losartan produced a statistically significant rise in the half-life of Ang-(1-7) in all 3 strains of rats. Plasma clearance of Ang-(1-7) was significantly greater in the untreated SD rats compared with either the SHR or TG+ rat. Lisinopril treatment was associated with reduced clearance of Ang-(1-7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SHR showed a statistically significant inhibition of 125I-Ang-(1-7) metabolism in the presence of lisinopril. These studies showed for the first time that the very short half-life of Ang-(1-7) in the circulation is primarily accounted for peptide metabolism by ACE. These findings suggest a novel role of ACE in the regulation of the production and metabolism of the two primary active hormones of the renin angiotensin system.
我们在21只麻醉的自发性高血压大鼠（SHR）、18只年龄匹配的正常血压斯普拉格-道利大鼠（SD）和36只mRen-2转基因大鼠（TG+）中，确定了血管紧张素-（1-7）[Ang-（1-7）]的清除和代谢机制。给所有3个品系的动物提供自来水或含有氯沙坦、赖诺普利或赖诺普利与氯沙坦组合的自来水，持续2周。在实验当天，以278 nmol·kg-1·min-1的速率输注Ang-（1-7）15分钟。此后，定期快速采集动脉血样本，通过放射免疫测定法检测血浆Ang-（1-7）水平。输注Ang-（1-7）对用赋形剂处理的SD大鼠影响极小，但在用赋形剂处理的SHR和TG+大鼠中引发双相升压/降压反应。在赖诺普利处理的大鼠中，输注Ang-（1-7）会升高血压，而氯沙坦处理消除了反应的升压成分，同时不改变动脉压的继发性下降。赖诺普利和氯沙坦联合处理消除了所有3个品系对Ang-（1-7）的心血管反应。在用赋形剂处理的SD、SHR和TG+大鼠中，Ang-（1-7）的半衰期（t1/2）平均分别为10±1、10±1和9±1秒。单独使用赖诺普利或与氯沙坦联合使用，在所有3个品系的大鼠中均使Ang-（1-7）的半衰期出现统计学上的显著升高。与SHR或TG+大鼠相比，未处理的SD大鼠中Ang-（1-7）的血浆清除率显著更高。赖诺普利处理与所有3个品系中Ang-（1-7）清除率降低有关。在SD和SHR的肺膜上进行的同步实验表明，在存在赖诺普利的情况下，125I-Ang-（1-7）代谢受到统计学上的显著抑制。这些研究首次表明，循环中Ang-（1-7）的极短半衰期主要是由ACE介导的肽代谢所致。这些发现提示了ACE在肾素-血管紧张素系统两种主要活性激素的产生和代谢调节中的新作用。
