Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM U1050, Paris F-75231 France.
Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris F-75231 France.
Clin Sci (Lond). 2021 Mar 26;135(6):775-791. doi: 10.1042/CS20201385.
In the brain, aminopeptidase A (APA), a membrane-bound zinc metalloprotease, generates angiotensin III from angiotensin II. Brain angiotensin III exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats and increases vasopressin release. Blocking brain angiotensin III formation by the APA inhibitor prodrug RB150/firibastat normalizes arterial BP in hypertensive deoxycorticosterone acetate (DOCA)-salt rats without inducing angiotensin II accumulation. We therefore hypothesized that another metabolic pathway of brain angiotensin II, such as the conversion of angiotensin II into angiotensin 1-7 (Ang 1-7) by angiotensin-converting enzyme 2 (ACE2) might be activated following brain APA inhibition. We found that the intracerebroventricular (icv) administration of RB150/firibastat in conscious DOCA-salt rats both inhibited brain APA activity and induced an increase in brain ACE2 activity. Then, we showed that the decreases in BP and vasopressin release resulting from brain APA inhibition with RB150/firibastat were reduced if ACE2 was concomitantly inhibited by MLN4760, a potent ACE2 inhibitor, or if the Mas receptor (MasR) was blocked by A779, a MasR antagonist. Our findings suggest that in the brain, the increase in ACE2 activity resulting from APA inhibition by RB150/firibastat treatment, subsequently increasing Ang 1-7 and activating the MasR while blocking angiotensin III formation, contributes to the antihypertensive effect and the decrease in vasopressin release induced by RB150/firibastat. RB150/firibastat treatment constitutes an interesting therapeutic approach to improve BP control in hypertensive patients by inducing in the brain renin-angiotensin system, hyperactivity of the beneficial ACE2/Ang 1-7/MasR axis while decreasing that of the deleterious APA/Ang II/Ang III/ATI receptor axis.
在大脑中，氨肽酶 A（APA）是一种膜结合的锌金属蛋白酶，可将血管紧张素 II 转化为血管紧张素 III。脑内血管紧张素 III 对高血压大鼠血压的控制产生持续的刺激作用，并增加血管加压素的释放。APA 抑制剂前药 RB150/firibastat 通过阻断脑内血管紧张素 III 的形成，使去氧皮质酮醋酸盐（DOCA）-盐高血压大鼠的动脉血压正常化，而不会引起血管紧张素 II 的积累。因此，我们假设脑 APA 抑制后，脑内血管紧张素 II 的另一种代谢途径，如血管紧张素转换酶 2（ACE2）将血管紧张素 II 转化为血管紧张素 1-7（Ang 1-7）可能会被激活。我们发现，在清醒的 DOCA-盐大鼠中，脑室内给予 RB150/firibastat 不仅抑制了脑 APA 活性，还诱导了脑 ACE2 活性的增加。然后，我们表明，用 MLN4760（一种有效的 ACE2 抑制剂）同时抑制 ACE2，或用 A779（一种 Mas 受体拮抗剂）阻断 Mas 受体，可降低 RB150/firibastat 抑制脑 APA 引起的血压和血管加压素释放的降低。我们的研究结果表明，在大脑中，RB150/firibastat 抑制 APA 引起的 ACE2 活性增加，随后增加 Ang 1-7 并激活 Mas 受体，同时阻断血管紧张素 III 的形成，有助于 RB150/firibastat 引起的降压作用和血管加压素释放的减少。RB150/firibastat 治疗构成了一种有趣的治疗方法，通过在大脑肾素-血管紧张素系统中诱导活性，增加有益的 ACE2/Ang 1-7/MasR 轴的活性，同时降低有害的 APA/Ang II/Ang III/ATI 受体轴的活性，从而改善高血压患者的血压控制。
