Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands.
Division of Nephrology and Transplantation, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands.
J Am Heart Assoc. 2022 Aug 2;11(15):e026426. doi: 10.1161/JAHA.122.026426. Epub 2022 Jul 25.
Background A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogen and lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensin rise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressors can raise arterial pressure after angiotensinogen depletion. Methods and Results Spontaneously hypertensive rats on a low-salt diet were treated with siRNA (10 mg/kg fortnightly) for 4 weeks, supplemented during the final 2 weeks with fludrocortisone (6 mg/kg per day), the α-adrenergic agonist midodrine (4 mg/kg per day), or a high-salt diet (all groups n=6-7). Pressor responsiveness to angiotensin II and norepinephrine was assessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogen by siRNA lowered plasma angiotensinogen concentrations by 99.2±0.1% and mean arterial pressure by 19 mm Hg. siRNA-mediated blood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversed by fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasma angiotensinogen concentrations in siRNA-treated rats, and nearly abolished plasma renin concentrations. To investigate whether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepatic angiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen in the siRNA-treated rats must have depended on the liver, most likely reflecting diminished cleavage by renin. Conclusions Intact pressor responsiveness to conventional vasopressors provides pharmacological means to regulate the blood pressure-lowering effect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.
单次给予靶向肝脏血管紧张素原的小干扰 RNA（siRNA）可消除肝血管紧张素原并降低血压。血管紧张素原的消除引起了人们对临床应用的关注，因为在低血容量时需要血管紧张素升高以维持灌注压。在这里，我们研究了血管紧张素原耗竭后常规血管加压药是否可以升高动脉压。
低盐饮食的自发性高血压大鼠接受 siRNA（每两周 10mg/kg）治疗 4 周，在最后 2 周补充氟氢可的松（每天 6mg/kg），α-肾上腺素能激动剂米多君（每天 4mg/kg）或高盐饮食（所有组 n=6-7）。在 siRNA 给药前后评估血管紧张素 II 和去甲肾上腺素的加压反应性。通过无线电遥测法测量血压。siRNA 耗竭肝血管紧张素原使血浆血管紧张素原浓度降低 99.2±0.1%，平均动脉压降低 19mmHg。siRNA 介导的血压降低可被静脉内血管紧张素 II 或去甲肾上腺素迅速逆转，或被氟氢可的松或高盐摄入逐渐逆转。米多君没有效果。出乎意料的是，氟氢可的松部分恢复了 siRNA 治疗大鼠的血浆血管紧张素原浓度，并几乎消除了血浆肾素浓度。为了研究这种血管紧张素原是否源自非肝脏来源，氟氢可的松被给予缺乏肝血管紧张素原的小鼠。氟氢可的松并未增加这些小鼠的血管紧张素原，这表明 siRNA 治疗大鼠中血管紧张素原的升高必须依赖于肝脏，很可能反映了肾素裂解的减少。
完整的加压反应性对常规血管加压药提供了调节血管紧张素原 siRNA 降压作用的药理学手段，并可能支持 siRNA 的未来治疗实施。
