Small Interfering RNA Therapeutics in Hypertension: A Viewpoint on Vasopressor and Vasopressor‐Sparing Strategies for Counteracting Blood Pressure Lowering by Angiotensinogen–Targeting Small Interfering RNA

Figure .. Mechanism of RNAi by GalNAc‐AGT‐siRNA (A) and RAS, mediators, clinical effects, and medications (B). *Accumulation and stability of GalNAc‐siRNA in hepatic endosomes and RISC recycling results in prolonged biochemical and clinical effect of GalNAc‐AGT‐siRNA. ‡Standard RAS medications cause a compensatory rise in renin with long‐term use because of loss of negative feedback mediated by Ang II (RAS escape). Near complete depletion of AGT by siRNA therapy could potentially prevent RAS escape. ACE indicates angiotensin‐converting enzyme; ACEI, angiotensin‐converting enzyme inhibitor; AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; ARB, angiotensin II receptor blocker; ASGPR, asialoglycoprotein receptor; AT1R, angiotensin II type 1 receptor; DRI, direct renin inhibitor; GalNAc, N‐acetylgalactosamine; mRNA, messenger RNA; RAS, renin‐angiotensin system; RISC, RNA‐induced silencing complex; RNAi, RNA interference; siRNA, small interfering RNA; and SNS, sympathetic nervous system.