Conventional Vasopressor andVasopressor-SparingStrategies toCounteract the Blood Pressure–LoweringEffect of Small Interfering RNA TargetingAngiotensinogen

Abstract

BACKGROUND: A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogenand lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensinrise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressorscan raise arterial pressure after angiotensinogen depletion.METHODS AND RESULTS: Spontaneously hypertensive rats on a low-saltdiet were treated with siRNA (10 mg/kg fortnightly) for4 weeks, supplemented during the final 2 weeks with fludrocortisone (6 mg/kg per day), the α-adrenergicagonist midodrine(4 mg/kg per day), or a high-saltdiet (all groups n=6–7).Pressor responsiveness to angiotensin II and norepinephrine wasassessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogenby siRNA lowered plasma angiotensinogen concentrations by 99.2±0.1% and mean arterial pressure by 19 mm Hg.siRNA-mediatedblood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversedby fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasmaangiotensinogen concentrations in siRNA-treatedrats, and nearly abolished plasma renin concentrations. To investigatewhether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepaticangiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen inthe siRNA-treatedrats 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 theblood pressure–loweringeffect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.