TY - JOUR
T1 - Conventional Vasopressor andVasopressor-SparingStrategies toCounteract the Blood Pressure–LoweringEffect of Small Interfering RNA TargetingAngiotensinogen
AU - Uijl, Estrellita
AU - Ye, Dien
AU - Ren, Liwei
AU - Mirabito Colafella, Katrina M.
AU - van Veghel, Richard
AU - Garrelds, Ingrid M.
AU - Lu, Hong S.
AU - Daugherty, Alan
AU - Hoorn, Ewout J.
AU - Nioi, Paul
AU - Foster, Don
AU - Jan Danser, A. H.
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/8/2
Y1 - 2022/8/2
N2 - 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.
AB - 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.
KW - adipose tissue
KW - glucocorticoid receptor
KW - receptor
KW - renin
KW - α-adrenergic
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U2 - 10.1161/JAHA.122.026426
DO - 10.1161/JAHA.122.026426
M3 - Article
C2 - 35876413
AN - SCOPUS:85135500091
SN - 2047-9980
VL - 11
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 15
M1 - e026426
ER -