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

Estrellita Uijl, Dien Ye, Liwei Ren, Katrina M. Mirabito Colafella, Richard van Veghel, Ingrid M. Garrelds, Hong S. Lu, Alan Daugherty, Ewout J. Hoorn, Paul Nioi, Don Foster, A. H. Jan Danser

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article numbere026426
JournalJournal of the American Heart Association
Volume11
Issue number15
DOIs
StatePublished - Aug 2 2022

Bibliographical note

Funding Information:
Drs Nioi and Foster are employees of Alnylam Pharmaceuticals. Dr Danser received a grant from Alnylam Pharmaceuticals, which has partially supported this work. The other authors report no conflicts.

Funding Information:
This work was partially supported by Alnylam Pharmaceuticals. Dr Mirabito Colafella was supported by a National Health and Medical Research Council of Australia CJ Martin Fellowship (number 1112125). Dr Ren was supported by a National Natural Science Foundation of China (grant number 81900668).

Publisher Copyright:
© 2022 The Authors.

Keywords

  • adipose tissue
  • glucocorticoid receptor
  • receptor
  • renin
  • α-adrenergic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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