Conventional Vasopressor and Vasopressor-Sparing Strategies to Counteract the Blood Pressure-Lowering Effect of Small Interfering RNA Targeting Angiotensinogen

Uijl, Estrellita1,2; Ye, Dien1,3,4; Ren, Liwei1,5; Mirabito Colafella, Katrina M.6,7; van Veghel, Richard1; Garrelds, Ingrid M.1; Lu, Hong S.3,4; Daugherty, Alan3,4; Hoorn, Ewout J.2; Nioi, Paul8; Foster, Don8; Danser, A. H. Jan1

2022-08-02

10.1161/JAHA.122.026426

JOURNAL OF THE AMERICAN HEART ASSOCIATION   Impact Factor & Quartile

2047-9980

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 alpha-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.

adipose tissue glucocorticoid receptor renin alpha-adrenergic receptor

SCI

English

Others

National Health and Medical Research Council of Australia CJ Martin Fellowship[1112125] ; National Natural Science Foundation of China[81900668]

Cardiovascular System & Cardiology

Cardiac & Cardiovascular Systems

WOS:000835553100004

WILEY

Web of Science

1.Erasmus MC, Univ Med Ctr Rotterdam, Dept Internal Med, Div Vasc Med & Pharmacol, Rotterdam, Netherlands
2.Erasmus MC, Univ Med Ctr Rotterdam, Dept Internal Med, Div Nephrol & Transplantat, Rotterdam, Netherlands
3.Univ Kentucky, Saha Cardiovasc Res Ctr, Lexington, KY USA
4.Univ Kentucky, Dept Physiol, Lexington, KY USA
5.Southern Univ Sci & Technol, Affiliated Hosp 1, Jinan Univ, Clin Med Coll 2,Shenzhen Peoples Hosp,Dept Pharm, Shenzhen, Peoples R China
6.Monash Univ, Biomed Discovery Inst, Cardiovasc Program, Melbourne, Vic, Australia
7.Monash Univ, Dept Physiol, Melbourne, Vic, Australia
8.Alnylam Pharmaceut, Cambridge, MA USA

Uijl, Estrellita,Ye, Dien,Ren, Liwei,et al. Conventional Vasopressor and Vasopressor-Sparing Strategies to Counteract the Blood Pressure-Lowering Effect of Small Interfering RNA Targeting Angiotensinogen[J]. JOURNAL OF THE AMERICAN HEART ASSOCIATION,2022,11(15).

Uijl, Estrellita.,Ye, Dien.,Ren, Liwei.,Mirabito Colafella, Katrina M..,van Veghel, Richard.,...&Danser, A. H. Jan.(2022).Conventional Vasopressor and Vasopressor-Sparing Strategies to Counteract the Blood Pressure-Lowering Effect of Small Interfering RNA Targeting Angiotensinogen.JOURNAL OF THE AMERICAN HEART ASSOCIATION,11(15).

Uijl, Estrellita,et al."Conventional Vasopressor and Vasopressor-Sparing Strategies to Counteract the Blood Pressure-Lowering Effect of Small Interfering RNA Targeting Angiotensinogen".JOURNAL OF THE AMERICAN HEART ASSOCIATION 11.15(2022).