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No evidence for brain renin-angiotensin system activation during DOCA-salt hypertension.

Authors :
Uijl, Estrellita
Ren, Liwei
Colafella, Katrina M. Mirabito
van Veghel, Richard
Garrelds, Ingrid M.
Domenig, Oliver
Poglitsch, Marko
Zlatev, Ivan
Kim, Jae B.
Huang, Stephen
Melton, Lauren
Hoorn, Ewout J.
Foster, Don
Danser, A. H. Jan
Source :
Clinical Science. Jan2021, Vol. 135 Issue 2, p259-274. 16p.
Publication Year :
2021

Abstract

Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin IIwas detected in all rats, whereas brainstem angiotensin IIwas detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19+- 1 mmHg and suppressed circulating renin and angiotensin II by>90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97+-0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
01435221
Volume :
135
Issue :
2
Database :
Academic Search Index
Journal :
Clinical Science
Publication Type :
Academic Journal
Accession number :
149539723
Full Text :
https://doi.org/10.1042/CS20201239