Renin inhibition and AT(1)R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling.
OBJECTIVE
Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone.


METHODS
We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin-angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days.


RESULTS
Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone.


CONCLUSIONS
Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.
Research Service, Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA. whaleyconnella@health.missouri.edu
Adam
A
Whaley-Connell
Javad
J
Habibi
Nathan
N
Rehmer
Sivakumar
S
Ardhanari
Melvin R
MR
Hayden
Lakshmi
L
Pulakat
Caroline
C
Krueger
Carlos M
CM
Ferrario
Vincent G
VG
DeMarco
James R
JR
Sowers
D000450:Aldosterone / Q000097:blood; D000577:Amides / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D048429:Cell Size; D004347:Drug Interactions; D005355:Fibrosis; D005650:Fumarates / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012083:Renin / Q000235:genetics; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling; D000092502:Renin Inhibitors
D000450:Aldosterone; D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D005650:Fumarates; D044140:Receptor, Angiotensin, Type 1; D012083:Renin; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000092502:Renin Inhibitors; C473112:Ren2 protein, mouse; C535029:Ren2 protein, rat; C446481:aliskiren