Renin inhibition and AT(1)R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling.

Abstract

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.

MATERIALS/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.

• Authors: Adam Whaley-Connell, Javad Habibi, Nathan Rehmer, Sivakumar Ardhanari, Melvin R Hayden, Lakshmi Pulakat, Caroline Krueger, Carlos M Ferrario, Vincent G DeMarco, James R Sowers
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 62 Issue 6 Pg. 861-72 (Jun 2013) ISSN: 1532-8600 [Electronic] United States
• PMID: 23352204 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Amides
• Angiotensin II Type 1 Receptor Blockers
• Fumarates
• Receptor, Angiotensin, Type 1
• Ren2 protein, mouse
• Ren2 protein, rat
• Tetrazoles
• Aldosterone
• aliskiren
• Valsartan
• Renin
• Valine

Topics

• Aldosterone (blood)
• Amides (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Blood Pressure
• Cell Size
• Drug Interactions
• Fibrosis
• Fumarates (pharmacology)
• Mice
• Myocardium (pathology, ultrastructure)
• Myocytes, Cardiac (drug effects, pathology)
• Oxidative Stress
• Rats
• Rats, Sprague-Dawley
• Rats, Transgenic
• Receptor, Angiotensin, Type 1 (metabolism)
• Renin (antagonists & inhibitors, genetics)
• Signal Transduction
• Tetrazoles (pharmacology)
• Valine (analogs & derivatives, pharmacology)
• Valsartan
• Ventricular Remodeling