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. 2011 Apr;300(4):H1484-91.
doi: 10.1152/ajpheart.01000.2010. Epub 2011 Jan 14.

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Javad Habibi  1 , Vincent G DeMarco, Lixin Ma, Lakshmi Pulakat, William E Rainey, Adam T Whaley-Connell, James R Sowers
Affiliations

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Javad Habibi et al. Am J Physiol Heart Circ Physiol. 2011 Apr.

Abstract

There is emerging evidence that aldosterone can promote diastolic dysfunction and cardiac fibrosis independent of blood pressure effects, perhaps through increased oxidative stress and inflammation. Accordingly, this investigation was designed to ascertain if mineralocorticoid receptor blockade improves diastolic dysfunction independently of changes in blood pressure through actions on myocardial oxidative stress and fibrosis. We used young transgenic (mRen2)27 [TG(mRen2)27] rats with increases in both tissue ANG II and circulating aldosterone, which manifests age-related increases in hypertension and cardiac dysfunction. Male TG(mRen2)27 and age-matched Sprague-Dawley rats were treated with either a low dose (∼1 mg·kg(-1)·day(-1)) or a vasodilatory, conventional dose (∼30 mg·kg(-1)·day(-1)) of spironolactone or placebo for 3 wk. TG(mRen2)27 rats displayed increases in systolic blood pressure and plasma aldosterone levels as well as impairments in left ventricular diastolic relaxation without changes in systolic function on cine MRI. TG(mRen2)27 hearts also displayed hypertrophy (left ventricular weight, cardiomyoctye hypertrophy, and septal wall thickness) as well as fibrosis (interstitial and perivascular). There were increases in oxidative stress in TG(mRen2)27 hearts, as evidenced by increases in NADPH oxidase activity and subunits as well as ROS formation. Low-dose spironolactone had no effect on systolic blood pressure but improved diastolic dysfunction comparable to a conventional dose. Both doses of spironolactone caused comparable reductions in ROS/3-nitrotryosine immunostaining and perivascular and interstitial fibrosis. These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure.

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Figures

Fig. 1.
Fig. 1.
Initial and final systolic blood pressure for control and spironolactone (Sp)-treated Sprague-Dawley (SD) and transgenic (mRen2)27 (R2) rats. Rats were divided into the following groups: SD control (SDC), R2 control (R2C), R2 rats treated with low-dose Sp (R2 LSp), and R2 rats treated with conventional-dose Sp (R2 Sp). *P < 0.05 vs. R2C rats.
Fig. 2.
Fig. 2.
A: typical cine MRI of SDC (top), R2C (middle), and R2 Sp rats after SP treatment (bottom). A total of 16 cine MRI frames were recorded in 1 entire cardiac cycle for each rat. The frames shown here are frames 7, 10, and 16, representing end-systolic, early diastolic, and end-diastolic phases, respectively. B–E: indexes of diastolic (B and C) and systolic (D and E) function derived from the analysis of cine MRI images. *P < 0.05 vs. R2C rats.
Fig. 3.
Fig. 3.
Markers of oxidative stress in cardiac tissue from control and Sp-treated SD and R2 rats. A: bar graph showing chemiluminescence-derived measures of total ROS formation. B: representative images (top) of 3-nitrotryisone (3-NTS) content, a marker for peroxynitrite formation, with average grayscale intensities (bottom). *P < 0.05 vs. R2C rats.
Fig. 4.
Fig. 4.
Measures of NADPH oxidase. A: bar graph showing means ± SE values of total NADPH oxidase enzyme activity in cardiac tissue. B: representative confocal images (top) of NADPH oxidase subunits [NADPH oxidase 2 (Nox2) and Rac1] with measures of average grayscale intensities (bottom). *P < 0.05 vs. R2C rats.
Fig. 5.
Fig. 5.
Markers of cardiac tissue hypertrophy for control and Sp-treated R2 rats. A and B: bar graphs showing increased septal wall thickness via cine MRI (A) and left ventricle + septum weight normalized to body weight [(LV + S)/BW; B] in R2C, R2 LSp, and R2 Sp rats compared with SDC rats. C: representative light micrographs of cardiomyocytes in cross section. D: bar graph showing average cardiomyoctye size expressed as cross-sectional area (in μm2). *P < 0.05 for paired comparisons.
Fig. 6.
Fig. 6.
Markers of fibrosis for control and Sp-treated R2 rats. A and B: representative light micrographs (top) showing collagen fiber staining (pink) upon Verhoeff-van Gieson staining in the interstitium (A) and adventitia (B) surrounding coronary arterioles with bar graphs of relative degrees of fibrosis (bottom). *P < 0.05 vs. R2C rats.
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