1.
Atrial natriuretic peptide (
ANP)-null mice (
Nppa(-/-)) exhibit
cardiac hypertrophy at baseline and adverse cardiac remodelling in response to transverse aortic constriction (TAC)-induced pressure overload stress. Previous studies have suggested that
natriuretic peptides could potentially oppose
mineralocorticoid signalling at several levels, including suppression of adrenal
aldosterone production, inhibition of
mineralocorticoid receptor (MR) activation or suppression of MR-mediated production of pro-inflammatory factors. Thus, we hypothesized that the MR blocker
eplerenone would prevent the exaggerated left ventricular (LV) remodelling/
fibrosis and dysfunction after TAC in
Nppa(-/-). 2. In the present study,
Nppa(-/-) and wild-type
Nppa(+/+) mice fed
eplerenone- or vehicle (oatmeal)-supplemented chow since weaning were subjected to TAC or
sham operation. The daily dose of
eplerenone administered was approximately 200 mg/kg. At 1 week after TAC, LV size and function were evaluated by echocardiogram and LV cross-sections were stained with
picrosirius red for
collagen volume measurement. Total
RNA was extracted from the LV for real-time polymerase chain reaction analysis of
osteopontin. 3.
Eplerenone had no effect on baseline
hypertrophy observed in
sham-operated
Nppa(-/-) compared with
Nppa(+/+) mice.
Eplerenone attenuated the TAC-induced increase in LV weight in both genotypes and completely prevented LV dilation, systolic dysfunction and interstitial
collagen deposition seen in
Nppa(-/-) mice after TAC. However, serum
aldosterone levels were lower in
Nppa(-/-) compared with
Nppa(+/+) wild types. No interaction between
eplerenone and genotype in
osteopontin mRNA levels was observed. 4.
Eplerenone prevents adverse cardiac remodelling related to pressure overload in
ANP-deficient mice, mainly due to an antifibrotic effect. The mechanism whereby
ANP deficiency leads to excess
hypertrophy,
fibrosis and early failure following TAC is increased profibrotic signals resulting from excess or unopposed MR activation, rather than increased levels of
aldosterone.