Background We have shown that atrial natriuretic peptide (ANP) null mice (Nppa-/-) exhibit exaggerated cardiac remodeling with increased interstitial and perivascular fibrosis and left ventricular (LV) dysfunction in response to transverse aortic constriction (TAC)-induced pressure overload stress. Since ANP reduces aldosterone expression, we hypothesized that aldosterone levels would be increased and would play a functional role in TAC-induced LV remodeling in ANP null mice and that the mineralocorticoid receptor blocker eplerenone (Epl) would prevent the exaggerated LV remodeling/fibrosis and dysfunction after TAC in this model.
Methods Nppa-/- and wild-type Nppa+/+ mice fed Epl supplemented chow (˜ 200 mg/kg/d) since weaning were subjected to TAC or sham operation. Vehicle (Veh)-treated mice were controls. At 1 week after TAC, LV size and function were evaluated by echocardiogram; LV cross sections were stained with picrosirius red for collagen volume measurement.
Results Epl attenuated the TAC-induced increase in LV weight and completely prevented the LV dilation, systolic dysfunction and interstitial and perivascular collagen deposition seen in Nppa-/- mice after TAC. Results are means ± SE. Normalized LV weight and LVEDD were determined by ANCOVA with body weight as a covariate. G × Epl = genotype × eplerenone interaction by 2-way ANOVA. *p < .05 vs. vehicle; †p < .05 vs. Nppa+/+ mice. (figure)
Conclusions Eplerenone prevents adverse cardiac remodeling related to systolic overload in ANP-deficient states, mainly due to an antifibrotic effect. We speculate that these observations may be relevant to the human conditions in which polymorphisms in ANP gene expression are related to increased blood pressure and cardiac pathology.