Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats

Background: Oral administration of spironolactone improves cardiac remodeling and its central infusion prevents the increase in sympathetic drive post-myocardial infarction (MI). We hypothesized that central actions of aldosterone contribute to cardiac remodeling post-MI. Objective: To compare the effects of intracerebroventricular (icv) infusion and oral administration of spironolactone on cardiac remodeling and left ventricle (LV) dysfunction post-MI in rats. Methods: Spironolactone was administered orally (80 mg/kg/day) or by icv infusion (100 ng/h), starting 1-3 days post-MI in Wistar rats and continued for 6 weeks. Results: At 6 weeks post-MI, in the rats treated with vehicle, LV peak systolic pressure (LVPSP) and LV dP/dt max were clearly decreased and LV end diastolic pressure (LVEDP) and plasma catecholamines and serum aldosterone increased. All these parameters improved with both oral and icv spironolactone. The MI-induced increases in, internal circumferences of LV and right ventricle (RV), and in interstitial and perivascular fibrosis, in both the LV and RV were significantly prevented/inhibited by both oral and icv spironolactone. Laminin, fibronectin and fibrillar collagen (visualized by scanning electron microscopy, SEM) increased in the non-infarcted part of the LV post-MI in the vehicle group, but not/less in rats on oral or icv spironolactone. Conclusions: Since the magnitude of beneficial effects of icv spironolactone at low doses was largely equal to that achieved with its oral administration at much higher doses, we propose that in addition to other sites of action, aldosterone appears to activate central nervous system (CNS) pathways and thereby influences peripheral mechanisms involved in cardiac remodeling. (C) 2004 European Society of Cardiology. Published by Elsevier B.V.