Role of aldosterone in cardiac remodeling post-myocardial infarction and after high salt diet

Abstract

High salt diet cardiac fibrosis by activating cardiac aldosterone . We hypothesized that enhanced cardiac aldosterone production by high salt intake may increase left ventricle (LV) weight and cardiomyocyte size and induce fibrosis in both ventricles. Regular salt (0.6%) or high salt (8%) diet, either without or with spironolactone (20 or 80 mg/kg/day) were given to Wistar rats for 4 and 8 weeks. Both LV weight and cardiomyocyte cross-sectional diameter were increased significantly by high salt diet after 4 and 8 weeks. Both LV and right ventricle (RV) collagen and fibrosis as well as mean arterial pressure (MAP) remained unchanged after 4 weeks, but increased significantly after 8 weeks on high salt diet. Spironolactone (80 mg/kg) prevented the high salt-induced increases in LV weight and cardiomyocyte cross-sectional diameter as well as LV and RV collagen and fibrosis, and attenuated the increase in MAP. Spironolactone (20 mg/kg) was somewhat less effective. The high salt induced changes in cardiac and cardiomyocyte hypertrophy, and cardiac fibrosis were prevented by spironolactone, which is consistent with the concept that cardiac aldosterone mediates these cardiac effects of high salt diet. Role of brain renin-angiotensin-aldosterone-system (RAAS) in cardiac remodeling post-MI. To assess the contribution of the brain RAAS in the activation of the cardiac RAAS and remodeling post-MI, Wistar rats with intracerebroventricular (icv) infusion of spironolactone and transgenic (TG) rats deficient in brain angiotensinogen were studied. An MI was induced by acute coronary artery ligation. Spironolactone was administered by icv infusion (100 ng/h) or orally (80 mg/kg/day) for 6 weeks post-MI in Wistar rats. TG rats and control Sprague-Dawley (SD) rats were followed for 8 weeks. MI decreased LV peak systolic pressure (LVPSP) and LV dP/dt max and increased LV end diastolic pressure (LVEDP) and plasma catecholamines and serum aldosterone, which were prevented or attenuated by both icv and oral spironolactone at 6 weeks post-MI. MI increased internal circumferences, cardiomyocyte diameter, fibrosis, laminin and fibronectin, and aldosterone in the LV or and RV, which were also significantly prevented/inhibited by both icv and oral spironolactone at 6 weeks post-MI in Wistar rats as well as at 8 weeks post-MI in TG rats. Magnitude of beneficial effects of icv spironolactone at low doses was largely equal to that achieved with its oral administration at much higher doses, indicating that in addition to other sites of actions, aldosterone appears to activate central nervous system (CNS) pathways and thereby influences peripheral mechanisms involved in cardiac remodeling. The findings in TG rats support the pivotal role of locally produced angiotensin II in the brain in cardiac remodeling post-MI. The brain RAAS appears to activate a cascade of events, among others an increase in cardiac aldosterone, which play a major role in cardiac remodeling post-MI.