Sub-optimal intrauterine environment such as maternal malnutrition, fetal hypoxia, alterations in renin-angiotensin-aldosterone system, or hormonal excess may play an important role in the development of later cardiovascular disease. This concept is known as ���fetal programming���. Programming results from adaptive changes in gene expression patterns in response to stressors. Previous our studies demonstrated that alterations in renin-angiotensin-aldosterone system in the developing rat kidney affect renal growth and development. The present study investigated whether and how mineralocorticoid receptor antagonist spironolactone affects cardiac growth and development through apoptosis and cell proliferation in the neonatal rat heart. Newborn rat pups were treated with spironolactone (200 mg/kg/d) or normal saline for 7 days, and hearts were removed for apoptosis [terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling (TUNEL)-positive cells] and for cell proliferation. Cell proliferation was determined by PCNA immunostaining. Spironolactone treatment resulted in a 50% mortality, reduced body weight, decreased heart weight, and decreased heart weight/body weight ratio (P <0.05). Spironolactone decreased proliferating myocytes by 32% (P <0.05), and reduced myocytes apoptosis by 29% (P <0.05). Spironolactone decreased proliferation and apoptosis of cardiac interstitial cells, however, there was no statistical significance. These results indicate that aldosterone inhibition in the developing rat heart induces cardiac growth impairment by decreasing proliferation and apoptosis of myocytes. We speculate that decreased cell proliferation and cellular turnover in the perinatal period may lead to maladaptive hypertrophy and myocardial dysfunction later in life.