Aldosterone induces myocyte apoptosis in the heart and skeletal muscles of rats in vivo

Over activation of the renin-angiotensin-aldosterone system is known to be cardiotoxic but the potential injurious effects on the skeletal musculature have not been investigated. Male Wistar rats were given subcutaneous injections of aldosterone (1 μg-10 mg kg-1) and killed 7 h later, or continuous infusion (1 mg kg-1 d-1) and killed 48 h later. The role of the mineralocorticoid receptor in mediating aldosterone-induced apoptosis in vivo was investigated using spironolactone (200 mg kg-1). The number of apoptotic (caspase 3 positive) myocytes was counted on cryosections of the heart, soleus and Tibialis Anterior muscles. Injections of aldosterone induced significant (P < 0.05) cardiomyocyte apoptosis (peak = 2.46 ± 0.6 per 104 viable myocytes) over the range of 100 μg-10 mg kg-1, whereas only administration of 1 mg kg-1 induced significant (P < 0.05) apoptosis (2.47 ± 0.8 per 104 viable myocytes) in the soleus muscle. In contrast, no apoptosis was detected in the striated muscles after administration of only the vehicle. Infusion of aldosterone induced less apoptosis than the same dose (1 mg kg-1) given as a single injection. Prior administration of spironolactone significantly (P < 0.05) protected the heart (90%) and soleus muscle (79%) against the apoptosis induced by a single injection of 1 mg kg-1 aldosterone. These data confirm a myotoxic effect of aldosterone on the heart and provide the first description of aldosterone-induced myocyte apoptosis in skeletal muscle. High circulating levels of aldosterone are clearly capable of damaging all types of striated muscle and this may lend support to the concept that heart failure is a generalised, rather than cardiac-specific, myopathy.