Angiotensin II induces apoptosis in vivo in skeletal, as well as cardiac, muscle of the rat

Our previous work has established that angiotensin II is cardiotoxic. Here we sought to investigate whether skeletal muscle is similarly susceptible to damage. Male Wistar rats were either given a single subcutaneous injection of angiotensin II (range 1 microg kg-1 to 10 mg kg-1) or only the vehicle and killed 7 h later, or implanted with preconditioned osmotic pumps dispensing 1 mg kg-1 day-1 angiotensin II and killed 9 or 18 h later. Apoptotic (caspase 3 positive) myocytes were counted on cryosections of the heart, soleus, tibialis anterior and diaphragm muscle. Single injections of 100 microg kg-1 to 10 mg kg-1 angiotensin II induced significant (P<0.05) myocyte apoptosis (per 10(4) viable myocytes) in the heart and this was heterogeneously distributed, peaking (5.7+/-0.6; P<0.05) at a point 6 mm from the apex, i.e. approximately three-quarters of the way towards the base. The slow-twitch soleus muscle was also damaged significantly (peak=2.6+/-0.4; P<0.05), while only the administration of 1 mg kg-1 induced significant (P<0.05) apoptosis in the fast-twitch tibialis anterior muscle (peak=1.2+/-0.3). Infusion of 1 mg kg-1 day-1 angiotensin II induced more myocyte apoptosis than a single bolus administration of the same dose, and in general there was a higher incidence of apoptosis in muscles harvested after 18 than after 9 h. Infusion of 1 mg kg-1 day-1 angiotensin II over 18 h induced significant (P<0.05) myocyte apoptosis in the heart (3.3+/-0.4), soleus (3.9+/-1), tibialis anterior (5.9+/-0.4) and diaphragm (19.8+/-5.6) muscle. Depending on the muscle type, angiotensin II induces myocyte apoptosis in skeletal muscle to a similar or greater extent as in cardiac muscle, supporting the hypothesis that angiotensin II is generally toxic to all striated muscles.