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

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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.