Beneficial effects on skeletal muscle of the angiotensin II type 1 receptor blocker irbesartan in experimental heart failure

Background-In congestive heart failure (CHF), skeletal muscle shows increas ed expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to m yocyte apoptosis, which is probably triggered by tumor necrosis factor-alph a (TNF alpha). Angiotensin II receptors are thought to play a role in contr olling apoptosis. We tested the hypothesis that angiotensin II receptor blo ckade could prevent skeletal muscle apoptosis in rats with CHF. Methods and Results-CHF was induced by injecting 36 rats with 30 mg/kg mono crotaline. Ten additional animals were injected with saline and acted as co ntrols. After 2 weeks, 18 of the 36 rats with CHF were treated with 7 mg.kg (-1).d(-1) irbesartan through osmotic minipumps, and 10 of the 36 rats were treated with 2 mg.kg(-1).d(-1) nifedipine in drinking water. After 2 addit ional weeks, rats were killed. Tibialis anterior cross-sectional area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and activated caspase s 3 and 9 were determined. as were plasma levels of TNF alpha and angiotens in II. Myocyte apoptosis and muscle atrophy were significantly decreased wi th irbesartan compared with untreated CHF rats. Irbesartan-treated rats had fewer cells labeled positively with terminal deoxynucleotidal transferase- mediated dUTP nick-end labeling and fewer caspases; however, they also had increased Bcl-2 levels and muscle fiber cross-sectional areas. The MHC patt ern in irbesartan-treated animals was similar to that in controls. Nifedipi ne animals behaved like the untreated CHF animals. Angiotensin II was incre ased 3- to if-fold in all CHF rats (treated and untreated). TNF alpha level s were decreased in irbesartan-treated rats but not in nifedipine-treated r ats. Conclusions-Angiotensin II receptor blockade can protect from the developme nt of apoptosis-dependent atrophy and from changes in MHCs. The reduction o f TNF alpha may play a role in this process.