title: Beneficial effects on skeletal muscle of the angiotensin II type 1 receptor blocker irbesartan in experimental heart failure.
abstract: BACKGROUND
  In congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-alpha (TNFalpha). Angiotensin II receptors are thought to play a role in controlling apoptosis. We tested the hypothesis that angiotensin II receptor blockade could prevent skeletal muscle apoptosis in rats with CHF.
  
  
  RESULTS
  CHF was induced by injecting 36 rats with 30 mg/kg monocrotaline. Ten additional animals were injected with saline and acted as controls. 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 additional weeks, rats were killed. Tibialis anterior cross-sectional area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and activated caspases 3 and 9 were determined, as were plasma levels of TNFalpha and angiotensin II. Myocyte apoptosis and muscle atrophy were significantly decreased with 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 pattern in irbesartan-treated animals was similar to that in controls. Nifedipine animals behaved like the untreated CHF animals. Angiotensin II was increased 3- to 4-fold in all CHF rats (treated and untreated). TNFalpha levels were decreased in irbesartan-treated rats but not in nifedipine-treated rats.
  
  
  CONCLUSIONS
  Angiotensin II receptor blockade can protect from the development of apoptosis-dependent atrophy and from changes in MHCS: The reduction of TNFalpha may play a role in this process.
authors.affiliation: CNR Unit for Muscle Pathophysiology, Department of Biomedical Sciences, University of Padua, Padua, Italy. ldl@civ.bio.unipd.it
authors.forename: L
authors.initials: L
authors.lastname: Dalla Libera
authors.forename: B
authors.initials: B
authors.lastname: Ravara
authors.forename: A
authors.initials: A
authors.lastname: Angelini
authors.forename: K
authors.initials: K
authors.lastname: Rossini
authors.forename: M
authors.initials: M
authors.lastname: Sandri
authors.forename: G
authors.initials: G
authors.lastname: Thiene
authors.forename: G
authors.initials: G
authors.lastname: Battista Ambrosio
authors.forename: G
authors.initials: G
authors.lastname: Vescovo
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D015918:Infusion Pumps, Implantable; D000077405:Irbesartan; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000473:pathology; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D009133:Muscular Atrophy / Q000517:prevention & control; D009543:Nifedipine / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D009124:Muscle Proteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D016686:Monocrotaline; D009543:Nifedipine; D000077405:Irbesartan