(Circulation. 2001;103:2195.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Beneficial Effects on Skeletal Muscle of the Angiotensin II Type 1 Receptor Blocker Irbesartan in Experimental Heart Failure
From the CNR Unit for Muscle Pathophysiology, Department of Biomedical Sciences (L.D.L., B.R., K.R., M.S.), and the Department of Cardiovascular Pathology (A.A., G.T.), University of Padua, Padua, Italy; Internal Medicine I, City Hospital, Venice, Italy (G.B.A.); and Internal Medicine, City Hospital, Adria, Italy (G.V.).
Correspondence to Giorgio Vescovo, MD, PhD, FESC, Internal Medicine, City Hospital, 45011 Adria (RO), Italy. E-mail ldl{at}civ.bio.unipd.it
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-
(TNF). 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.
Methods and 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
TNF 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). TNF
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
TNF may play a role in this
process.
Key Words: heart failure • irbesartan • muscles • apoptosis • tumor necrosis factor
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