Selective endothelin receptor blockade reverses mitochondrial dysfunction in canine heart failure.
OBJECTIVE
Mitochondrial enzymatic activity reductions in both myocardial and skeletal muscle tissues have been reported in a canine model of pacing-induced congestive heart failure (CHF). Endothelin-1 (ET-1), a vasoconstrictor peptide with diverse biological properties, has been implicated in CHF pathogenesis, and ET-1 receptor blockade has been shown to attenuate CHF progression. We hypothesized that the beneficial effect of ET-1 receptor blockade may be mediated in part by improved mitochondrial function.


METHODS
Myocardium and skeletal muscle tissues were evaluated for respiratory complex I-V and citrate synthase activity levels in paced animals treated with and without LU 135252, a specific type A ET-1 receptor (ET(A)) antagonist.


RESULTS
Specific activity levels of complex V and III, which were 65% to 85% lower in both cardiac and skeletal muscle in paced compared to unpaced animals, were significantly increased in ET(A) antagonist-treated animals (50%-300% compared to untreated paced animals). Levels of other mitochondrial respiratory complex activities including complex I, II, and IV as well as citrate synthase were not significantly changed.


CONCLUSIONS
These findings suggest that endothelin activation may be involved in the myocardial dysfunction and mitochondrial enzyme deficiencies observed in pacing-induced CHF. Improvement of mitochondrial function may be a novel mechanism mediating the beneficial effect of ET(A) receptor blockade in CHF.
Marín-García
José
J
The Molecular Cardiology and Neuromuscular Institute, Highland Park, New Jersey 08904, USA.
Goldenthal
Michael J
MJ
Moe
Gordon W
GW
D000251:Adenosine Triphosphatases / Q000187:drug effects; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002352:Carrier Proteins; D002950:Citrate (si)-Synthase / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy*; D006439:Hemodynamics / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases; D008955:Models, Cardiovascular; D009097:Multienzyme Complexes / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010666:Phenylpropionates / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D002352:Carrier Proteins; D065128:Endothelin Receptor Antagonists; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan; D002950:Citrate (si)-Synthase; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein