Selective endothelin receptor blockade reverses mitochondrial dysfunction in canine heart failure

Abstract

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 (ETA) 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 ETA 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 ETA receptor blockade in CHF.