Effect of inhibitors of mitochondrial respiratory chain complexes on the electromechanical activity in human...

THE AIM OF THE STUDY was to investigate the effect of inhibitors of mitochondrial respiratory chain complexes I, III, and IV on the electromechanical activity in human myocardium.

The experiments were performed on the human myocardial strips obtained from patients with heart failure (NYHA class III or IV) using a conventional method of registration of myocardial electromechanical activity. Under the perfusion with physiological Tyrode solution (control), contraction force (P) was 0.94±0.12 mN (n=16), relaxation time (t₅₀) was 173.38±5.03 ms (n=15), action potential durations measured at 50% (AP₅₀) and 90% (AP₉₀) repolarization were 248.96±13.38 ms and 398.59±17.93 ms, respectively (n=13).

The inhibition of respiratory chain complex I by rotenone (3 × 10⁻⁵ M, the highest concentration applied) decreased contraction force of human myocardium to 48.99%±14.74% (n=3) (P<0.05); AP₅₀, to 81.34%±15.81%; and AP₉₀, to 87.28%±7.25% (n=3) (P>0.05) of control level, while relaxation time and resting tension remained almost unchanged. Antimycin A, an inhibitor of complex III, applied at the highest concentration (3 × 10⁻⁴ M) reduced P to 41.66%±8.8% (n=5) (P<0.001) and marginally increased t₅₀ and decreased the durations of AP. Anoxia (3 mM Na₂S₂O₄) that inhibits the activity of complex IV reduced the contraction force to 9.23%±3.56% (n=6) (P<0.001), AP₅₀ and AP₉₀ to 65.46%±9.95% and 71.07%±8.39% (n=5) (P<0.05) of control level, respectively; furthermore, the resting tension augmented (contracture developed).

Our results show that the inhibition of respiratory chain complex IV had the strongest inhibitory effect on the electromechanical activity of failing human myocardium.