Chronic Wy‐14,643 administration attenuates myocardial respiratory capacity and contractile function

We hypothesized that chronic in vivo Wy‐14,643 treatment exerts direct effects on myocardial mitochondrial respiratory function and contractile function. Wy‐14,643 was administered to Wistar rats for 14 consecutive days and compared with matched controls. State 3 mitochondrial respiration was lower in the Wy‐14,643 group while state 4 respiration was significantly increased. In agreement, oligomycin‐insensitive proton leak was increased and the respiratory control index significantly decreased. The rate of ADP phosphorylation decreased by 44.9 ± 1.9% (p≤0.05 vs. control). Left ventricular systolic and developed pressures were lower while rate pressure product declined by 36 ± 2.6% (p≤0.01 vs. control) after Wy‐14,643 treatment. We show that chronic in vivo Wy‐14,643 administration to rats impairs myocardial mitochondrial oxidative phosphorylation and increases proton leak, contributing to a decreased rate of ATP synthesis and contractile function. These factors should be considered when employing Wy‐14,643 for both in vitro and in vivo experiments.