Inhibition of the mitochondrial Mg²⁺-ATPase by propranolol

The in vitro effects of propranolol, a commonly used β-adrenergic blocker, on the membrane structure and function of rat heart mitochondria were investigated. It was found that the respiratory control and oxidative phosphorylation of the isolated mitochondria decreased concomitantly when the drug was added to the assay medium. At the concentration higher than 1.0 × 10^-4 M, propranolol significantly inhibited the State 3 respiration but had little effect on the State 4 respiration of the mitochondria. On the other hand, the drug exhibited noncompetitive inhibitions toward the Mg²⁺-ATPase activity of submitochondrial particles and purified enzyme preparations at the concentrations ranging from 3.0 × 10^-4 to 1.5 × 10^-3 M. The inhibitory constants of propranolol toward the enzyme activity in submitochondrial particles and in the purified preparation were estimated to be 6.7 × 10^-4 and 1.4 × 10^-3 M, respectively. However, the drug did not show significant effect on the activity of any of the enzyme complexes of the mitochondrial respiratory chain. It is thus concluded that propranolol impairs the mitochondrial respiration and oxidative phosphorylation mainly through its inhibition of the Mg²⁺-ATPase activity of the mitochondria. This effect of propranolol may explain, at least partly, its depression effects on the cardiac functions of the animal.