Calcium antagonists and Bay K8644 promote depolarization of the rat heart mitochondrial membrane potential: Further evidence for a role in alteration of oxidative metabolism

Abstract

Studies were carried out using a tetraphenylphosphonium (TPP +)-selective electrode to monitor the effect of selected calcium (Ca 2+) antagonists and the dihydropyridine Ca 2+ agonist Bay K8644 on membrane potential (Ψ) associated with isolated rat heart mitochondria. Verapamil and diltiazem ( 10–500 μM), standard Ca 2+ antagonists, produced a depolarization of both liver and heart mitochondria at concentrations >150 μM. In contrast, nitrendipine (10–200 μM), a dihydropyridine compound, produced a concentration-related inhibition of Ψ in mitochondria from both sources, effects which were statistically significant at concentrations <50 μM. Cinnarizine (10–100 μM) and bepridil (10–100 μM) also produced inhibition of heart Ψ, these effects being particularly noted in the presence of bepridil, where depolarization of the membrane was statistically significant with only 10 μM drug. The results indicate the complexity of action of these drugs at the mitochondrial level. In general, drug actions on Ψ appear to be correlated with previously reported effects on Ca 2+ transportation rather than oxidative phosphorylation associated with rat heart mitochondria. The findings also illustrate that the mitochondrial actions of cardiovascular compounds may be of relevance in situ, particularly during ischaemia/reperfusion when mitochondria become loaded with Ca 2+.