CALCIUM-ANTAGONISTS AND BAY K8644 PROMOTE DEPOLARIZATION OF THE RAT-HEART MITOCHONDRIAL-MEMBRANE POTENTIAL - FURTHER EVIDENCE FOR A ROLE INALTERATION OF OXIDATIVE-METABOLISM

Studies were carried out using a tetraphenylphosphonium (TPP+)-selecti ve electrode to monitor the effect of selected calcium (Ca2+) antagoni sts and the dihydropyridine Ca2+ agonist Bay K8644 on membrane potenti al (PSI) associated with isolated rat heart mitochondria. Verapamil an d diltiazem (10-500 muM), standard Ca2+ antagonists, produced a depola rization of both liver and heart mitochondria at concentrations >150 m uM. In contrast, nitrendipine (10-200 muM), a dihydropyridine compound , produced a concentration-related inhibition of PSI in mitochondria f rom both sources, effects which were statistically significant at conc entrations >50 muM. Cinnarizine (10-100 muM) and bepridil (10-100 muM) also produced inhibition of heart PSI, these effects being particular ly noted in the presence of bepridil, where depolarization of the memb rane was statistically significant with only 10 muM drug. The results indicate the complexity of action of these drugs at the mitochondrial level. In general, drug actions on PSI appear to be correlated with pr eviously reported effects on Ca2+ transportation rather than oxidative phosphorylation associated with rat heart mitochondria. The findings also illustrate that the mitochondrial actions of cardiovascular compo unds may be of relevance in situ, particularly during ischaemia/reperf usion when mitochondria become loaded with Ca2+.