Calcium antagonists and Bay K8644 promote depolarization of the rat heart mitochondrial membrane potential. Further evidence for a role in alteration of oxidative metabolism.
Studies were carried out using a tetraphenylphosphonium (TPP+)-selective electrode to monitor the effect of selected calcium (Ca2+) antagonists and the dihydropyridine Ca2+ agonist Bay K8644 on membrane potential (psi) associated with isolated rat heart mitochondria. Verapamil and diltiazem (10-500 microM), standard Ca2+ antagonists, produced a depolarization of both liver and heart mitochondria at concentrations > 150 microM. In contrast, nitrendipine (10-200 microM), a dihydropyridine compound, produced a concentration-related inhibition of psi in mitochondria from both sources, effects which were statistically significant at concentrations > 50 microM. Cinnarizine (10-100 microM) and bepridil (10-100 microM) also produced inhibition of heart psi, these effects being particularly noted in the presence of bepridil, where depolarization of the membrane was statistically significant with only 10 microM 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 previously reported effects on Ca2+ 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 Ca2+.
Fox
R M
RM
School of Health Sciences, University of Sunderland, Tyne and Wear, U.K.
Morgan
R M
RM
Markham
A
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D001693:Biological Transport, Active; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004566:Electrodes; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009861:Onium Compounds / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium; C013289:tetraphenylphosphonium