Effects of Ca2+ channel antagonist subtypes on mitochondrial Ca2+ transport

This study was carried out to define the effects of various Ca2+ channel modulatory drugs on mitochondrial Ca2+ movements. Bovine adrenal medulla mitochondria took up Ca2+ at an initial rate of 6.8 nmol mg protein-1 5 s-1, with a Km of 15 microM and a Bmax of 30 nmol mg protein-1. At 30 microM, neit...

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Bibliographic Details
Published in:European journal of pharmacology 1995-03, Vol.289 (1), p.73-80
Main Authors: UCEDA, G, GARCIA, A. G, GUANTES, J. M, MICHELENA, P, MONTIEL, C
Format: Article
Language:English
Subjects:
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology
Adrenal Medulla - drug effects
Adrenal Medulla - metabolism
Animals
Biological and medical sciences
Biological Transport - drug effects
Calcium - metabolism
Calcium Channel Blockers - classification
Calcium Channel Blockers - pharmacology
Cardiovascular system
Cattle
Diltiazem - pharmacology
Flunarizine - pharmacology
In Vitro Techniques
Medical sciences
Miscellaneous
Mitochondria - drug effects
Mitochondria - metabolism
Nitrendipine - pharmacology
Pharmacology. Drug treatments
Verapamil - pharmacology
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Summary:This study was carried out to define the effects of various Ca2+ channel modulatory drugs on mitochondrial Ca2+ movements. Bovine adrenal medulla mitochondria took up Ca2+ at an initial rate of 6.8 nmol mg protein-1 5 s-1, with a Km of 15 microM and a Bmax of 30 nmol mg protein-1. At 30 microM, neither verapamil, diltiazem, nitrendipine nor Bay K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate] affected the initial rate of Ca2+ uptake. Ca(2+)-loaded mitochondria retained their Ca2+ contents in the presence of ruthenium red for at least 30 min. Cinnarizine and flunarizine, but not verapamil, diltiazem, isradipine, Bay K 8644 or nitrendipine, caused a fast and dramatic Na(+)-independent Ca2+ loss. Other Ca2+ channel antagonists assayed such as penfluridol, R56865 [N-[1-(4-(4-fluorophenoxy)butyl)]-4-piperidinyl-N-methyl-2- benzothiazolamine], lidoflazine, R87926 [(+)-(S)-4-(2-benzothiazolyl-methylamino)-alpha-[(3,4-difluorophenoxy ) methyl] 1 piperidine] and sabeluzole, also had a mitochondrial Ca2+ depleting effect which seemed to be directly related to their octanol/water partition coefficient. The Na(+)-dependent Ca2+ efflux from mitochondria was completely inhibited by diltiazem and greatly blocked by nitrendipine. Isradipine caused a moderate blockade and Bay K 8644 and verapamil had no effect. All these data open the possibility of developing novel Ca2+ channel antagonists having selective actions on plasmalemmal Ca2+ channels, and others with additional and different effects on mitochondrial Ca2+ transport.
ISSN:0922-4106
0014-2999
1879-0712
DOI:10.1016/0922-4106(95)90170-1