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Effects of Ca2+ channel antagonist subtypes on mitochondrial Ca2+ transport
G Uceda1, A G García, J M Guantes
1Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Abstract:
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Certain calcium channel blockers impact mitochondrial calcium movement. Some drugs, like cinnarizine and flunarizine, cause rapid calcium loss from mitochondria, while others affect calcium efflux differently.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Mitochondria play a crucial role in cellular calcium homeostasis.
- Calcium channel modulatory drugs are widely used, but their effects on mitochondria are not fully understood.
Purpose of the Study:
- To investigate the impact of various calcium channel modulatory drugs on mitochondrial calcium uptake and release.
- To characterize the differential effects of these drugs on mitochondrial calcium dynamics.
Main Methods:
- Bovine adrenal medulla mitochondria were used to study calcium uptake and efflux kinetics.
- The effects of verapamil, diltiazem, nitrendipine, Bay K 8644, cinnarizine, flunarizine, and other calcium channel antagonists were assessed.
- Sodium-dependent and independent calcium movements were differentiated.
Main Results:
- Verapamil, diltiazem, nitrendipine, and Bay K 8644 did not affect initial mitochondrial calcium uptake rates.
- Cinnarizine and flunarizine induced rapid, sodium-independent mitochondrial calcium efflux.
- Other tested calcium channel antagonists also depleted mitochondrial calcium, correlating with their lipophilicity.
- Diltiazem and nitrendipine differentially inhibited sodium-dependent calcium efflux.
Conclusions:
- The study reveals distinct effects of calcium channel modulatory drugs on mitochondrial calcium transport.
- Drug effects on mitochondrial calcium dynamics vary significantly, independent of their plasma membrane channel activity.
- These findings suggest potential for developing novel drugs targeting specific mitochondrial calcium transport pathways.