Mitochondrial Na+/Ca2+-Exchanger Blocker CGP37157 Protects against Chromaffin Cell Death Elicited by Veratridine

Mitochondrial calcium (Ca 2+ ) dyshomeostasis constitutes a critical step in the metabolic crossroads leading to cell death. Therefore, we have studied here whether 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3 H )-one (CGP37157; CGP), a blocker of the mitochondrial Na + /Ca 2+ -exc...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2009-09, Vol.330 (3), p.844
Main Authors: Santos M. Nicolau, Antonio M. G. de Diego, Lorena Cortés, Javier Egea, José C. González, Marta Mosquera, Manuela G. López, Jesús Miguel Hernández-Guijo, Antonio G. García
Format: Article
Language:English
Subjects:
Animals
Calcium Channels - drug effects
Calcium Channels - metabolism
Calcium Signaling - drug effects
Cattle
Cell Death - drug effects
Cells, Cultured
Chromaffin Cells - drug effects
Chromaffin Cells - enzymology
Clonazepam - analogs & derivatives
Clonazepam - pharmacology
Coloring Agents
Cytochromes c - metabolism
L-Lactate Dehydrogenase - metabolism
Membrane Potentials - drug effects
Mitochondria - drug effects
Mitochondria - metabolism
Patch-Clamp Techniques
Reactive Oxygen Species
Sodium Channels - drug effects
Sodium Channels - metabolism
Sodium-Calcium Exchanger - antagonists & inhibitors
Tetrazolium Salts
Thiazepines - pharmacology
Thiazoles
Veratridine - antagonists & inhibitors
Veratridine - toxicity
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Summary:Mitochondrial calcium (Ca 2+ ) dyshomeostasis constitutes a critical step in the metabolic crossroads leading to cell death. Therefore, we have studied here whether 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3 H )-one (CGP37157; CGP), a blocker of the mitochondrial Na + /Ca 2+ -exchanger (mNCX), protects against veratridine-elicited chromaffin cell death, a model suitable to study cell death associated with Ca 2+ overload. Veratridine produced a concentration-dependent cell death, measured as lactate dehydrogenase released into the medium after a 24-h incubation period. CGP rescued cells from veratridine-elicited death in a concentration-dependent manner; its EC 50 was approximately 10 μM, and 20 to 30 μM caused near 100% cytoprotection. If preincubated for 30 min and washed out for 3 min before adding veratridine, CGP still afforded significant cytoprotection. At 30 μM, CGP blocked the veratridine-elicited free radical production, mitochondrial depolarization, and cytochrome c release. At this concentration, CGP also inhibited the Na + and Ca 2+ currents by 50 to 60% and the veratridine-elicited oscillations of cytosolic Ca 2+ . This drastic cytoprotective effect of CGP could be explained in part through its regulatory actions on the mNCX.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.109.154765