Mitochondrial Na ϩ /Ca 2ϩ -Exchanger Blocker CGP37157 Protects against Chromaffin Cell Death Elicited by Veratridine

ABSTRACT Mitochondrial calcium (Ca 2ϩ ) 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(3H)-one (CGP37157; CGP), a blocker of the mitochondrial Na . This drastic cytoprotective effect of CGP could be explained in part through its regulatory actions on the mNCX. In general, it is accepted that a dysregulation of the mechanism that fine tunes the transient or more sustained levels of the cytosolic Ca 2ϩ concentrations ([Ca 2ϩ ] c ), leads to excitotoxic neuronal death ABBREVIATIONS: mNCX, mitochondrial Na ϩ /Ca 2ϩ -exchanger; DMSO, dimethyl sulfoxide; FPL64176, FPL, 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester; 30 K ϩ /FPL, 30 mM K ϩ /0.3 M FPL; MTT formazan, 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan, thiazolyl blue formazan; CGP37157, 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one; TTX, tetrodotoxin citrate, octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethan o-10aH- [1,3] dioxocino [6,5-d]pyrimidin