RT Journal Article
SR Electronic
T1 Mitochondrial Na<sup>+</sup>/Ca<sup>2+</sup>-Exchanger Blocker CGP37157 Protects against Chromaffin Cell Death Elicited by Veratridine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 844
OP 854
DO 10.1124/jpet.109.154765
VO 330
IS 3
A1 Santos M. Nicolau
A1 Antonio M. G. de Diego
A1 Lorena Cortés
A1 Javier Egea
A1 José C. González
A1 Marta Mosquera
A1 Manuela G. López
A1 Jesús Miguel Hernández-Guijo
A1 Antonio G. García
YR 2009
UL http://jpet.aspetjournals.org/content/330/3/844.abstract
AB Mitochondrial calcium (Ca2+) 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+/Ca2+-exchanger (mNCX), protects against veratridine-elicited chromaffin cell death, a model suitable to study cell death associated with Ca2+ 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 EC50 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 Ca2+ currents by 50 to 60% and the veratridine-elicited oscillations of cytosolic Ca2+. This drastic cytoprotective effect of CGP could be explained in part through its regulatory actions on the mNCX. The American Society for Pharmacology and Experimental Therapeutics