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Mitochondrial Na+/Ca2+-exchanger blocker CGP37157 protects against chromaffin cell death elicited by veratridine.
J Pharmacol Exp Ther. 2009 Sep; 330(3):844-54.JP

Abstract

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(3H)-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 microM, and 20 to 30 microM 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 microM, 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.

Authors+Show Affiliations

Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029-Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19509314

Citation

Nicolau, Santos M., et al. "Mitochondrial Na+/Ca2+-exchanger Blocker CGP37157 Protects Against Chromaffin Cell Death Elicited By Veratridine." The Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 3, 2009, pp. 844-54.
Nicolau SM, de Diego AM, Cortés L, et al. Mitochondrial Na+/Ca2+-exchanger blocker CGP37157 protects against chromaffin cell death elicited by veratridine. J Pharmacol Exp Ther. 2009;330(3):844-54.
Nicolau, S. M., de Diego, A. M., Cortés, L., Egea, J., González, J. C., Mosquera, M., López, M. G., Hernández-Guijo, J. M., & García, A. G. (2009). Mitochondrial Na+/Ca2+-exchanger blocker CGP37157 protects against chromaffin cell death elicited by veratridine. The Journal of Pharmacology and Experimental Therapeutics, 330(3), 844-54. https://doi.org/10.1124/jpet.109.154765
Nicolau SM, et al. Mitochondrial Na+/Ca2+-exchanger Blocker CGP37157 Protects Against Chromaffin Cell Death Elicited By Veratridine. J Pharmacol Exp Ther. 2009;330(3):844-54. PubMed PMID: 19509314.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial Na+/Ca2+-exchanger blocker CGP37157 protects against chromaffin cell death elicited by veratridine. AU - Nicolau,Santos M, AU - de Diego,Antonio M G, AU - Cortés,Lorena, AU - Egea,Javier, AU - González,José C, AU - Mosquera,Marta, AU - López,Manuela G, AU - Hernández-Guijo,Jesús Miguel, AU - García,Antonio G, Y1 - 2009/06/09/ PY - 2009/6/11/entrez PY - 2009/6/11/pubmed PY - 2009/9/22/medline SP - 844 EP - 54 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 330 IS - 3 N2 - 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(3H)-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 microM, and 20 to 30 microM 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 microM, 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19509314/Mitochondrial_Na+/Ca2+_exchanger_blocker_CGP37157_protects_against_chromaffin_cell_death_elicited_by_veratridine_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19509314 DB - PRIME DP - Unbound Medicine ER -