Bepridil exacerbates glutamate-induced deterioration of calcium homeostasis and cultured nerve cell injury.
Application of 50 microM bepridil (BPD) to cultured nerve cells did not greatly affect the resting cytoplasmic Ca2+ concentration ([Ca2+]i) but caused its pronounced increase both during prolonged glutamate (GLU, 100 microM) treatment and, especially, in the postglutamate period in case of partial [Ca2+]i recovery. In contrast, in cells exhibiting a high [Ca2+]i plateau in the postglutamate period, BPD application either did not cause any additional elevation of [Ca2+]i or caused a very small increase. Under identical conditions replacement of external Na+ by Li+ or N-methyl-D-glucamine (NMDG) either did not change [Ca2+]i or produced a very small increase, strongly indicating that the BPD-evoked Ca2+ responses could not be explained solely by Na+/Ca2+ exchange inhibition but resulted from some other BPD effects. Indeed, in experiments with Rhodamine 123-loaded neurons it has been shown that 50 microM BPD induced prominent mitochondrial depolarization which is known to abolish the mitochondrial Ca2+ uptake. Finally it was revealed that BPD application to the cell culture either in the period of a prolonged (15 min) GLU action or, especially, in the postglutamate period greatly exacerbated delayed neuronal death, apparently due to a complex inhibitory action of the drug on both Ca2+ buffering and Ca2+ extrusion systems.
Storozhevykh
T P
TP
Institute of Pediatrics, Russian Academy of Medical Sciences, Moscow, Russia.
Sorokina
E G
EG
Vinskaya
N P
NP
Pinelis
V G
VG
Vergun
O V
OV
Fayuk
D A
DA
Sobolevskiy
A I
AI
Khodorov
B I
BI
D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D015764:Bepridil / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009417:Nerve Tissue / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger
D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D001224:Aspartic Acid; D018698:Glutamic Acid; D015764:Bepridil; D000252:Calcium-Transporting ATPases; D002118:Calcium