Flunarizine blocks elevation of free cytosolic calcium in synaptosomes following sustained depolarization.
Gerbil cerebral cortical synaptosomes loaded with the fluorescent calcium probe FURA-2 were used to study depolarization-induced presynaptic cytosolic free calcium concentration, as an in vitro model of cerebral ischemia. The depolarization-induced increase in intrasynaptosomal cytosolic free calcium concentration is not sodium-dependent or sodium channel-dependent and may be due to an influx of extrasynaptosomal calcium resulting from a cadmium- and omega-conotoxin-sensitive, nickel-, nifedipine-, and nimodipine-insensitive voltage-regulated channel. The depolarization-induced increase in intrasynaptosomal free cytosolic calcium concentration is also inhibited by flunarizine, a calcium antagonist that has protective effects in animal models of cerebral anoxia and ischemia. Our results suggest that presynaptic calcium uptake following depolarization may be mediated in part by an N-type channel. Flunarizine may block presynaptic calcium accumulation, in part, by blocking this N-type channel; this blockade may be just one of several mechanisms by which flunarizine exerts protective effects following cerebral ischemia.
Cohan
S L
SL
Department of Neurology, Georgetown University School of Medicine, Washington, D.C. 20007.
Redmond
D J
DJ
Chen
M
M
Wilson
D
D
Cyr
P
P
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D004594:Electrophysiology; D005444:Flunarizine / Q000494:pharmacology*; D005456:Fluorescent Dyes; D016257:Fura-2; D005849:Gerbillinae; D008297:Male; D011188:Potassium / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D015220:Calcium Channels; D005456:Fluorescent Dyes; D005444:Flunarizine; D011188:Potassium; D002118:Calcium; D016257:Fura-2