Effects of flunarizine on induced calcium transients as measured in fura-2-loaded neurons of the rat dorsal root ganglion.
The effect of the calcium entry blocker flunarizine on a high-potassium induced increase of intracellular free calcium was studied. The experiments were done with neurons isolated from rat dorsal root ganglia and loaded with the calcium-sensitive dye fura-2. The increase of calcium induced by 60 mmol/l potassium was abolished after removal of extracellular calcium, was reversibly reduced by 50 mumol/l cadmium (76% inhibition), 50 mumol/l nickel (25% inhibition) and 10 mumol/l nifedipine (18% inhibition), and reversibly increased after removal of extracellular sodium (26% increase). The potassium induced increase of intracellular calcium is, therefore, mediated by transmembrane calcium influx, probably to a large extent through cadmium-sensitive calcium channels. Flunarizine (5 min incubation followed 1 min wash-out) reduced the amplitude of the high-potassium induced calcium increase in a dose-dependent manner (Kd = 370 +/- 100 nmol/l; mean +/- SEM; n = 8), causing complete inhibition at a concentration of 10 mumol/l in the majority of cells. Flunarizine (> or = 1 mumol/l) caused a reversible increase of the resting level of intracellular calcium in some cells, an effect which disappeared in the absence of extracellular calcium. The drug (1 mumol/l had no influence on the time course of recovery of intracellular calcium subsequent to a rise induced by high-potassium or by the calcium ionophore A23,187. It is concluded that flunarizine acts as an inhibitor of depolarization-mediated calcium influx. At a concentration of 1 mumol/l, the drug presumably has no effect on cellular calcium extrusion and/or sequestration mechanisms.
Leybaert
L
L
Laboratorium voor Normale en Pathologische Fysiologie, Universiteit Gent, Belgium.
De Ley
G
G
de Hemptinne
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D005444:Flunarizine / Q000494:pharmacology*; D016257:Fura-2; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D012964:Sodium; D005444:Flunarizine; D011188:Potassium; D002118:Calcium; D016257:Fura-2