Effect of dantrolene on KCl- or NMDA-induced intracellular Ca2+ changes and spontaneous Ca2+ oscillation in cultured rat frontal cortical neurons

Dantrolene has been known to affect intracellular Ca2+ concentration ([Ca2+](i)) by inhibiting Ca2+ release from intracellular stores in cultured neurons. We were interested in examining this property of dantrolene in influencing the [Ca2+](i) affected by the NMDA receptor ligands, KCl, L-type Ca2+ channel blocker nifedipine, and two other intracellular Ca2+-mobilizing agents caffeine and bradykinin. Effect of dantrolene on the spontaneous oscillation of [Ca2+](i) was also examined. Dantrolene in mu M concentrations dose-dependently inhibited the increase in [Ca2+](i) elicited by NMDA and KCl. AP-5, MK-801 (NMDA an antagonists), and nifedipine respectively reduced the NMDA and KCl-induced increase in [Ca2+](i). Dantrolene, added to the buffer solution together with the antagonists or nifedipine, caused a further reduction in [Ca2+](i) to a degree similar to that seen with dantrolene alone inhibiting the increase in [Ca2+](i) caused by NMDA or KCl. At 30 mu M, dantrolene partially inhibited caffeine-induced increase in [Ca2+](i) whereas it has no effect on the bradykinin-induced change in [Ca2+](i). The spontaneous oscillation of [Ca2+](i) in frontal cortical neurons was reduced both in amplitude and in base line concentration in the presence of 10 mu M dantrolene. Our results indicate that dantrolene's mobilizing effects on intracellular Ca2+ stores operate independently from the influxed Ca2+ and that a component of the apparent increase in [Ca2+](i) elicited by NMDA or KCl represents a dantrolene-sensitive Ca2+ release from intracellular stores. Results also suggest that dantrolene does not affect the IP3-gated release of intracellular Ca2+ and that the spontaneous Ca2+ oscillation is, at least partially, under the control of Ca2+ mobilization from internal stores.