Flufenamic acid blocks depolarizing afterpotentials and phasic firing in rat supraoptic neurones.
Depolarizing afterpotentials (DAPs) that follow action potentials in magnocellular neurosecretory cells (MNCs) are thought to underlie the generation of phasic firing, a pattern that optimizes vasopressin release from the neurohypophysis. Previous work has suggested that the DAP may result from the Ca(2+)-dependent reduction of a resting K(+) conductance. Here we examined the effects of flufenamic acid (FFA), a blocker of Ca(2+)-dependent non-selective cation (CAN) channels, on DAPs and phasic firing using intracellular recordings from supraoptic MNCs in superfused explants of rat hypothalamus. Application of FFA, but not solvent (0.1 % DMSO), reversibly inhibited (IC(50) = 13.8 microM; R = 0.97) DAPs and phasic firing with a similar time course, but had no significant effects (P > 0.05) on membrane potential, spike threshold and input resistance, nor on the frequency and amplitude of spontaneous synaptic potentials. Moreover, FFA did not affect (P > 0.05) the amplitude, duration, undershoot, or frequency-dependent broadening of action potentials elicited during the spike trains used to evoke DAPs. These findings suggest that FFA inhibits the DAP by directly blocking the channels responsible for its production, rather than by interfering with Ca(2+) influx. They also support a role for DAPs in the generation of phasic firing in MNCs. Finally, the absence of a depolarization and increased membrane resistance upon application of FFA suggests that the DAP in MNCs may not be due to the inhibition of resting K(+) current, but to the activation of CAN channels.
Ghamari-Langroudi
Masoud
M
Centre for Research in Neuroscience, Montreal General Hospital & McGill University, 1650 Cedar Avenue, Montreal, QC, Canada H3G 1A4.
Bourque
Charles W
CW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D004558:Electric Stimulation; D004594:Electrophysiology; D005439:Flufenamic Acid / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010904:Pituitary Gland, Posterior / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D013495:Supraoptic Nucleus / Q000166:cytology / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007473:Ion Channels; D005439:Flufenamic Acid; D002118:Calcium