Studies on the prevention of nigericin action in neuroblastoma X glioma hybrid (NG108-15) cells.
Electrophysiological analysis of neuroblastoma X glioma hybrid (NG108-15) cells was used as an in vitro neuronal model system to evaluate antagonists of the K+-selective carboxylic ionophore, nigericin. Changes in membrane electrical characteristics induced by nigericin with and without the simultaneous administration of antagonists were measured using intracellular microelectrode techniques. Bath application of nigericin (3 microM) produced a severe hyperpolarization and blocked the generation of action potentials in response to electrical stimulation. Simultaneous administration of nigericin plus the Na+-K+ pump inhibitor ouabain or drugs known to influence Ca++ signaling in cells, i.e., quinidine, compound R24571, verapamil or haloperidol, was able to significantly attenuate the hyperpolarization. All antagonists acted in a concentration-dependent manner. However, nigericin plus maximally effective concentrations of ouabain (1 microM), verapamil (3 microM) and haloperidol (3 and 10 microM) resulted in moderate-to-severe depolarization by the end of 24 min. superfusions, suggesting that the concentrations of antagonists were excessive and that NG108-15 cell damage had occurred. In addition, none of the compounds studied was able to effectively prevent nigericin-induced blockade of action potentials. Thus, none of these antagonists appears suitable for transition to in vivo antidotal protection studies.
Doebler
J A
JA
Neurotoxicology Branch, Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. jeffrey.doebler@amedd.army.mil
D002121:Calcium Channel Blockers / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007476:Ionophores / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism*; D009550:Nigericin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007476:Ionophores; D010042:Ouabain; D014700:Verapamil; D011802:Quinidine; D009550:Nigericin