Gramicidin toxicity in NG108-15 cells: protective effects of acetamidine and guanidine.
Studies were conducted using a novel in vitro approach to investigate the efficacy of acetamidine hydrochloride (ACE) and guanidine hydrochloride (GUAN), previously shown to block gramicidin D (GRAM) channels in artificial membranes, in preventing the toxic effects of GRAM in NG108-15 (neuroblastoma x glioma hybrid) cells. Specifically, intracellular microelectrode techniques were employed to examine changes in membrane resting potential (Vm) and input resistance (Rin). At 1 micromol/L, ACE significantly reduced loss of Vm induced by 1 or 10 microg/ml GRAM, although higher concentrations of ACE did not afford enhanced antagonism. GUAN, in contrast, produced a concentration-dependent antagonism of GRAM-induced Vm and Rin loss, with high concentrations (10 or 100 micromol/L) completely preventing diminutions in both Vm and Rin. In control cells superfused without GRAM, ACE produced a direct, concentration-dependent reduction in Vm and Rin, whereas GUAN hyperpolarized NG108-15 cells but did not alter Rin. These data represent the initial demonstration of the reversal of GRAM toxicity in an intact cell system.
Doebler
J A
JA
Neurotoxicology Branch, Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA. jeffrey.doebler@amedd.army.mil
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D004347:Drug Interactions; D017097:Electric Impedance; D004594:Electrophysiology; D005910:Glioma; D006096:Gramicidin / Q000633:toxicity*; D019791:Guanidine / Q000494:pharmacology*; D006822:Hybrid Cells / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology*; D051381:Rats; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D000578:Amidines; D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D010277:Parasympathomimetics; D014361:Trypsin Inhibitors; D006096:Gramicidin; D019791:Guanidine; C023731:acetamidine