Anoxia-induced depolarization in CA1 hippocampal neurons: role of Na+-dependent mechanisms.
We have previously shown that (1) removal of extracellular sodium (Na+) reduces the anoxia-induced depolarization in neurons in brain-slice preparations and (2) amiloride, which blocks Na+-dependent exchangers, prevents anoxic injury in cultured neocortical neurons. Since anoxia-induced depolarization has been linked to neuronal injury, we have examined in this study the role of Na+-dependent exchangers and voltage-gated Na+ channels in the maintenance of membrane properties of CA1 neurons at rest and during acute hypoxia. We recorded intracellularly from CA1 neurons in hippocampal slices, monitored Vm and measured input resistance (Rm) with periodic injections of negative current. We found that tetrodotoxin (TTX, 1 microM) hyperpolarized CA1 neurons at rest and significantly attenuated both the rate of depolarization (delta Vm/dt) and the rate of decline of Rm (delta Rm/dt) by about 60% during the early phase of hypoxia. The effect of TTX was dose-dependent. Amiloride (1 mM) decreased Vm and increased Rm in the resting condition but changed little the effect of hypoxia on neuronal function. Benzamil and 5-(N-ethyl-N-isopropyl)-2',4'-amiloride (EIPA), two specific inhibitors of Na+ dependent exchangers, were similar to amiloride in their effect. We conclude that neuronal membrane properties are better maintained during anoxia by reducing the activity of TTX-sensitive channels and not by the action of Na+-dependent exchangers.
Fung
M L
ML
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
Haddad
G G
GG
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology*; D002534:Hypoxia, Brain / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D004232:Diuretics; D015222:Sodium Channels; C013407:benzamil; D013779:Tetrodotoxin; D000584:Amiloride; D012964:Sodium; D010100:Oxygen; C039614:ethylisopropylamiloride