title: Exacerbated responses to oxidative stress by an Na(+) load in isolated nerve terminals: the role of ATP depletion and rise of [Ca(2+)](i).
abstract: We have explored the consequences of a [Na(+)](i) load and oxidative stress in isolated nerve terminals. The Na(+) load was achieved by veratridine (5-40 microM), which allows Na(+) entry via a voltage-operated Na(+) channel, and oxidative stress was induced by hydrogen peroxide (0.1-0.5 mM). Remarkably, neither the [Na(+)](i) load nor exposure to H(2)O(2) had any major effect on [Ca(2+)](i), mitochondrial membrane potential (Deltapsim), or ATP level. However, the combination of an Na(+) load and oxidative stress caused ATP depletion, a collapse of Deltapsim, and a progressive deregulation of [Ca(2+)](i) and [Na(+)](i) homeostasis. The decrease in the ATP level was unrelated to an increase in [Ca(2+)](i) and paralleled the rise in [Na(+)](i). The loss of Deltapsim was prevented in the absence of Ca(2+) but unaltered in the presence of cyclosporin A. We conclude that the increased ATP consumption by the Na,K-ATPase that results from a modest [Na(+)](i) load places an additional demand on mitochondria metabolically compromised by an oxidative stress, which are unable to produce a sufficient amount of ATP to fuel the ATP-driven ion pumps. This results in a deregulation of [Na(+)](i) and [Ca(2+)](i), and as a result of the latter, collapse of Deltapsim. The vicious cycle generated in the combined presence of Na(+) load and oxidative stress could be an important factor in the neuronal injury produced by ischemia or excitotoxicity, in which the oxidative insult is superimposed on a disturbed Na(+) homeostasis.
authors.affiliation: Department of Medical Biochemistry, Neurochemical Group, Semmelweis University of Medicine, Budapest H-1444, Hungary.
authors.forename: C
authors.initials: C
authors.lastname: Chinopoulos
authors.forename: L
authors.initials: L
authors.lastname: Tretter
authors.forename: A
authors.initials: A
authors.lastname: Rozsa
authors.forename: V
authors.initials: V
authors.lastname: Adam-Vizi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D002540:Cerebral Cortex; D016291:Dizocilpine Maleate / Q000494:pharmacology; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006168:Guinea Pigs; D006706:Homeostasis / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010042:Ouabain / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D017470:Receptors, Glutamate / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016877:Oxidants; D017470:Receptors, Glutamate; D013779:Tetrodotoxin; D010042:Ouabain; D016291:Dizocilpine Maleate; D014701:Veratridine; D000255:Adenosine Triphosphate; D012964:Sodium; D006861:Hydrogen Peroxide; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium