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Exacerbated Responses to Oxidative Stress by an Na+Load in Isolated Nerve Terminals: the Role of ATP Depletion and Rise of [Ca2+]i

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 μm), 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 H2O2 had any major effect on [Ca2+]i, mitochondrial membrane potential (Δψm), or ATP level. However, the combination of an Na+ load and oxidative stress caused ATP depletion, a collapse of Δψm, and a progressive deregulation of [Ca2+]i and [Na+]i homeostasis. The decrease in the ATP level was unrelated to an increase in [Ca2+]i and paralleled the rise in [Na+]i. The loss of Δψm was prevented in the absence of Ca2+ 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 [Ca2+]i, and as a result of the latter, collapse of Δψm. 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.