We have explored the consequences of a [Na
1
]
i
load and
oxidative stress in isolated nerve terminals. The Na
1
load was
achieved by veratridine (5–40
m
M
), which allows Na
1
entry via
a voltage-operated Na
1
channel, and oxidative stress was
induced by hydrogen peroxide (0.1–0.5 m
M
). Remarkably, nei-
ther the [Na
1
]
i
load nor exposure to H
2
O
2
had any major effect
on [Ca
2
1
]
i
, mitochondrial membrane potential (
D
c
m), or ATP
level. However, the combination of an Na
1
load and oxidative
stress caused ATP depletion, a collapse of
D
c
m, and a pro-
gressive deregulation of [Ca
2
1
]
i
and [Na
1
]
i
homeostasis. The
decrease in the ATP level was unrelated to an increase in
[Ca
2
1
]
i
and paralleled the rise in [Na
1
]
i
. The loss of
D
c
m was
prevented in the absence of Ca
2
1
but unaltered in the presence
of cyclosporin A. We conclude that the increased ATP con-
sumption by the Na,K–ATPase that results from a modest
[Na
1
]
i
load places an additional demand on mitochondria met-
abolically compromised by an oxidative stress, which are un-
able to produce a sufficient amount of ATP to fuel the ATP-
driven ion pumps. This results in a deregulation of [Na
1
]
i
and
[Ca
2
1
]
i
, and as a result of the latter, collapse of
D
c
m. The
vicious cycle generated in the combined presence of Na
1
load
and oxidative stress could be an important factor in the neuro-
nal injury produced by ischemia or excitotoxicity, in which the
oxidative insult is superimposed on a disturbed Na
1
homeostasis