1. The affect of extracellular Cd2+ on CNS white matter was studied us
ing an isolated rat optic nerve preparation. A 100-min exposure to 200
mu M Cd2+ reduced the area of the compound action potential (CAP) rec
orded from the optic nerve to 32.6 +/- 3.8% (mean +/- SE) of the preex
posure area, compared with a reduction to 74.9 +/- 2.9% after 100 min
in control conditions (P > 0,001). This CAP reduction was not reversed
after 120 min of reperfusion with Cd2+-free solution, or by perfusion
with Cd2+ chelators. 2. Cd2+-induced CAP loss occurred in the absence
of extracellular Ca2+. increasing extracellular Ca2+ concentration to
16 mM, however, prevented Cd2+-induced CAP loss. Once evident, Cd2+ i
nduced CAP reduction could not subsequently be reversed by addition of
16 mM Ca2+. 3. Low concentrations of Cd2+ (60 mu M) did not significa
ntly reduce CAP area. This concentration of Cd2+ combined with high ex
tracellular K+ (30 mM) caused CAP loss that was blocked by 10 mu M nif
edipine, an antagonist of L-type voltage-gated Ca2+ channels. 4. Treat
ment with pharmacological inhibitors of membrane proteins known to be
inhibited by Cd2+ did not affect the CAP. These included inhibitors of
voltage-gated Ca2+ channels, Ca2+-activated K+ channels, Ca2+-ATPase
and the Na+/Ca2+ exchanger. 5. Treatment with pharmacological agents t
hat inhibit calmodulin or disrupt tubulin, two intracellular proteins
affected by Cd2+ did not affect CAP area. 6. The effect of Cd2+ was no
t prevented by pretreatment with (+)-cyanidanol-3, an agent that preve
nts Cd2+-induced lipid peroxidation. 7. Treatment with antimycin A, a
inhibitor of mitochondrial respiration, resulted in irreversible CAP r
eduction with a time course and extent similar to that produced by 200
mu M Cd2+. Cd2+-induced CAP reduction was prevented by 1 mM cysteine,
which prevents Cd2+-induced disruption of mitochondrial respiration.8
. The ultrastructure of optic nerves exposed to 200 mu M Cd2+ for 100
min was characterized by swollen mitochondria with disrupted cristae a
nd dissolution of microtubules, which were replaced by flocculent debr
is. Occasional regions of axonal swelling and empty spaces beneath the
myelin also were found. Qualitatively similar changes in mitochondria
and cytoskeletal elements were found in optic nerves exposed to antim
ycin A for 100 min. Astrocytes also displayed disrupted mitochondria a
nd had an electron lucent appearance under both conditions. 9. The neu
rological injury produced by exposure to Cd2+ is characterized by lesi
ons of CNS white matter. Our results indicate that Cd2+-induced white
matter injury in vitro results largely from disruption of mitochondria
l respiration after Cd2+ influx through routes that include voltage-ga
ted Ca2+ channels.