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Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242
The goal of this study was to examine
the role of endogenous copper/zinc (CuZn)-superoxide dismutase (SOD) on
superoxide levels and on responses of cerebral blood vessels to stimuli
that are mediated by nitric oxide (acetylcholine) and
cyclooxygenase-dependent mechanisms (bradykinin and arachidonic acid).
Levels of superoxide in the rabbit basilar artery were measured using
lucigenin-enhanced chemiluminescence (5 µM lucigenin).
Diethyldithiocarbamate (DDC; 10 mM), an inhibitor of CuZn-SOD,
increased superoxide levels by ~2.4-fold (P < 0.05)
from a baseline value of 1.0 ± 0.2 relative light
units · min
1 · mm2
(means ± SE). The diameter of cerebral arterioles (baseline
diameter, 99 ± 3 µm) was also measured using a closed cranial
window in anesthetized rabbits. Topical application of DDC attenuated
responses to acetylcholine, bradykinin, and arachidonate, but not
nitroprusside. For example, 10 µM arachidonic acid dilated cerebral
arterioles by 40 ± 5 and 2 ± 2 µm under control
conditions and after DDC, respectively (P < 0.05).
These inhibitory effects of DDC were reversed by the superoxide
scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (10 mM).
Arachidonate increased superoxide levels in the basilar artery
moderately under normal conditions and this increase was greatly
augmented in the presence of DDC. These findings suggest that
endogenous CuZn-SOD limits superoxide levels under basal conditions and
has a marked influence on increases in superoxide in vessels exposed to
arachidonic acid. The results also suggest that nitric oxide- and
cyclooxygenase-mediated responses in the cerebral microcirculation are
dependent on normal activity of CuZn-SOD.
cerebral arterioles; basilar artery; acetylcholine; nitric oxide; arachidonic acid; bradykinin
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