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Departments of Pediatrics and Physiology, Biophysics Research Institute, and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Peroxynitrite (ONOO
)
is a contractile agonist of rat middle cerebral arteries. To determine
the mechanism responsible for this component of ONOO
bioactivity, the present study examined the effect of
ONOO on ionic current and channel activity in rat
cerebral arteries. Whole cell recordings of voltage-clamped cells were
made under conditions designed to optimize K+ current. The
effects of iberiotoxin, a selective inhibitor of large-conductance
Ca2+-activated K+ (BK) channels, and
ONOO (10-100 µM) were determined. At a
pipette potential of +50 mV, ONOO inhibited 39% of
iberiotoxin-sensitive current. ONOO was selective
for iberiotoxin-sensitive current, whereas decomposed ONOO had no effect. In excised, inside-out membrane
patches, channel activity was recorded using symmetrical K+
solutions. Unitary currents were sensitive to increases in internal Ca2+ concentration, consistent with activity due to BK
channels. Internal ONOO dose dependently inhibited
channel activity by decreasing open probability and mean open times.
The inhibitory effect of ONOO could be overcome by
reduced glutathione. Glutathione, added after ONOO,
restored whole cell current amplitude to control levels and reverted
single-channel gating to control behavior. The inhibitory effect of
ONOO on membrane K+ current is
consistent with its contractile effects in isolated cerebral arteries
and single myocytes. Taken together, our data suggest that
ONOO has the potential to alter cerebral vascular
tone by inhibiting BK channel activity.
free radical; glutathione
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