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Departments of Anesthesia and Pharmacology, University of Pennsylvania, and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
Nitric oxide (NO),
opioids, and ATP-sensitive K+
(KATP) channel activation
contribute to hypoxia-induced pial artery dilation. NO releasers and
cGMP analogs increase opioid concentration in cerebrospinal fluid (CSF)
and elicit dilation via KATP
channel activation. Opioids themselves also elicit dilation via
KATP channel activation. This
study was designed to investigate the relationships among the above
mechanisms in hypoxic pial artery dilation using newborn pigs equipped
with a closed cranial window. Cromakalim (10
8 and
106 M), a
KATP agonist, produced dilation
that was unchanged by the NO synthase inhibitor
N-nitro-L-arginine
(L-NNA,
106 and
103 M): 13 ± 1 and 31 ± 1 vs. 14 ± 1 and 31 ± 1% before and after 103 M
L-NNA. Cromakalim dilation also
was not associated with increased CSF cGMP and was unchanged by the Rp
diastereomer of 8-bromoguanosine 3',5'-cyclic
monophosphothioate, a cGMP antagonist. Glibenclamide (106 M), a
KATP antagonist, attenuated
hypoxic dilation but hypoxia-associated CSF cGMP release was unchanged:
457 ± 12 and 935 ± 30 vs. 458 ± 11 and 921 ± 22 fmol/ml. Coadministration of
L-NNA with glibenclamide had no
further effect on the already diminished hypoxic dilation but blocked
the hypoxia-associated rise in CSF cGMP. Cromakalim had no effect on
CSF methionine enkephalin: 1,012 ± 28 and 1,062 ± 32 pg/ml.
These data show that KATP channel
agonists do not elicit dilation via NO/cGMP and do not release opioids.
NO release during hypoxia also is independent of
KATP channel activation. These
data suggest that hypoxic dilation results from the sequential release
of NO, cGMP, and opioids, which in turn activate the
KATP channel.
newborn; cyclic nucleotides; cerebral circulation
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