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 KATPchannel 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 10−6 M), a KATP agonist, produced dilation that was unchanged by the NO synthase inhibitor N-nitro-l-arginine (l-NNA, 10−6 and 10−3 M): 13 ± 1 and 31 ± 1 vs. 14 ± 1 and 31 ± 1% before and after 10−3 Ml-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 (10−6 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 ofl-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.
Mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone induces vasorelaxation without involving KATP
channel activation in smooth muscle cells of arteries
