Relationship among NO, the KATP channel, and opioids in hypoxic pial artery dilation

Nitric oxide (NO), opioids, and ATP-sensitive K+ (K-ATP) 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 K-ATP channel activation. Opioids themselves also elicit dilation via K-ATP 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 K-ATP 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) 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 (10(-6) M), a K-ATP 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 K-ATP channel agonists do not elicit dilation via NO/cGMP and do not release opioids. NO release during hypoxia also is independent of K-ATP channel activation. These data suggest that hypoxic dilation results from the sequential release of NO, cGMP, and opioids, which in turn activate the K-ATP channel.