RELATIONSHIP AMONG NO, THE K-ATP CHANNEL, AND OPIOIDS IN HYPOXIC PIALARTERY DILATION

Nitric oxide (NO), opioids, and ATP-sensitive K+ (K-ATP) channel activ ation 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 thems elves also elicit dilation via K-ATP channel activation. This study wa s designed to investigate the relationships among the above mechanisms in hypoxic pial artery dilation using newborn pigs equipped with a cl osed 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 v s. 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 uncha nged by the Rp diastereomer of 8-bromoguanosine 3',5'-cyclic monophosp hothioate, a cGMP antagonist. Glibenclamide (10(-6) M), a K-ATP antago nist, attenuated hypoxic dilation but hypoxia-associated CSF cGMP rele ase was unchanged: 457 +/- 12 and 935 +/- 30 vs. 458 +/- 11 and 921 +/ - 22 fmol/ml. Coadministration of L-NNA with glibenclamide had no furt her effect on the already diminished hypoxic dilation but blocked the hypoxia-associated rise in CSF cGMP. Cromakalim had no effect on CSF m ethionine 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 an d do not release opioids. NO release during hypoxia also is independen t of K-ATP channel activation. These data suggest that hypoxic dilatio n results from the sequential release of NO, cGMP, and opioids, which in turn activate the K-ATP channel.