ROLE OF NEURONAL NO SYNTHASE IN RELATIONSHIP BETWEEN NO AND OPIOIDS IN HYPOXIA-INDUCED PIAL ARTERY DILATION

Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, via the formation of guanosine 3',5'-cyclic monopho sphate (cGMP) and subsequent release of Metenkephalin and Leu-enkephal in in the newborn pig. In separate studies, these opioids were also ob served to elicit NO-dependent pial dilation. The present study was des igned to investigate the role of the neuronal isoform of NO synthase ( NOS) in hypoxic pial dilation, associated opioid release, and opioid d ilation in piglets equipped with a closed cranial window. Tetrodotoxin (10(-6) M) attenuated the dilation resulting from hypoxia (PO2 simila r to 35 mmHg; 25 +/- 1 vs. 14 +/- 1%). Similarly, 7-nitroindazole, sod ium salt (7-NINA, 10(-6) M), a purported neuronal NOS inhibitor, atten uated hypoxic pial dilation (26 +/- 1 vs. 14 +/- 2%). Hypoxic dilation was accompanied by elevated cerebrospinal (CSF) cGMP, which was block ed by 7-NINA(433 +/- 19 and 983 +/- 36 vs. 432 +/- 19 and 441 +/- 19 f mol/ml for control and hypoxia in absence and presence of 7-NINA, resp ectively). Additionally, hypoxic dilation was also accompanied by elev ated CSF Met-enkephalin, which was attenuated by 7-NINA (1,027 +/- 47 and 2,871 +/- 134 vs. 779 +/- 78 and 1,551 +/- 42 pg/ml for control an d hypoxia in absence and presence of 7-NINA, respectively). In contras t, Met-enkephalin (10(-10), 10(-8), and 10(-6) M) induced dilation tha t was unchanged by 7-NINA(7 +/- 1, 12 +/- 1, and 18 +/- 1 vs. 6 +/- 1, 10 +/- 1, and 17 +/- 1%, respectively). N-methyl-D-aspartate (NMDA, 1 0(-8) and 10(-6) M), an activator of neuronal NOS, induced pial dilati on that was blocked by 7-NINA(10 +/- 1 and 20 +/- 2 vs. 1 +/- 1 and 2 +/- 1%, respectively). However, sodium nitroprusside-induced dilation was unchanged by 7-NINA. These data indicate that neuronal NOS contrib utes to hypoxic pial artery dilation but not to opioid-induced dilatio n. Furthermore, these data suggest that neuronally derived NO contribu tes to hypoxic dilation, at least in part, via formation of cGMP and t he subsequent release of opioids.