INHIBITORY EFFECTS OF HYPOXIA AND ADENOSINE ON N-METHYL-D-ASPARTATE-INDUCED PIAL ARTERIOLAR DILATION IN PIGLETS

Our previous studies have indicated that oxygen radicals, produced dur ing reoxygenation following short-term arterial hypoxia, lead to susta ined suppression of cerebral arteriolar responses to N-methyl-D-aspart ate (NMDA). However, whether arteriolar dilator responses to NMDA are reduced during arterial hypoxia has never been examined. In this study , we determined whether hypoxia or hypoxia-related metabolites such as adenosine or nitric oxide (NO) will reduce NMDA-induced arteriolar di lation. We have also determined the location of NMDA receptor-and brai n nitric oxide synthase (bNOS)-positive neurons in the cerebral cortex . In anesthetized piglets, pial arteriolar diameters were determined u sing intravital microscopy. Baseline arteriolar diameters were similar to 100 mu m. Topical application of NMDA at concentrations of 10(-5), 5 X 10(-5) and 10(-4) M resulted in dose-dependent vasodilation (9 +/ - 2, 18 +/- 2 and 29 +/- 2% above baseline, respectively, n = 21). Adm inistration of theophylline (20 mg/kg, i.v.) had no effect on NMDA-dep endent vasodilation, but it did block dilation to hypoxia (inhalation of 8.5% O-2). In theophylline-treated animals, NMDA responses were com pletely abolished during hypoxia (28 +/- 2 vs. 2 +/- 1%, respectively to 10(-4) M, n = 7) while sodium nitroprusside (SNP, 10(-4) M) still d ilated pial arterioles normally. NMDA-induced vasodilation was not mod ified after application and removal of adenosine (10(-4) M; n = 5) or SNP (10(-5) M; n = 4), or when SNP (10(-7) M) was coapplied with NMDA (n = 6). Conversely, coapplication of adenosine (10(-6) M) attenuated NMDA responses (31 +/- 5 vs. 20 +/- 3%, n = 7). We also found that NMD A receptor- and bNOS-containing neurons were located predominantly in layers II/III of the cortex. Proximity of these neurons to the cortica l surface is consistent with diffusion of NO to pial arterioles as the mechanism of dilation to NMDA. We conclude that NMDA-induced cerebral arteriolar dilation is inhibited by hypoxia alone and by exogenous ad enosine, but not by NO. (C) 1998 Elsevier Science B.V.