N(ω)-nitro-L-arginine influences cerebral metabolism in awake sheep

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide (NO). An inhibitor of NO formation, N(ω)-nitro-L- arginine (LNA, 100 μg/kg iv), was given to conscious sheep (n = 6) during normoxia and again in hypocapnic hypoxia (arterial PO₂ ~38 Torr). Blood samples were obtained from the aorta and sagittal sinus, and cerebral blood flow (CBF) was measured with 15-μm radiolabeled microspheres. During normoxia, LNA elevated (P < 0.05) mean arterial pressure from 82 ± 3 to 88 ± 2 (SE) mmHg and cerebral perfusion pressure (CPP) from 72 ± 3 to 79 ± 3 mmHg, CBF was unchanged, and cerebral lactate release (CLR) rose temporarily from 0.0 ± 1.9 to 13.3 ± 8.7 μmol · min^-1 · 100 g^-1 (P < 0.05). The glucose-O₂ index declined (P < 0.05) from 1.67 ± 0.16 to 1.03 ± 0.4 μmol · min^-1 · 100 g^-1. Hypoxia increased CBF from 59.9 ± 5.4 to 122.5 ± 17.5 ml · min^-1 · 100 g^-1 and the glucose-O₂ index from 1.75 ± 0.43 to 2.49 ± 0.52 μmol · min^-1 · 100 g^-1 and decreased brain CO₂ output, brain respiratory quotient, and CPP (all P < 0.05), while cerebral O₂ uptake, CLR, and CPP were unchanged. LNA given during hypoxia decreased CBF to 77.7 ± 11.8 ml · min^-1 · 100 g^-1 and cerebral O₂ uptake from 154 ± 22 to 105.2 ± 12.4 μmol · min^-1 · 100 g^-1 and further elevated mean arterial pressure to 98 ± 2 mmHg (all P < 0.05), CLR was unchanged, and, surprisingly, brain CO₂ output and respiratory quotient were reduced dramatically to negative values (P < 0.05). The sheep lay down and became behaviorally unresponsive. Normal behavior returned during normoxia. These results indicate that LNA can cross the blood-brain barrier and exert striking effects on cerebral metabolism. The hemodynamic response is likely secondary to impaired NO production in both vascular endothelium and brain tissue.