Nitric oxide synthase inhibition in healthy adults reduces regional and total cerebral macrovascular blood flow and microvascular perfusion.

Abstract

KEY POINTS\nCerebral blood flow (CBF) is vital for brain health, but the signals key to regulating CBF remain unclear. Nitric oxide (NO) is produced in the brain, but its importance in regulating CBF remains controversial since prior studies have not studied all regions of the brain simultaneously. Using modern MRI approaches, a drug that inhibits enzymes that make NO (L-NMMA) reduced CBF up to 11% in different brain regions. NO helps maintain proper CBF in healthy adults. These data will help us understand if reductions in CBF which occur during aging or cardiovascular disease are related to shifts in NO signaling.\n\n\nABSTRACT\nThe importance of nitric oxide (NO) in regulating cerebral blood flow (CBF) remains unresolved, due in part to methodological approaches, which lack comprehensive assessment of both global and regional effects. Importantly, NO synthase (NOS) expression and activity appear greater in some anterior brain regions, suggesting region-specific NOS influence on CBF. We hypothesized that NO contributes to basal CBF in healthy adults, in a regionally distinct pattern that predominates in the anterior circulation. 14 healthy adults (7 females; 24±5 years) underwent two magnetic resonance imaging (MRI) study visits with saline (placebo) or the NOS inhibitor, L-NMMA, administered in a randomized, single-blind approach. 4D Flow MRI quantified total and regional macrovascular CBF, whereas arterial spin labeling (ASL) MRI quantified total and regional microvascular perfusion. L-NMMA (or volume-matched saline) was infused intravenously for 5 minutes prior to imaging. L-NMMA reduced CBF (L-NMMA: 722±100 vs. placebo: 771±121 mL/min, p = 0.01) with similar relative reductions (5-7%) in anterior and posterior cerebral circulations, due in part to reduced cross sectional area of 9 of 11 large cerebral arteries. Global microvascular perfusion (ASL) was reduced by L-NMMA (L-NMMA: 42±7 vs. placebo: 47±8 mL/100g/min, p = 0.02), with 7-11% reductions in both hemispheres of frontal, parietal, and temporal lobes, and in the left occipital lobe. We conclude NO contributes to macrovascular and microvascular regulation including larger artery resting diameter. Contrary to our hypothesis, the influence of NO on cerebral perfusion appears regionally uniform in healthy young adults. Abstract figure legends EC, endothelial cell; L-arg, L-arginine; L-NMMA, NG -monomethyl-L-arginine; NO, nitric oxide; NOS, nitric oxide synthase. NO contributes to the maintenance of resting brain blood flow in humans. Inhibition of nitric oxide synthase by L-NMMA in endothelial cells leads to reduced bulk flow and regional perfusion. This article is protected by copyright. All rights reserved.