{"doi":"10.1113/jp282475","title":"Brain Blood Flow: The More You N.O. ","abstract":"Adequate cerebral blood flow (CBF) regulation is essential for maintaining brain health and the functions of daily living. Decreased basal CBF is associated with several neurological disorders, cerebrovascular disease, cognitive decline and a lower quality of life. The mechanisms underlying CBF regulation are complex and not entirely clear, but nitric oxide (NO) and NO synthase (NOS) have been shown to play a role in CBF regulation. NO is a potent vasodilator produced by endothelial cells to regulate vascular tone and blood flow (Joshi et al. 2000). It is difficult to measure NO in vivo due to its short half-life; therefore, investigators often assess NOS enzyme activity (via pharmacological blockade) to quantify NO signalling. While the role of NOS in peripheral blood flow regulation is well studied, its contribution to CBF regulation remains incompletely understood as previous studies have reported mixed findings. For example, some studies have observed reductions in CBF following pharmacological inhibition of NOS via intravenous infusion of NG-monomethyl-l-arginine (L-NMMA) in healthy adults (White et al. 1999) and via intra-carotid infusion in patient populations (Joshi et al. 2000). In contrast, other studies have observed no effect on CBF after NOS inhibition via intravenous infusion in healthy adults (Hjorth et al. 2003; Hoiland et al. 2020). Additionally, regional differences in the contribution of NO to CBF remain unclear, highlighting a knowledge gap. Therefore, in a recent Journal of Physiology article, Carter et al. (2021) sought to determine the role played by NO in regional and global CBF at the macrovascular and microvascular levels through magnetic resonance imaging (MRI) approaches in healthy young adults (Carter et al. 2021). The authors hypothesized that (1) NO plays a role in basal CBF regulation in healthy young adults and (2) NOS activity differs by brain regions. Fourteen healthy, sedentary adults (7 females, 24 ± 5 years) free of cardiovascular and metabolic diseases and not taking any medications, participated in this randomized, single-blinded, placebo-controlled study. Female participants were studied during the early follicular phase of the menstrual cycle except for one participant. All participants completed two visits (at least 24 h apart), which included intravenous administration of L-NMMA or placebo (saline) during MRI scanning. L-NMMA and saline were infused for 5 min at 0.6 mg/kg/min (mean 200 ± 24 mg) with a maintenance infusion for 10—11 min at 1 mg/kg/min to detect CBF changes during continuous inhibition of NOS. Phase-contrast vastly undersampled isotropic projection reconstruction, a validated MRI sequence for the assessment of macrovascular perfusion, was utilized to simultaneously determine CBF (volume per unit of time) and vessel diameter (cross-sectional area) in the large cerebral arteries (e.g. internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), vertebral artery) and used to calculate total, anterior and posterior CBF. Background-suppressed pseudo-continuous arterial spin labelling MRI was utilized to quantify microvascular perfusion (flow per unit of tissue) in the bilateral frontal, occipital, parietal and temporal lobes, and the MCA, ACA and PCA territories (Carter et al. 2021). In agreement with Carter et al.’s hypothesis, there were significant reductions in total macrovascular CBF by 6%, anterior CBF by 5%, and posterior CBF by 7% (all P < 0.05) following L-NMMA administration compared to saline. In contrast, previous studies have reported no change in CBF velocity, an estimate of CBF, after L-NMMA infusion measured by transcranial Doppler (TCD) ultrasound (Hjorth et al. 2003; Hoiland et al. 2020) in the cerebral macrovasculature. Transcranial Doppler ultrasound is a relatively inexpensive, non-invasive technique that has demonstrated high reproducibility. However, it does not measure vessel diameter w","journal":"The Journal of Physiology","year":2021,"id":212435,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":802740,"name":"Kamila U. Pollin","orcid":"0000-0001-6096-2517","position":1,"is_corresponding":false},{"id":658493,"name":"Lyndsey E. DuBose","orcid":"0000-0002-3566-4531","position":2,"is_corresponding":false},{"id":384853,"name":"Kanokwan Bunsawat","orcid":"0000-0002-5950-6634","position":3,"is_corresponding":false},{"id":802739,"name":"Soolim Jeong","orcid":"0000-0003-1097-9980","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-18T23:52:27.434608Z","pmid":"34863039","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}