Nitric oxide is fundamental to neurovascular coupling in humans

Abstract

Key points Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular coupling in humans. Isovolumic haemodilution did not alter neurovascular coupling. Intravenous infusion of a nitric oxide synthase inhibitor reduced the neurovascular coupling response by ∼30%, indicating that nitric oxide is integral to neurovascular coupling in humans. Abstract Nitric oxide is a vital neurovascular signalling molecule in preclinical models, yet the mechanisms underlying neurovascular coupling (NVC) in humans have yet to be elucidated. To investigate the contribution of nitric oxide to NVC in humans, we utilized a visual stimulus paradigm to elicit an NVC response in the posterior cerebral circulation. Two distinct mechanistic interventions were conducted on young healthy males: (1) NVC was assessed during intravenous infusion of saline (placebo) and the non‐selective competitive nitric oxide synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA, 5 mg kg−1 bolus & subsequent 50 μg kg−1 min−1 maintenance dose; n = 10). The order of infusion was randomized, counterbalanced and single blinded. A subset of participants in this study (n = 4) underwent a separate intervention with phenylephrine infusion to independently consider the influence of blood pressure changes on NVC (0.1–0.6 μg kg−1 min−1 constant infusion). (2) NVC was assessed prior to and following isovolumic haemodilution, whereby 20% of whole blood was removed and replaced with 5% human serum albumin to reduce haemoglobin concentration (n = 8). For both protocols, arterial and internal jugular venous blood samples were collected at rest and coupled with volumetric measures of cerebral blood flow (duplex ultrasound) to quantify resting cerebral metabolic parameters. l‐NMMA elicited a 30% reduction in the peak (P = 0.01), but not average (P = 0.11), NVC response. Neither phenylephrine nor haemodilution influenced NVC. Nitric oxide signalling is integral to NVC in humans, providing a new direction for research into pharmacological treatment of humans with dementia.

Neurovascular coupling: Sending this signal here, hope you pick it up loud and clear

“…First, the study by Hoiland et al (2020) does not provide insight into which isoform(s) of NOS were involved (neuronal and/or endothelial). Second, only males were studied (Dorner et al 2003;Hoiland et al 2020), despite the fact that conditions such as Alzheimer's disease are more often present in women. Third, studies of NVC in humans with known genetic variants that reduce or enhance NO signalling would provide an independent experimental strategy.…”

“…This concept has now translated from preclinical models to human brain and retina. Hoiland et al (2020) include the investigation of awake humans using a natural visual stimulus to activate NVC. A careful and systematic quantification of various determinants of CBF was included.…”

“…Commonly used doses of L-NMMA in humans do not fully inhibit NOS (Lauer et al 2001). Thus, although L-NMMA affected brain and retinal NVC (Dorner et al 2003;Hoiland et al 2020), the contribution made by NO may well be underestimated. Additional mediators very probably contribute to NVC, particularly potassium ion (Iadecola, 2017).…”

“…2003; Hoiland et al . 2020), the contribution made by NO may well be underestimated. Additional mediators very probably contribute to NVC, particularly potassium ion (Iadecola, 2017).…”

Advancing our k'NO'wledge for neurovascular coupling of brain blood flow in humans

“…In a recent issue of The Journal of Physiology , Hoiland et al. (2020) outlined important advancements for the mechanistic understanding of NVC in humans utilizing a randomized, blinded and placebo controlled experimental design. In a cohort of healthy males, two hypotheses were tested to determine whether NVC was affected by (1) NO synthase inhibition by N G ‐monomethyl‐ L ‐arginine (L‐NMMA) to block neuronal NO production, and by (2) isovolumic hemodilution, where ∼20% blood volume was removed and replaced with human serum albumin to attenuate the erythrocyte‐dependent component of NO production.…”