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.

The purpose of this study was to compare the integrated intracranial cerebrovascular reactivity (CVR) and hypercapnic ventilatory response between children and adults and to explore the dynamic response of the middle cerebral artery mean velocity (MCA V ). Children (n = 20; 9.9 ± 0.7 years of age) and adults (n = 21; 24.4 ± 2.0 years of age) completed assessment of CVR over 240 s using a fixed fraction of inspired CO 2 (0.06). Baseline MCA V was higher in the adult females compared with the males (P ≤ 0.05). The MCA V was greater in female children compared with male children (P ≤ 0.05) and in female adults compared with male adults (P ≤ 0.05) with hypercapnia. Relative CVR was similar in children and adults (3.71 ± 1.06 versus 4.12 ± 1.32% mmHg −1 ; P = 0.098), with absolute CVR being higher in adult females than males (3.27 ± 0.86 versus 2.53 ± 0.70 cm s −1 mmHg −1 ; P ≤ 0.001). Likewise, the hypercapnic ventilatory response did not differ between the children and adults (1.89 ± 1.00 versus 1.77 ± 1.34 l min −1 mmHg −1 ; P = 0.597), but was lower in adult females than males (1.815 ± 0.37 versus 2.33 ± 1.66 l min −1 mmHg −1 ; P ≤ 0.05). The heart rate response to hypercapnia was greater in children than in adults (P = 0.001).A monoexponential regression model was used to characterize the dynamic onset, consisting of a delay term, amplitude and time constant ( ). The results revealed that MCA V was faster in adults than in children (34 ± 18 versus 74 ± 28 s; P = 0.001). Our study provides new insight into the impact of age and sex on CVR and the dynamic response of the MCA V to hypercapnia.

Recent work demonstrated an influence of ventilation on cerebrovascular reactivity to CO 2 ; however, the concomitant influence of changes in mean arterial blood pressure (MAP) on ventilation-induced differences in cerebral blood flow (CBF) has yet to be examined in this context.Healthy participants (n = 15; 25 ± 3 years of age; 179 ± 6 cm height; 74 ± 10 kg weight; 3 female) underwent end-tidal forcing to increase their partial pressure of end-tidal CO 2 by +3, +6 and +9 mmHg above baseline in 5-min sequential steps while maintaining iso-oxia. This protocol was then repeated twice, with participants hyperventilating and hypoventilating by ∼30% compared to the first trial. Intra-cranial and extra-cranial CBF were measured using ultrasound. The MAP (finger photo-plethysmography) was higher during the hyperventilation and hypoventilation trials compared to normal ventilation (main effects, P < 0.05 for both). While internal carotid artery blood flow was higher during the hyperventilation trial compared to normal ventilation (P = 0.01), this was due to a higher MAP, as indicated by analysis of conductance values (P = 0.68) or inclusion of MAP in covariate analysis (P = 0.11). Global CBF (P = 0.11) and vertebral artery blood flow (P = 0.93) were unaffected by the magnitude of ventilation. Further, CO 2 reactivity was not affected by the different breathing trials (P > 0.05 for all). Retrospective analysis of a larger data set (n = 53) confirmed these observations and demonstrated no relationships between the ventilatory and global CBF response to hypercapnia (r 2 = 0.04; P = 0.14). Therefore, when differences in MAP are accounted for, cerebrovascular CO 2 reactivity (assessed via end-tidal forcing) is independent of the magnitude of ventilation.