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We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in-flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro- and macrovascular dilatation. This contemporary review focuses on in vivo human work - with reference to seminal preclinical work where necessary - on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a - likely non-obligatory - combination of: (1) nitric oxide synthases, (2) deoxygenation-coupled S-nitrosothiols, (3) potassium channel-related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin-related mechanisms, reductions in O 2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex-, heredity-, age-, and disease-related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Passive hyperthermia causes cerebral hypoperfusion primarily from heat-induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro-inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water-perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet-poor plasma via cells expressing CD62E (activated endothelial cells), CD31 + /CD42b - (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan-leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P-values all >0.05). However, when blood CO 2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31 + /CD42b - (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO 2 /pH-mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. KEY POINTS: The hyperthermia-induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow. We tested the hypothesis that the respiratory-induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow. At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross-brain microvesicle kinetics. However, when core temperature was increased by 2°C with CO 2 /pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO 2 /pH-mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia. These new findings suggest that the heat-induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVR CO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVR CO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross-species study using small and large animals, we comprehensively tested the agreement and validity of multiple single-beat surrogate metrics of LV contractility against the field-standard metrics derived from inferior vena cava occlusion (IVCO). Fifty-six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single-beat metrics of LV contractility. All single-beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load-independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single-beat metrics, only LV maximal pressure normalized to end-diastolic volume (EDV), end-systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate-to-excellent agreement with their IVCO-derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large-animal models. Our findings demonstrate that single-beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small- and large-animal models KEY POINTS: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology. We comprehensively test the underlying assumptions of multiple single-beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs. We show that when performing caval occlusion is unfeasible, single-beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species. We report that maximal left-ventricular (LV)-pressure normalized to end-diastolic volume (EDV), LV end-systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single-beat metrics to measure cardiac inotropic function in both small- and large-animal models., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Key Points: We investigated the influence of arterial P C O 2 ( P aC O 2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in P aC O 2 prior to and following intravenous NaHCO 3 to acutely elevate arterial pH and [HCO 3 - ]. The NVC response was not altered following NaHCO 3 between stepwise P aC O 2 stages; therefore, NVC is acutely mediated by P aC O 2 rather than the prevailing arterial [H + ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg P aC O 2 and the absolute peak change was reduced by -19% with +10 mmHg P aC O 2 irrespective of acutely elevated arterial pH/[HCO 3 - ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness., Abstract: Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial P C O 2 ( P aC O 2 ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, P aC O 2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in P aC O 2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO 3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO 3 ] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27-38% with -10 mmHg P aC O 2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO - ] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27-38% with -10 mmHg P aC O 2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO 3 (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of P aC O 2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg P aC O 2 irrespective of acutely elevated arterial pH/[HCO 3 - ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by P aC O 2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Key Points: We investigated the influence of arterial PCO 2 (PaCO 2 ) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO 2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO 3 - ). Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO 3 - ] (i.e. buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H + ]/pH were consistent with the altered relationship between PaCO 2 and [H + ]/pH following ACZ at high altitude (i.e. leftward x-intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO 2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO 2 rather than arterial pH., Abstract: Alterations in acid-base balance with progressive acclimatization to high altitude have been well-established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid-base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ -0.07 ± 0.04 and base excess: Δ -5.7 ± 1.9 mEq⋅l -1 , trial effects: P < 0.001 and P < 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO 3 ; pH: Δ -0.01 ± 0.04 and base excess: Δ -1.5 ± 2.1 mEq⋅l - ; pH: Δ -0.01 ± 0.04 and base excess: Δ -1.5 ± 2.1 mEq⋅l -1 , trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO 2 (PaCO 2 ), i.e. cerebrovascular CO 2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. Δ -3.4 ± 2.3 mmHg PaCO 2 , trial effect: P < 0.001) was sufficient to offset any elevations in CBF induced via the ACZ-mediated metabolic acidosis. Between trials at high altitude, we observed consistent leftward shifts in both the PaCO 2 -pH and CBV-pH responses across the CO 2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO 2 - rather than pH - the absolute CBV and sensitivity of CBV-PaCO 2 was unchanged between trials at high altitude. Taken together, following acclimatization, CO 2 -mediated changes in cerebrovascular tone rather than arterial [H + ]/pH is integral to CBF regulation at high altitude., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Key Points: We investigated the influence of arterial P C O 2 ( P aC O 2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO 3 - ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in P aC O 2 (i.e. cerebrovascular CO 2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO 3 - ) to acutely elevate arterial pH and [HCO 3 - ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of P aC O 2 , indicating that CBF is acutely regulated by P aC O 2 rather than arterial pH. The cerebrovascular responses to changes in arterial H + /pH were altered in keeping with the altered relationship between P aC O 2 and H + /pH following NaHCO 3 - infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO 3 - infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO 3 - independent of P aC O 2 levels., Abstract: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial P C O 2 ( P aC O 2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in P aC O 2 or intravascular bicarbonate ([HCO 3 - ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO 2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in P aC O 2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO 3 - ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L -1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO 3 - ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L -1 ; P < 0.001). Absolute CBF was not different at each stage of CO 2 reactivity (P = 0.629) following NaHCO 3 - , irrespective of a higher pH (P < 0.001) at each matched stage of P aC O 2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg P aC O 2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg P aC O 2 ; P = 0.151) reactivity to P aC O 2 were altered pre- to post-NaHCO 3 - . When indexed against arterial [H + ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO 3 - , respectively. These changes in reactivity to [H + ] were, however, explained by alterations in buffering between P aC O 2 and arterial H + /pH consequent to NaHCO 3 - . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min -1 , 7% ± 12%; P = 0.047) following NaHCO 3 - during isocapnic breathing providing support for a direct influence of HCO 3 - on cerebrovascular tone independent of P aC O 2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by P aC O 2 rather than arterial pH., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Key Points: Iron acts as a cofactor in the stabilization of the hypoxic-inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high-altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature., Abstract: To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the haematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: (1) a 9-day ascent to 5050 m (20 lowlanders; 12 Sherpa), and (2) following partial acclimatization (11 ± 4 days) to 5050 m (18 lowlanders; 20 Sherpa), where both groups received an i.v. infusion of either iron (iron (iii)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050 m (P = 0.016 and P = 0.029, respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050 m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxaemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (P = 0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxaemia ( P I O 2  = 67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Key Points: Brachial artery (BA) shear-mediated dilatation is a widely used assessment of vascular function with links to coronary artery health and cardiovascular risk. Cerebral vascular health is often interrogated using cerebrovascular (middle cerebral artery velocity) reactivity to carbon dioxide. We show that endothelium-dependent diameter (dilator) responses are not significantly related between the internal carotid artery (ICA) and BA; nor are endothelium-independent responses. Additionally, ICA endothelium-dependent responses are not related to middle cerebral artery velocity or ICA blood flow reactivity responses to carbon dioxide. Therefore, assessment of large extracranial cerebral artery vascular health should be quantified via methods specific to the vessel, not via peripheral endothelial function or cerebrovascular reactivity to carbon dioxide., Abstract: This study compared internal carotid artery (ICA) and brachial artery (BA) endothelium-dependent and -independent vasodilation. We hypothesized that endothelium-dependent and -independent vasodilation of the ICA and BA would be neither similar in magnitude nor correlated between vessels. In 19 healthy adults (23 ± 6 years, 24 ± 3 kg/m 2 , six female), endothelium-dependent dilatation in the ICA was determined via Duplex ultrasound during transiently elevated shear stress caused by increased partial pressure of end-tidal carbon dioxide using dynamic end-tidal forcing (+9 mmHg; cerebral flow-mediated dilatation, cFMD). BA endothelium-dependent dilatation was assessed via standard flow-mediated dilatation (FMD). Endothelium-independent dilatation in the ICA and BA was assessed concurrently for 10 min following administration of 400 µg sublingual glyceryl trinitrate (GTN). Endothelium-dependent vasodilation of the ICA (3.4 ± 2.4%) was lower than (P = 0.013) and not correlated to that of the BA (7.9 ± 3.3%; r 2  = 0.00, P = 0.93). Including baseline diameter and shear-rate area under the curve as covariates maintained the difference between cFMD and FMD (3.3 ± 4.2% vs. 7.8 ± 3.8%, P = 0.03), while including baseline diameter and baseline shear rate-adjusted area under the curve as covariates abolished it (5.9 ± 3.7% vs. 5.9.8 ± 3.5%, P = 0.99). GTN-mediated vasodilation of the ICA (14.3 ± 2.9%) was lower than (P = 0.002) and not correlated to that of the BA (25.5 ± 8.8%; r 2  = 0.12, P = 0.19). Adjusting for baseline diameter eliminated the differences in GTN-induced vasodilation (ICA: 20.1 ± 5.8% vs. BA: 20.4 ± 5.5%; P = 0.93). Differences in endothelium-dependent responses, and the lack of correlations between arteries, indicates that endothelium-dependent function cannot be assumed to be related across cerebral and peripheral vasculatures in young, healthy humans., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

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 N G -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., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: Changes in haematocrit influence nitric oxide signalling through alterations in shear stress stimuli and haemoglobin scavenging of nitric oxide; these two regulatory factors have not been assessed simultaneously Isovolumic haemodilution led to a marked increase in brachial artery flow-mediated dilatation in humans The increase in flow-mediated dilatation occurred in the face of an unaltered shear stress stimulus for vasodilatation and reduced resting steady-state nitric oxide levels in the blood Collectively, our data point towards haemoglobin scavenging of nitric oxide as a key regulatory factor of brachial flow-mediated dilatation and highlight the importance of the simultaneous consideration of nitric oxide production and inactivation when investigating vascular function in humans ABSTRACT: Haemoglobin (Hb) may impact the transduction of endothelium-dependent and nitric oxide (NO)-mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and haematocrit (Hct) would increase brachial artery flow-mediated dilatation (FMD). In 11 healthy males (28 ± 7 years; 23 ± 2 kg m -2 ), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone-based chemiluminescence) were measured before and after isovolumic haemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Haemodilution reduced Hct by 18 ± 2% (P < 0.001) and whole blood viscosity by 22 ± 5% (P < 0.001). Plasma nitrite (P = 0.01), S-nitrosothiols (P = 0.03) and total red blood cell NO (P = 0.001) were collectively reduced by ∼15-40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that haemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium-dependent NO-mediated vasodilatation in healthy humans., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: Aerobic exercise elicits increases in cerebral blood flow (CBF), as well as core body temperature; however, the isolated influence of temperature on CBF regulation during exercise has not been investigated The present study assessed CBF regulation and neurovascular coupling during submaximal cycling exercise and temperature-matched passive heat stress during isocapnia (i.e. end-tidal P C O 2 was held constant) Submaximal cycling exercise and temperature-matched passive heat stress provoked ∼16% increases in vertebral artery blood flow, independent of changes in end-tidal P C O 2 and blood pressure External carotid artery blood flow increased by ∼43% during both exercise and passive heat stress, with no change in internal carotid artery blood flow Neurovascular coupling (i.e. the relationship between local increases in cerebral metabolism and appropriately matched increases in regional cerebral blood flow) is preserved during both exercise and temperature-matched passive heat stress ABSTRACT: Acute moderate-intensity exercise increases core temperature (T c ; +0.7-0.8°C); however, such exercise increases cerebral blood flow (CBF; +10-20%) mediated via small elevations in arterial P C O 2 and metabolism. The present study aimed to isolate the role of T c from P C O 2 on CBF regulation during submaximal exercise. Healthy adults (n = 11; 10 males/one female; 26 ± 4 years) participated in two interventions each separated by ≥48 h: (i) 60 min of semi-recumbent cycling (EX; 50% workload max) and (ii) 75 min of passive heat stress (HS; 49°C water-perfused suit) to match the exercise-induced increases in T c (EX: Δ0.75 ± 0.33°C vs. HS: Δ0.77 ± 0.33°C, P = 0.855). Blood flow (Q) in the internal and external carotid arteries (ICA and ECA, respectively) and vertebral artery (VA) (Duplex ultrasound) was measured. End-tidal P C O 2 and P O 2 were effectively clamped to resting values within each condition. The Q ICA was unchanged with EX and HS interventions (P = 0.665), consistent with the unchanged end-tidal P C O 2 (P = 0.327); whereas, Q VA was higher throughout both EX and HS (EX: Δ16 ± 21% vs. HS: Δ16 ± 23%, time effect: P = 0.006) with no between condition differences (P = 0.785). These increases in Q VA contributed to higher global CBF throughout both EX and HS (EX: Δ12 ± 20% vs. HS: Δ14 ± 14%, time effect: P = 0.029; condition effect: P = 0.869). The Q ECA increased throughout both EX and HS (EX: Δ42 ± 58% vs. HS: Δ53 ± 28%, time effect: P < 0.001; condition effect: P = 0.628). Including blood pressure as a covariate did not alter these CBF findings (all P > 0.05). Overall, these data provide new evidence for temperature-mediated elevations in posterior CBF during exercise that are independent of changes in P C O 2 and blood pressure., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: It was unknown whether respiratory alkalosis impacts the global cerebral metabolic response as well as the cerebral pro-oxidation and inflammatory response in passive hyperthermia. This study demonstrated that the cerebral metabolic rate was increased by ∼20% with passive hyperthermia of up to +2°C oesophageal temperature, and this response was unaffected by respiratory alkalosis. Additionally, the increase in cerebral metabolism did not significantly impact the net cerebral release of oxidative and inflammatory markers. These data indicate that passive heating of up to +2°C core temperature in healthy young men is not enough to confer a major oxidative and inflammatory burden on the brain, but it does markedly increase the cerebral metabolic rate, independently of P aC O 2 ., Abstract: There is limited information concerning the impact of arterial P C O 2 /pH on heat-induced alteration in cerebral metabolism, as well as on the cerebral oxidative/inflammatory burden of hyperthermia. Accordingly, we sought to address two hypotheses: (1) passive hyperthermia will increase the cerebral metabolic rate of oxygen (CMRO 2 ) consistent with a combined influence of Q10 and respiratory alkalosis; and (2) the net cerebral release of pro-oxidative and pro-inflammatory markers will be elevated in hyperthermia, particularly in poikilocapnic hyperthermia. Healthy young men (n = 6) underwent passive heating until an oesophageal temperature of 2°C above resting was reached. At 0.5°C increments in core temperature, CMRO 2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery-jugular venous oxygen content difference (cannulation). Net cerebral glucose/lactate exchange, and biomarkers of oxidative and inflammatory stress were also measured. At +2.0°C oesophageal temperature, arterial P C O 2 was restored to normothermic values using end-tidal forcing. The primary findings were: (1) while CMRO 2 was increased (P < 0.05) by ∼20% with hyperthermia of +1.5-2.0°C, this was not influenced by respiratory alkalosis, and (2) although biomarkers of pro-oxidation and pro-inflammation were systemically elevated in hyperthermia (P < 0.05), there were no differences in the trans-cerebral exchange kinetics. These novel data indicate that passive heating of up to +2°C core temperature in healthy young men is not enough to confer a major oxidative and inflammatory burden on the brain, despite it markedly increasing CMRO 2 , irrespective of arterial pH., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: Sherpa have lived in the Nepal Himalaya for 25-40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives. We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH. The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema., Abstract: Debilitating side effects of hypoxia manifest within the central nervous system; however, high-altitude natives of the Tibetan plateau, the Sherpa, experience negligible cerebral effects compared to lowland natives at extreme altitude. Phenotypical optimization of the oxygen cascade has been demonstrated in the systemic circulation of Tibetans and Sherpa, likely underscoring their adapted capacity to thrive at altitude. Yet, little is known as to how the cerebral circulation of Sherpa may be adapted. To examine potential differences in cerebral oxygen delivery in Sherpa compared to lowlanders we measured arterial blood gases and global cerebral blood flow (duplex ultrasound) during a 9 day ascent to 5050 m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400 m (-30.3 ± 21.6%; P < 0.01) and 4371 m (-14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modelling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximately 100 mL min -1 (∼17-34%) lower cerebral blood flow in Sherpa compared to lowlanders across ascent to altitude (P = 0.046). To ascertain the role of chronic hypoxia independent of the ascent, Sherpa who had not recently descended were also examined at 5050 m. In these Sherpa, cerebral oxygen delivery was also lower compared to lowlanders (∼22% lower; P < 0.01). We highlight new information about the influence of race and genetic adaptation in the regulation of cerebral oxygen delivery. The lower cerebral oxygen delivery in the Sherpa potentially represents a positive adaptation considering Sherpa endure less deleterious cerebral consequences than lowlanders at altitude., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Key Points: The reduced oxygen tension of high altitude compromises performance in lowlanders. In this environment, Sherpa display superior performance, but little is known on this issue. Sherpa present unique genotypic and phenotypic characteristics at the muscular level, which may enhance resistance to peripheral fatigue at high altitude compared to lowlanders. We studied the impact of gradual ascent and exposure to high altitude (5050 m) on peripheral fatigue in age-matched lowlanders and Sherpa, using intermittent electrically-evoked contractions of the knee extensors. Peripheral fatigue (force loss) was lower in Sherpa during the first part of the protocol. Post-protocol, the rate of force development and contractile impulse recovered faster in Sherpa than in lowlanders. At any time, indices of muscle oxygenation were not different between groups. Muscle contractile properties in Sherpa, independent of muscle oxygenation, were less perturbed by non-volitional fatigue. Hence, elements within the contractile machinery contribute to the superior physical performance of Sherpa at high altitude., Abstract: Altitude-related acclimatisation is characterised by marked muscular adaptations. Lowlanders and Sherpa differ in their muscular genotypic and phenotypic characteristics, which may influence peripheral fatigability at altitude. After gradual ascent to 5050 m, 12 lowlanders and 10 age-matched Sherpa (32 ± 10 vs. 31 ± 11 years, respectively) underwent three bouts (separated by 15 s rest) of 75 intermittent electrically-evoked contractions (12 pulses at 15 Hz, 1.6 s between train onsets) of the dominant leg quadriceps, at the intensity which initially evoked 30% of maximal voluntary force. Trains were also delivered at minutes 1, 2 and 3 after the protocol to measure recovery. Tissue oxygenation index (TOI) and total haemoglobin (tHb) were quantified by a near-infrared spectroscopy probe secured over rectus femoris. Superficial femoral artery blood flow was recorded using ultrasonography, and delivery of oxygen was estimated (eDO 2 ). At the end of bout 1, peak force was greater in Sherpa than in lowlanders (91.5% vs. 84.5% baseline, respectively; P < 0.05). Peak rate of force development (pRFD), the first 200 ms of the contractile impulse (CI 200 ), and half-relaxation time (HRT) recovered faster in Sherpa than in lowlanders (percentage of baseline at 1 min: pRFD: 89% vs. 74%; CI 200 : 91% vs. 80%; HRT: 113% vs. 123%, respectively; P < 0.05). Vascular measures were pooled for lowlanders and Sherpa as they did not differ during fatigue or recovery (P < 0.05). Mid bout 3, TOI was decreased (90% baseline) whereas tHb was increased (109% baseline). After bout 3, eDO 2 was markedly increased (1266% baseline). The skeletal muscle of Sherpa seemingly favours repeated force production at altitude for similar oxygen delivery compared to lowlanders., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Key Points: Our objective was to quantify endothelial function (via brachial artery flow-mediated dilatation) at sea level (344 m) and high altitude (3800 m) at rest and following both maximal exercise and 30 min of moderate-intensity cycling exercise with and without administration of an α 1 -adrenergic blockade. Brachial endothelial function did not differ between sea level and high altitude at rest, nor following maximal exercise. At sea level, endothelial function decreased following 30 min of moderate-intensity exercise, and this decrease was abolished with α 1 -adrenergic blockade. At high altitude, endothelial function did not decrease immediately after 30 min of moderate-intensity exercise, and administration of α 1 -adrenergic blockade resulted in an increase in flow-mediated dilatation. Our data indicate that post-exercise endothelial function is modified at high altitude (i.e. prolonged hypoxaemia). The current study helps to elucidate the physiological mechanisms associated with high-altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function., Abstract: We examined the hypotheses that (1) at rest, endothelial function would be impaired at high altitude compared to sea level, (2) endothelial function would be reduced to a greater extent at sea level compared to high altitude after maximal exercise, and (3) reductions in endothelial function following moderate-intensity exercise at both sea level and high altitude are mediated via an α 1 -adrenergic pathway. In a double-blinded, counterbalanced, randomized and placebo-controlled design, nine healthy participants performed a maximal-exercise test, and two 30 min sessions of semi-recumbent cycling exercise at 50% peak output following either placebo or α 1 -adrenergic blockade (prazosin; 0.05 mg kg  -1 ). These experiments were completed at both sea-level (344 m) and high altitude (3800 m). Blood pressure (finger photoplethysmography), heart rate (electrocardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (ultrasound) were recorded before, during and following exercise. Endothelial function assessed by brachial artery flow-mediated dilatation (FMD) was measured before, immediately following and 60 min after exercise. Our findings were: (1) at rest, FMD remained unchanged between sea level and high altitude (placebo P = 0.287; prazosin: P = 0.110); (2) FMD remained unchanged after maximal exercise at sea level and high altitude (P = 0.244); and (3) the 2.9 ± 0.8% (P = 0.043) reduction in FMD immediately after moderate-intensity exercise at sea level was abolished via α 1 -adrenergic blockade. Conversely, at high altitude, FMD was unaltered following moderate-intensity exercise, and administration of α 1 -adrenergic blockade elevated FMD (P = 0.032). Our results suggest endothelial function is differentially affected by exercise when exposed to hypobaric hypoxia. These findings have implications for understanding the chronic impacts of hypoxaemia on exercise, and the interactions between the α 1 -adrenergic pathway and endothelial function., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Key Points: The present study describes the cerebral oxidative and non-oxidative metabolism in man during a prolonged apnoea (ranging from 3 min 36 s to 7 min 26 s) that generates extremely low levels of blood oxygen and high levels of carbon dioxide. The cerebral oxidative metabolism, measured from the product of cerebral blood flow and the radial artery-jugular venous oxygen content difference, was reduced by ∼29% at the termination of apnoea, although there was no change in the non-oxidative metabolism. A subset study with mild and severe hypercapnic breathing at the same level of hypoxia suggests that hypercapnia can partly explain the cerebral metabolic reduction near the apnoea breakpoint. A hypercapnia-induced oxygen-conserving response may protect the brain against severe oxygen deprivation associated with prolonged apnoea., Abstract: Prolonged apnoea in humans is reflected in progressive hypoxaemia and hypercapnia. In the present study, we explore the cerebral metabolic responses under extreme hypoxia and hypercapnia associated with prolonged apnoea. We hypothesized that the cerebral metabolic rate for oxygen (CMRO2 ) will be reduced near the termination of apnoea, attributed in part to the hypercapnia. Fourteen elite apnoea-divers performed a maximal apnoea (range 3 min 36 s to 7 min 26 s) under dry laboratory conditions. In a subset study with the same divers, the impact of hypercapnia on cerebral metabolism was determined using varying levels of hypercapnic breathing, against the background of similar hypoxia. In both studies, the CMRO2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery-internal jugular venous oxygen content difference. Non-oxidative cerebral metabolism was calculated from the ratio of oxygen and carbohydrate (lactate and glucose) metabolism. The CMRO2  was reduced by ∼29% (P < 0.01, Cohen's d = 1.18) near the termination of apnoea compared to baseline, although non-oxidative metabolism remained unaltered. In the subset study, in similar backgrounds of hypoxia (arterial O2 tension: ∼38.4 mmHg), severe hypercapnia (arterial CO2 tension: ∼58.7 mmHg), but not mild-hypercapnia (arterial CO2 tension: ∼46.3 mmHg), depressed the CMRO2 (∼17%, P = 0.04, Cohen's d = 0.87). Similarly to the apnoea, there was no change in the non-oxidative metabolism. These data indicate that hypercapnia can partly explain the reduction in CMRO2 near the apnoea breakpoint. This hypercapnic-induced oxygen conservation may protect the brain against severe hypoxaemia associated with prolonged apnoea., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Key Points: Cerebral blood flow increases during hypercapnia and decreases during hypocapnia; it is unknown if vasomotion of the internal carotid artery is implicated in these responses. Indomethacin, a non-selective cyclooxygenase inhibitor (used to inhibit prostaglandin synthesis), has a unique ability to blunt cerebrovascular carbon dioxide reactivity, while other cyclooxygenase inhibitors have no effect. We show significant dilatation and constriction of the internal carotid artery during hypercapnia and hypocapnia, respectively. Indomethacin, but not ketorolac or naproxen, reduced the dilatatory response of the internal carotid artery to hypercapnia The differential effect of indomethacin compared to ketorolac and naproxen suggests that indomethacin inhibits vasomotion of the internal carotid artery independent of prostaglandin synthesis inhibition., Abstract: Extra-cranial cerebral blood vessels are implicated in the regulation of cerebral blood flow during changes in arterial CO2 ; however, the mechanisms governing CO2 -mediated vasomotion of these vessels in humans remain unclear. We determined if cyclooxygenase inhibition with indomethacin (INDO) reduces the vasomotor response of the internal carotid artery (ICA) to changes in end-tidal CO2 (P ETC O2). Using a randomized single-blinded placebo-controlled study, participants (n = 10) were tested on two occasions, before and 90 min following oral INDO (1.2 mg kg(-1) ) or placebo. Concurrent measurements of beat-by-beat velocity, diameter and blood flow of the ICA were made at rest and during steady-state stages (4 min) of iso-oxic hypercapnia (+3, +6, +9 mmHg P ETC O2) and hypocapnia (-3, -6, -9 mmHg P ETC O2). To examine if INDO affects ICA vasomotion independent of cyclooxygenase inhibition, two participant subsets (each n = 5) were tested before and following oral ketorolac (post 45 min, 0.25 mg kg(-1) ) or naproxen (post 90 min, 4.2 mg kg(-1) ). During pre-drug testing in the INDO trial, the ICA dilatated during hypercapnia at +6 mmHg (4.72 ± 0.45 vs. 4.95 ± 0.51 mm; P < 0.001) and +9 mmHg (4.72 ± 0.45 mm vs. 5.12 ± 0.47 mm; P < 0.001), and constricted during hypocapnia at -6 mmHg (4.95 ± 0.33 vs. 4.88 ± 0.27 mm; P < 0.05) and -9 mmHg (4.95 ± 0.33 vs. 4.82 ± 0.27 mm; P < 0.001). Following INDO, vasomotor responsiveness of the ICA to hypercapnia was reduced by 67 ± 28% (0.045 ± 0.015 vs. 0.015 ± 0.012 mm mmHg P ETC O2(-1) ). There was no effect of the drug in the ketorolac and naproxen trials. We conclude that: (1) INDO markedly reduces the vasomotor response of the ICA to changes in P ETC O2; and (2) INDO may be reducing CO2 -mediated vasomotion via a mechanism(s) independent of cyclooxygenase inhibition., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Cerebrovascular reactivity impacts CO₂-[H(+)] washout at the central chemoreceptors and hence has marked influence on the control of ventilation. To date, the integration of cerebral blood flow (CBF) and ventilation has been investigated exclusively with measures of anterior CBF, which has a differential reactivity from the vertebrobasilar system and perfuses the brainstem. We hypothesized that: (1) posterior versus anterior CBF would have a stronger relationship to central chemoreflex magnitude during hypercapnia, and (2) that higher posterior reactivity would lead to a greater hypoxic ventilatory decline (HVD). End-tidal forcing was used to induce steady-state hyperoxic (300 mmHg P ET ,O₂) hypercapnia (+3, +6 and +9 mmHg P ET ,CO₂) and isocapnic hypoxia (45 mmHg P ET ,O₂) before and following pharmacological blunting (indomethacin; INDO; 1.45 ± 0.17 mg kg(-1)) of resting CBF and reactivity. In 22 young healthy volunteers, ventilation, intra-cranial arterial blood velocities and extra-cranial blood flows were measured during these challenges. INDO-induced blunting of cerebrovascular flow responsiveness (CVR) to CO₂ was unrelated to variability in ventilatory sensitivity during hyperoxic hypercapnia. Further results in a sub-group of volunteers (n = 9) revealed that elevations of P ET,CO₂ via end-tidal forcing reduce arterial-jugular venous gradients, attenuating the effect of CBF on chemoreflex responses. During isocapnic hypoxia, vertebral artery CVR was related to the magnitude of HVD (R(2) = 0.27; P < 0.04; n = 16), suggesting that CO₂-[H(+)] washout from central chemoreceptors modulates hypoxic ventilatory dynamics. No relationships were apparent with anterior CVR. As higher posterior, but not anterior, CVR was linked to HVD, our study highlights the importance of measuring flow in posterior vessels to investigate CBF and ventilatory integration., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)