Acute dietary NOsupplementation may abolish altitude-induced reduction in endothelial function, and can serve as a dietary strategy to ensure peripheral vascular function in lowland subjects entering high altitude environments.

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Key points Thermal and hypoxic stress commonly coexist in environmental, occupational and clinical settings, yet how the brain tolerates these multi‐stressor environments is unknown Core cooling by 1.0°C reduced cerebral blood flow (CBF) by 20–30% and cerebral oxygen delivery (CDO2) by 12–19% at sea level and high altitude, whereas core heating by 1.5°C did not reliably reduce CBF or CDO2 Oxygen content in arterial blood was fully restored with acclimatisation to 4330 m, but concurrent cold stress reduced CBF and CDO2 Gross indices of cognition were not impaired by any combination of thermal and hypoxic stress despite large reductions in CDO2 Chronic hypoxia renders the brain susceptible to large reductions in oxygen delivery with concurrent cold stress, which might make monitoring core temperature more important in this context Abstract Real‐world settings are composed of multiple environmental stressors, yet the majority of research in environmental physiology investigates these stressors in isolation. The brain is central in both behavioural and physiological responses to threatening stimuli and, given its tight metabolic and haemodynamic requirements, is particularly susceptible to environmental stress. We measured cerebral blood flow (CBF, duplex ultrasound), cerebral oxygen delivery (CDO2), oesophageal temperature, and arterial blood gases during exposure to three commonly experienced environmental stressors – heat, cold and hypoxia – in isolation, and in combination. Twelve healthy male subjects (27 ± 11 years) underwent core cooling by 1.0°C and core heating by 1.5°C in randomised order at sea level; acute hypoxia (PET,O2 = 50 mm Hg) was imposed at baseline and at each thermal extreme. Core cooling and heating protocols were repeated after 16 ± 4 days residing at 4330 m to investigate any interactions with high altitude acclimatisation. Cold stress decreased CBF by 20–30% and CDO2 by 12–19% (both P < 0.01) irrespective of altitude, whereas heating did not reliably change either CBF or CDO2 (both P > 0.08). The increases in CBF with acute hypoxia during thermal stress were appropriate to maintain CDO2 at normothermic, normoxic values. Reaction time was faster and slower by 6–9% with heating and cooling, respectively (both P < 0.01), but central (brain) processes were not impaired by any combination of environmental stressors. These findings highlight the powerful influence of core cooling in reducing CDO2. Despite these large reductions in CDO2 with cold stress, gross indices of cognition remained stable.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear‐mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)‐dependency of CVR and cSMD. Eleven volunteers underwent a steady‐state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA) or volume‐matched saline (placebo; single‐blinded and counter‐balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra‐arterial blood pressure and PaCnormalO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$. Paired arterial and jugular venous blood sampling allowed for the determination of trans‐cerebral NO2− exchange (ozone‐based chemiluminescence). l‐NMMA reduced arterial NO2− by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady‐state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCnormalO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. −1.8 ± 8.2 nM/min at 120 s post‐CO2; P = 0.044) shifted trans‐cerebral NO2− exchange towards a greater net release (a negative value indicates release). Although this trans‐cerebral NO2− release was abolished by l‐NMMA, CVR did not differ between the saline and l‐NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l‐NMMA impact peak internal carotid artery dilatation during the steady‐state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l‐NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady‐state CVR. Further, our novel transient CO2 test of cSMD is largely NO‐dependent and provides an in vivo bioassay of NO‐mediated cerebrovascular function in humans. Key points Emerging evidence indicates that a transient CO2 stimulus elicits shear‐mediated dilatation of the internal carotid artery, termed cerebral shear‐mediated dilatation. Whether or not cerebrovascular reactivity to a steady‐state CO2 stimulus is NO‐dependent remains unclear in humans. During both a steady‐state cerebrovascular reactivity test and a transient CO2 test of cerebral shear‐mediated dilatation, trans‐cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non‐selective NO synthase inhibitor NG‐monomethyl‐l‐arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady‐state CO2 test; however, cerebral shear‐mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG‐monomethyl‐l‐arginine. NO is not obligatory for cerebrovascular reactivity to CO2, but is a key contributor to cerebral shear‐mediated dilatation.