The jugular venous-to-arterial P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during rebreathing and end-tidal forcing: Relationship with cerebral perfusion.

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and arterial P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference (Pjv-a CO2 )] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv-a CO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end-tidal forcing (ETF) protocols (termed: ETF-1 and ETF-2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF-1 (n = 11) and ETF-2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv-a CO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF-1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF-2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv-a CO2 difference did not change during the rebreathing protocol (-0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF-1 (-3.9 ± 1.1 mmHg; P < 0.001) and ETF-2 (-3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv-a CO2 difference during ETF (-0.095 ± 0.089 mmHg cm-1  s-1 ; P = 0.001) but not during rebreathing (-0.028 ± 0.045 mmHg · cm-1  · s-1 ; P = 0.067). These findings suggest that, although the Pjv-a CO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2 . KEY POINTS: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow. We assessed these assumptions by measuring arterial and jugular venous bulb P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end-tidal forcing. The difference between arterial and jugular venous bulb P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ remained present during both rebreathing and end-tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during end-tidal forcing but not rebreathing. These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings.

Recent insights into mechanisms of hypoxia-induced vasodilatation in the human brain.

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 O2 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.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

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 PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . 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 PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; 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.

Brachial artery responses to acute hypercapnia: The roles of shear stress and adrenergic tone.

NEW FINDINGS: What is the central question of this study? What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia? What is the main finding and its importance? In healthy young adults, shear-mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α1-adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. ABSTRACT: We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α1-adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α1-adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end-tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end-tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α1-adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α1-adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear-mediated vasodilatation in the BA.

Acid-base balance and cerebrovascular regulation.

The regulation and defence of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid-base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid-base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension (PCO2 ), bicarbonate (HCO3- ) and pH. These factors interact to influence (1) the time course of acid-base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial blood, extracellular fluid and intracellular brain tissue). We propose that alterations in arterial [HCO3- ] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid-base regulation; and (2) the regulation of CBF by direct changes in arterial vs. extravascular/interstitial PCO2 and pH - the latter recognized as the proximal compartment which alters vascular smooth muscle cell regulation of CBF. Taken together, these results substantiate two key ideas: first, that the regulation of CBF is affected by the severity of metabolic/respiratory disturbances, including the extent of partial/full acid-base compensation; and second, that the regulation of CBF is independent of arterial pH and that diffusion of CO2 across the blood-brain barrier is integral to altering perivascular extracellular pH. Overall, by realizing the integrative relationships between CBF, PCO2 , HCO3- and pH, experimental studies may provide insights to improve CBF regulation in clinical practice with treatment of systemic acid-base disorders.

Alterations in arterial CO2 rather than pH affect the kinetics of neurovascular coupling in humans.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ]. 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 PCO2 ( PaCO2 ) 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, PaCO2 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 PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO3- ] (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 PaCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO3 (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ] (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 PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3- ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in PaCO2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3- ) to acutely elevate arterial pH and [HCO3- ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of PaCO2 , indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between PaCO2 and H+ /pH following NaHCO3- infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3- infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3- independent of PaCO2 levels. ABSTRACT: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial PCO2 ( PaCO2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in PaCO2 or intravascular bicarbonate ([HCO3- ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3- ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO3- ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L-1 ; P < 0.001). Absolute CBF was not different at each stage of CO2 reactivity (P = 0.629) following NaHCO3- , irrespective of a higher pH (P < 0.001) at each matched stage of PaCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg PaCO2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg PaCO2 ; P = 0.151) reactivity to PaCO2 were altered pre- to post-NaHCO3- . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3- , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between PaCO2 and arterial H+ /pH consequent to NaHCO3- . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3- during isocapnic breathing providing support for a direct influence of HCO3- on cerebrovascular tone independent of PaCO2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by PaCO2 rather than arterial pH.

Cerebral blood flow, cerebrovascular reactivity and their influence on ventilatory sensitivity.

NEW FINDINGS: What is the topic of this review? Cerebrovascular reactivity to CO2 , which is a principal factor in determining ventilatory responses to CO2 through the role reactivity plays in determining cerebral extra- and intracellular pH. What advances does it highlight? Recent animal evidence suggests central chemoreceptor vasculature may demonstrate regionally heterogeneous cerebrovascular reactivity to CO2 , potentially as a protective mechanism against excessive CO2 washout from the central chemoreceptors, thereby allowing ventilation to reflect the systemic acid-base balance needs (respiratory changes in PaCO2 ) rather than solely the cerebral needs. Ventilation per se does not influence cerebrovascular reactivity independent of changes in PaCO2 . ABSTRACT: Alveolar ventilation and cerebral blood flow are both predominantly regulated by arterial blood gases, especially arterial PCO2 , and so are intricately entwined. In this review, the fundamental mechanisms underlying cerebrovascular reactivity and central chemoreceptor control of breathing are covered. We discuss the interaction of cerebral blood flow and its reactivity with the control of ventilation and ventilatory responsiveness to changes in PCO2 , as well as the lack of influence of ventilation itself on cerebrovascular reactivity. We briefly summarize the effects of arterial hypoxaemia on the relationship between ventilatory and cerebrovascular response to both PCO2 and PO2 . We then highlight key methodological considerations regarding the interaction of reactivity and ventilatory sensitivity, including the following: regional heterogeneity of cerebrovascular reactivity; a pharmacological approach for the reduction of cerebral blood flow; reactivity assessment techniques; the influence of mean arterial blood pressure; and sex-related differences. Finally, we discuss ventilatory and cerebrovascular control in the context of high altitude and congestive heart failure. Future research directions and pertinent questions of interest are highlighted throughout.

The stability of cerebrovascular CO2 reactivity following attainment of physiological steady-state.

NEW FINDINGS: What is the central question of this study? During a steady-state cerebrovascular CO2 reactivity test, do different data extraction time points change the outcome for cerebrovascular CO2 reactivity? What is the main finding and its importance? Once steady-state end-tidal pressure of CO2 and haemodynamics were achieved, cerebral blood flow was stable, and so cerebrovascular CO2 reactivity values remained unchanged regardless of data extraction length (30 vs. 60 s) and time point (at 2-5 min). ABSTRACT: This study assessed cerebrovascular CO2 reactivity (CVR) and examined data extraction time points and durations with the hypotheses that: (1) there would be no difference in CVR values when calculated with cerebral blood flow (CBF) measures at different time points following the attainment of physiological steady-state, (2) once steady-state was achieved there would be no difference in CVR values derived from 60 to 30 s extracted means, and (3) that changes in V̇E would not be associated with any changes in CVR. We conducted a single step iso-oxic hypercapnic CVR test using dynamic end-tidal forcing (end-tidal PCO2 , +9.4 ± 0.7 mmHg), and transcranial Doppler and Duplex ultrasound of middle cerebral artery (MCA) and internal carotid artery (ICA), respectively. From the second minute of hypercapnia onwards, physiological steady-state was apparent, with no subsequent changes in end-tidal PCO2 , PO2 or mean arterial pressure. Therefore, CVR measured in the ICA and MCA was stable following the second minute of hypercapnia onwards. Data extraction durations of 30 or 60 s did not give statistically different CVR values. No differences in CVR were detected following the second minute of hypercapnia after accounting for mean arterial pressure via calculated conductance or covariation of mean arterial pressure. These findings demonstrate that, provided the PCO2 stimulus remains in a steady-state, data extracted from any minute of a CVR test during physiological steady-state conditions produce equivalent CVR values; any change in the CVR value would represent a failure of CVR mechanisms, a change in the magnitude of the stimulus, or measurement error.

Internal carotid and brachial artery shear-dependent vasodilator function in young healthy humans.

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/m2 , 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%; r2  = 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%; r2  = 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.

Evidence for direct CO2 -mediated alterations in cerebral oxidative metabolism in humans.

AIM: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. METHODS: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady-state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial-internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). RESULTS: The CMRO2 was altered by 0.5 mL × min-1 (95% CI: -0.6 to -0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: -13.2 to -6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo- and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: -15.4 to -0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: -11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. CONCLUSION: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production.

Cerebral endothelium-dependent function and reactivity to hypercapnia: the role of α1-adrenoreceptors.

We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function [cerebral shear-mediated dilation (cSMD)] in the internal carotid artery (ICA) with and without systemic α1-adrenoreceptor blockade via Prazosin. We hypothesized that CVR would be reduced, whereas cSMD would remain unchanged, after Prazosin administration when compared with placebo. In 15 healthy adults (3 female, 26 ± 4 years), we conducted ICA duplex ultrasound during CVR [target +10 mmHg partial pressure of end-tidal carbon dioxide ([Formula: see text]) above baseline, 5 min] and cSMD (+9 mmHg [Formula: see text] above baseline, 30 s) using dynamic end-tidal forcing with and without α1-adrenergic blockade (Prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind, and randomized design. The CVR in the ICA was not different between placebo and Prazosin (P = 0.578). During CVR, the reactivities of mean arterial pressure and cerebrovascular conductance to hypercapnia were also not different between conditions (P = 0.921 and P = 0.664, respectively). During Prazosin, cSMD was lower (1.1 ± 2.0% vs 3.8 ± 3.0%; P = 0.032); however, these data should be interpreted with caution due to the elevated baseline diameter (+1.3 ± 3.6%; condition: P = 0.0498) and lower shear rate (-14.5 ± 23.0%; condition: P < 0.001). Therefore, lower cSMD post α1-adrenoreceptor blockade might not indicate a reduction in cerebral endothelial function per se, but rather, that α1-adrenoreceptors contribute to resting cerebral vascular restraint at the level of the ICA.NEW & NOTEWORTHY We assessed steady-state hypercapnic cerebrovascular reactivity and cerebral endothelium-dependent function, with and without α1-adrenergic blockade (Prazosin), in a placebo-controlled, double-blind, and randomized study, to assess the contribution of α1-adrenergic receptors to cerebrovascular CO2 regulation. After administration of Prazosin, cerebrovascular reactivity to CO2 was not different compared with placebo despite lower blood flow, whereas cerebral endothelium-dependent function was reduced, likely due to elevated baseline internal carotid arterial diameter. These findings suggest that α1-adrenoreceptor activity does not influence cerebral blood flow regulation to CO2 and cerebral endothelial function.

Distinct contributions of skin and core temperatures to flow-mediated dilation of the brachial artery following passive heating.

We measured acute vascular responses to heat stress to examine the hypothesis that macrovascular endothelial-dependent dilation is improved in a shear-dependent manner, which is further modified by skin temperature. Twelve healthy males performed whole body heating (+1.3°C esophageal temperature), bilateral forearm heating (∼38°C skin temperature), and a time-matched (∼60 min) control condition on separate days in a counterbalanced order. Bilateral assessments of blood flow and brachial artery flow-mediated dilation (FMD) were performed before and 10 min after each condition with duplex Doppler ultrasound. To isolate the influence of shear stress, a pneumatic cuff was inflated (∼90 mmHg) around the right forearm during each condition to attenuate heat-induced rises in blood flow and shear stress. After forearm heating, FMD increased [cuffed: 4.7 (2.9)% to 6.8 (1.5)% and noncuffed: 5.1 (2.8)% to 6.4 (2.6)%] in both arms (time P < 0.01). Whole body heating also increased FMD in the noncuffed arm from 3.6 (2.2)% to 9.2 (3.2)% and in the cuffed arm from to 5.6 (3.0)% to 8.6 (4.9)% (time P < 0.01). After the time control, FMD decreased [cuffed: 6.3 (2.4)% to 4.7 (2.2)% and noncuffed: 6.1 (3.0)% to 4.5 (2.6)%] in both arms (time P = 0.03). Multiple linear regression (adjusted R2 = 0.421 P = 0.003) revealed that changes in esophageal temperature, skin temperatures, and heart rate explained the majority of the variance in this model (34%, 31%, and 21%, respectively). Our findings indicate that, in addition to shear stress, skin and core temperatures are likely important contributors to passive heating-induced vascular adaptations.NEW & NOTEWORTHY The primary determinant of vascular adaptations to lifestyle interventions, such as exercise and heat therapy, is repeated elevations in vascular shear stress. Whether skin or core temperatures also modulate the vascular adaptation to acute heat exposure is unknown, likely due to difficulty in dissociating the thermal and hemodynamic responses to heat. We found that skin and core temperatures modify the acute vascular responses to passive heating irrespective of the magnitude of increase in shear stress.