This study examined the relationship between cerebral blood flow (CBF) and end-tidal Pco₂ (PetCO₂) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PetCO₂ in a range of 22 to 50 Torr with a constant end-tidal Po₂ (100 Torr) in eight subjects. PetCO₂ and end-tidal Po₂ were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PetCO₂ was changed by 2 Torr every 2 min from hypocapnia to hypercapnia ( protocol I) and vice-versa ( protocol D). Over the range of PetCO₂ studied, the sensitivity of peak blood velocity to changes in PetCO₂ (CBF-PetCO₂ sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PetCO₂ sensitivity; for a given PetCO₂, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PetCO₂ sensitivity varies depending on the level of PetCO₂ and the protocol that is used. The mechanisms underlying these responses require further investigation.

Objective To test the hypothesis that aerobic exercise is associated with improvements in cognition and cerebrovascular regulation, we enrolled 206 healthy low-active middle-aged and older adults (mean ± SD age 65.9 ± 6.4 years) in a supervised 6-month aerobic exercise intervention and assessed them before and after the intervention. Methods The study is a quasi-experimental single group pre/postintervention study. Neuropsychological tests were used to assess cognition before and after the intervention. Transcranial Doppler ultrasound was used to measure cerebral blood flow velocity. Cerebrovascular regulation was assessed at rest, during euoxic hypercapnia, and in response to submaximal exercise. Multiple linear regression was used to examine the association between changes in cognition and changes in cerebrovascular function. Results The intervention was associated with improvements in some cognitive domains, cardiorespiratory fitness, and cerebrovascular regulation. Changes in executive functions were negatively associated with changes in cerebrovascular resistance index (CVRi) during submaximal exercise (β = −0.205, p = 0.013), while fluency improvements were positively associated with changes in CVRi during hypercapnia (β = 0.106, p = 0.03). Conclusion The 6-month aerobic exercise intervention was associated with improvements in some cognitive domains and cerebrovascular regulation. Secondary analyses showed a novel association between changes in cognition and changes in cerebrovascular regulation during euoxic hypercapnia and in response to submaximal exercise.

The relative importance of CO₂ and sympathetic stimulation in the regulation of cerebral and peripheral vasculatures has not been previously studied in humans. We investigated the effect of sympathetic activation, produced by isometric handgrip (HG) exercise, on cerebral and femoral vasculatures during periods of isocapnia and hypercapnia. In 14 healthy males (28.1 ± 3.7 (mean ±s.d.) years), we measured flow velocity (; transcranial Doppler ultrasound) in the middle cerebral artery during euoxic isocapnia (ISO, +1 mmHg above rest) and two levels of euoxic hypercapnia (HC5, end‐tidal P_CO2, P, =+5 mmHg above ISO; HC10, P=+10 above ISO). Each P_ET,CO2 level was maintained for 10 min using the dynamic end‐tidal forcing technique, during which increases in sympathetic activity were elicited by a 2‐min HG at 30% of maximal voluntary contraction. Femoral blood flow (FBF; Doppler ultrasound), muscle sympathetic nerve activity (MSNA; microneurography) and mean arterial pressure (MAP; Portapres) were also measured. Hypercapnia increased and FBF by 5.0 and 0.6% mmHg⁻¹, respectively, and MSNA by 20–220%. Isometric HG increased MSNA by 50% and MAP by 20%, with no differences between ISO, HC5 and HC10. During the ISO HG there was an increase in cerebral vascular resistance (CVR; 20 ± 11%), while remained unchanged. During HC5 and HC10 HG, increased (13% and 14%, respectively), but CVR was unchanged. In contrast, HG‐induced sympathetic stimulation increased femoral vascular resistance (FVR) during ISO, HC5 and HC10 (17–41%), while there was a general decrease in FBF below ISO. The HG‐induced increases in MSNA were associated with increases in FVR in all conditions (r= 0.76–0.87), whereas increases in MSNA were associated with increases in CVR only during ISO (r= 0.91). In summary, in the absence of hypercapnia, HG exercise caused cerebral vasoconstriction, myogenically and/or neurally, which was reflected by increases in CVR and a maintained . In contrast, HG increased FVR during conditions of ISO, HC5 and HC10. Therefore, the cerebral circulation is more responsive to alterations in P_CO2, and less responsive to sympathetic stimulation than the femoral circulation.

Rationale: Acute mountain sickness (AMS) may affect individuals who (rapidly) ascend to altitudes higher than 2,000–3,000 m. A more serious consequence of rapid ascent may be high-altitude pulmonary edema, a hydrostatic edema associated with increased pulmonary capillary pressures. Acetazolamide is effective against AMS, possibly by increasing ventilation and cerebral blood flow (CBF). In animals, it inhibits hypoxic pulmonary vasoconstriction. Objectives: We examined the influence of acetazolamide on the response to hypoxia of ventilation, CBF, and pulmonary vascular resistance (PVR). Methods: In this double-blind, placebo-controlled, randomized study, nine subjects ingested 250 mg acetazolamide every 8 h for 3 d. On the fourth test day, we measured the responses of ventilation, PVR, and CBF to acute isocapnic hypoxia (20 min) and sustained poikilocapnic hypoxia (4 h). Ventilation was measured with pneumotachography. Hypoxia was achieved with dynamic end-tidal forcing. The maximum pressure difference across the tricuspid valve (ΔPmax, a good index of PVR) was measured with Doppler echocardiography. CBF was measured by transcranial Doppler ultrasound. Results: In normoxia, acetazolamide increased ventilation and reduced ΔPmax, but did not influence CBF. The ventilatory and CBF responses to acute isocapnic hypoxia were unaltered, but the rise in ΔPmax was reduced by 57%. The increase in ΔPmax by sustained poikilocapnic hypoxia observed after placebo was reduced by 34% after acetazolamide, the ventilatory response was increased, but the CBF response remained unaltered. Conclusions: Acetazolamide has complex effects on ventilation, PVR, and CBF that converge to optimize brain oxygenation and may be a valuable means to prevent/treat high-altitude pulmonary edema.

Aging is associated with decreased vascular compliance and diminished neurovascular- and hypercapnia-evoked cerebral blood flow (CBF) responses. However, the interplay between arterial stiffness and reduced CBF responses is poorly understood. It was hypothesized that increased cerebral arterial stiffness is associated with reduced evoked responses to both, a flashing checkerboard visual stimulation (i.e., neurovascular coupling), and hypercapnia. To test this hypothesis, twenty older (64±8y; mean±SD) and ten young (30±5y) subjects underwent a visual stimulation (VS) and a hypercapnic test. Blood velocity through the posterior (PCA) and middle cerebral (MCA) arteries was measured concurrently using transcranial Doppler ultrasound. Cerebral and systemic vascular stiffness were calculated from the cerebral blood velocity and systemic blood pressure waveforms, respectively. Cerebrovascular (MCA: young=76±15%, older=98±19%, p=0.004; PCA: young=80±16%, older=106±17%, p< 0.001) and systemic (young=59±9% and older=80±9%, p< 0.001) augmentation indices (AI) were higher in the older group. CBF responses to VS (PCA: p< 0.026) and hypercapnia (PCA: p≤0.018; MCA: p≤0.042) were lower in the older group. A curvilinear model fitted to cerebral AI and age showed AI increases until ~60 years of age, after which the increase levels off (PCA: R2=0.45, p< 0.001; MCA: R2=0.31, p< 0.001). Finally, MCA, but not PCA, hypercapnic reactivity was inversely related to cerebral AI (MCA: R2=0.28, p=0.002; PCA: R2=0.10, p=0.104). A similar inverse relationship was not observed with the PCA blood flow response to VS (R2=0.06, p=0.174). In conclusion, older subjects had reduced neurovascular- and hypercapnia-mediated CBF responses. Furthermore, lower hypercapnia-mediated blood flow responses through the MCA were associated with increased vascular stiffness. These findings suggest the reduced hypercapnia-evoked CBF responses through the MCA, in older individuals may be secondary to vascular stiffening.