Kevin W. Wildfong

Impact of transient hypotension on regional cerebral blood flow in humans.

We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow (CBF) and intracranial velocities. Participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities (transcranial Doppler; TCD), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery (ICA) and vertebral artery (VA) blood flow (ICABF and VABF respectively) were also obtained. Overall, blood pressure was reduced by ~20% from baseline in both trials (P<0.001). In the isocapnic trial, end-tidal carbon dioxide was successfully clamped at baseline with hypotension, whereas in the poikilocapnic trial it was reduced by 11.1 mmHg (P<0.001) with hypotension. The decline in the ICABF with hypotension was comparable between trials (-139 ± 82 ml; ~30%; P<0.0001); however, the decline in the VABF was -28 ± 22 ml/min (~21%) greater in the poikilocapnic trial compared with the isocapnic trial (P=0.002). Regardless of trial, the blood flow reductions in ICA (-26 ± 14%) and VA (-27 ± 14%) were greater than the decline in MCA (-21 ± 15%) and PCA (-19 ± 10%) velocities respectively (P ≤ 0.01). Significant reductions in the diameter of both the ICA (~5%) and the VA (~7%) contributed to the decline in cerebral perfusion with systemic hypotension, independent of hypocapnia. In summary, our findings indicate that blood flow in the VA, unlike the ICA, is sensitive to changes hypotension and hypocapnia. We show for the first time that the decline in global CBF with hypotension is influenced by arterial constriction in the ICA and VA. Additionally, our findings suggest TCD measures of blood flow velocity may modestly underestimate changes in CBF during hypotension with and without hypocapnia, particularly in the posterior circulation.

Indomethacin‐induced impairment of regional cerebrovascular reactivity: implications for respiratory control

Anterior and posterior cerebral circulations have differential reactivity to changes in arterial blood gases, but the implications for the chemoreflex control of breathing are unclear. Indomethacin‐induced blunting of cerebrovascular flow responsiveness did not affect central or peripheral respiratory chemoreflex magnitude using steady‐state end‐tidal forcing techniques. Posterior reactivity was related to hypoxic ventilatory decline, suggesting that CO2 washout from central chemoreceptors modulates hypoxic ventilatory dynamics. Our data indicate that steady‐state end‐tidal forcing techniques reduce the arterial–venous gradients, attenuating the effect of brain blood flow on ventilatory responses. Our study confirms the importance of measuring posterior cerebrovasculature when investigating the link between cerebral blood flow and the chemical control of breathing.

Impact of hypocapnia and cerebral perfusion on orthostatic tolerance

Vasovagal syncope (a common form of fainting) is frequently associated with excessive breathing and leads to reductions in carbon dioxide (hypocapnia) and cerebral hypoperfusion. The prevention of hypocapnia during orthostatic stress has been shown to improve orthostatic tolerance, but it still remains to be quantified in a larger population, with a more sustained orthostatic stress. Resting brain blood flow has been shown to impact orthostatic tolerance; however, the importance of resting brain blood flow per se in the pathophysiology of vasovagal syncope has not been clearly explicated. Our findings show that cerebral hypoperfusion either at rest or induced by hypocapnia at pre‐syncope do not impact on orthostatic tolerance, probably due to a compensatory increase in oxygen extraction of the brain.

Shear-mediated dilation of the internal carotid artery occurs independent of hypercapnia

Evidence for shear stress as a regulator of carotid artery dilation in response to increased arterial CO2 was recently demonstrated in humans during sustained elevations in CO2 (hypercapnia); however, the relative contributions of CO2 and shear stress to this response remains unclear. We examined the hypothesis that, after a 30-s transient increase in arterial CO2 tension and consequent increase in internal carotid artery shear stress, internal carotid artery diameter would increase, indicating shear-mediated dilation, in the absence of concurrent hypercapnia. In 27 healthy participants, partial pressures of end-tidal O2 and CO2, ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), internal carotid artery flow, diameter, and shear stress (high-resolution duplex ultrasound), and middle cerebral artery blood velocity (transcranial Doppler) were measured during 4-min steady-state and transient 30-s hypercapnic tests (both +9 mmHg CO2). Internal carotid artery dilation was lower in the transient compared with steady-state hypercapnia (3.3 ± 1.9 vs. 5.3 ± 2.9%, respectively, P < 0.03). Increases in internal carotid artery shear stress preceded increases in diameter in both transient (time: 16.8 ± 13.2 vs. 59.4 ± 60.3 s, P < 0.01) and steady-state (time: 18.2 ± 14.2 vs. 110.3 ± 79.6 s, P < 0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient (r2 = 0.44, P < 0.01) but not steady-state (r2 = 0.02, P = 0.53) trial. Collectively, these results suggest that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans. This study further promotes the application and development of hypercapnia as a clinical strategy for the assessment of cerebrovascular vasodilatory function and health in humans.NEW & NOTEWORTHY Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2 test, and is strongly correlated to shear area under the curve. Assessing carotid shear-mediated dilation may provide a future avenue for assessing cerebrovascular health and the risk of cerebrovascular events.

Carbon dioxide‐mediated vasomotion of extra‐cranial cerebral arteries in humans: a role for prostaglandins?

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.

Role of CO2 in the cerebral hyperemic response to incremental normoxic and hyperoxic exercise

Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2 ); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end-tidal Po2(PetO2 ) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (V̇e) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While V̇ewas uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, V̇ewas increased to prevent PetCO2 from rising above resting values (∼40 mmHg). Although PetCO2 differed by 2 ± 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (∼12-15%) and extracranial (15-20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (∼17-29%) were greater compared with poikilocapnic normoxia (∼8-20%) at intensities >40% Wmax(P< 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2.

Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans

Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end-tidal gases were comparable (P > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.

Extra- and intracranial blood flow regulation during the cold pressor test: influence of age

We determined how the extra- and intracranial circulations respond to generalized sympathetic activation evoked by a cold pressor test (CPT) and whether this is affected by healthy aging. Ten young [23 ± 2 yr (means ± SD)] and nine older (66 ± 3 yr) individuals performed a 3-min CPT by immersing the left foot into 0.8 ± 0.3°C water. Common carotid artery (CCA) and internal carotid artery (ICA) diameter, velocity, and flow were simultaneously measured (duplex ultrasound) along with middle cerebral artery and posterior cerebral artery mean blood velocity (MCAvmean and PCAvmean) and cardiorespiratory variables. The increases in heart rate (~6 beats/min) and mean arterial blood pressure (~14 mmHg) were similar in young and older groups during the CPT (P < 0.01 vs. baseline). In the young group, the CPT elicited an ~5% increase in CCA diameter (P < 0.01 vs. baseline) and a tendency for an increase in CCA flow (~12%, P = 0.08); in contrast, both diameter and flow remained unchanged in the older group. Although ICA diameter was not changed during the CPT in either group, ICA flow increased (~8%, P = 0.02) during the first minute of the CPT in both groups. Whereas the CPT elicited an increase in MCAvmean and PCAvmean in the young group (by ~20 and ~10%, respectively, P < 0.01 vs. baseline), these intracranial velocities were unchanged in the older group. Collectively, during the CPT, these findings suggest a differential mechanism(s) of regulation between the ICA compared with the CCA in young individuals and a blunting of the CCA and intracranial responses in older individuals.NEW & NOTEWORTHY Sympathetic activation evoked by a cold pressor test elicits heterogeneous extra- and intracranial blood vessel responses in young individuals that may serve an important protective role. The extra- and intracranial responses to the cold pressor test are blunted in older individuals.

Cerebrovascular response to the cold pressor test – the critical role of carbon dioxide

What is the central question of this study? What is the role of carbon dioxide in the cerebral blood flow (CBF) response to the cold pressor test (CPT)? What is the main finding and its importance? The CBF response was elevated during the isocapnic (controlled CO2) CPT in the middle cerebral artery and the internal carotid artery compared with the poikilocapnic (uncontrolled CO2) CPT, owing to ventilation‐associated reductions in end‐tidal CO2. Furthermore, the common carotid artery vasodilated to a greater extent during the isocapnic compared with the poikilocapnic CPT, whereas the internal carotid artery vasoconstricted during both CPTs. Our data highlight the importance of CO2 control when investigating the CBF response to the CPT.

Acute hypoxaemia and vascular function in healthy humans

What is the central question of this study? Endothelium‐dependent flow‐mediated dilatation (FMD) is impaired during acute (60 min) exposure to moderate hypoxia. We examined whether FMD is impaired to the same degree during exposure to milder hypoxia. Additionally, we assessed whether smooth muscle vasodilatory capacity [glyceryl trinitrate (GTN)‐induced dilatation] is impaired during acute hypoxic exposure. What is the main finding and its importance? A graded impairment in FMD and GTN‐induced dilatation was evident during acute (≤60 min) exposure to mild and moderate hypoxia. This study is the first to document these graded impairments, and provides rationale to examine the relationship between graded increases in sympathetic nerve activity with hypoxia on FMD and GTN‐induced dilatation.