Matched increases in cerebral artery shear stress, irrespective of stimulus, induce similar changes in extra-cranial arterial diameter in humans.

The mechanistic role of arterial shear stress in the regulation of cerebrovascular responses to physiological stimuli (exercise and hypercapnia) is poorly understood. We hypothesised that, if shear stress is a key regulator of arterial dilation, then matched increases in shear, induced by distinct physiological stimuli, would trigger similar dilation of the large extra-cranial arteries. Participants ( n = 10) participated in three 30-min experimental interventions, each separated by ≥48 h: (1) mild-hypercapnia (FICO2:∼0.045); (2) submaximal cycling (EX; 60%HRreserve); or (3) resting (time-matched control, CTRL). Blood flow, diameter, and shear rate were assessed (via Duplex ultrasound) in the internal carotid and vertebral arteries (ICA, VA) at baseline, during and following the interventions. Hypercapnia and EX produced similar elevations in blood flow and shear rate through the ICA and VA ( p < 0.001), which were both greater than CTRL. Vasodilation of ICA and VA diameter in response to hypercapnia (5.3 ± 0.8 and 4.4 ± 2.0%) and EX (4.7 ± 0.7 and 4.7 ± 2.2%) were similar, and greater than CTRL ( p < 0.001). Our findings indicate that matched levels of shear, irrespective of their driving stimulus, induce similar extra-cranial artery dilation. We demonstrate, for the first time in humans, an important mechanistic role for the endothelium in regulating cerebrovascular response to common physiological stimuli in vivo

Chemoreflex Mediated Arrhythmia during Apnea at 5050m in Low but not High Altitude Natives

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P &lt; 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir −39 ± 18 beats/min; P &lt; 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P &lt; 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir −10 ± 14 beats/min; P &lt; 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P &lt; 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW &amp; NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings. </jats:p

Role of Cerebral Blood Flow in Extreme Breath Holding

The role of cerebral blood flow (CBF) on a maximal breath-hold (BH) in ultra-elite divers was examined. Divers (n = 7) performed one control BH, and one BH following oral administration of the non-selective cyclooxygenase inhibitor indomethacin (1.2 mg/kg). Arterial blood gases and CBF were measured prior to (baseline), and at BH termination. Compared to control, indomethacin reduced baseline CBF and cerebral delivery of oxygen (CDO(2)) by about 26% (p < 0.01). Indomethacin reduced maximal BH time from 339 ± 51 to 319 ± 57 seconds (p = 0.04). In both conditions, the CDO(2) remained unchanged from baseline to the termination of apnea. At BH termination, arterial oxygen tension was higher following oral administration of indomethacin compared to control (4.05 ± 0.45 vs. 3.44 ± 0.32 kPa). The absolute increase in CBF from baseline to the termination of apnea was lower with indomethacin (p = 0.01). These findings indicate that the impact of CBF on maximal BH time is likely attributable to its influence on cerebral H(+) washout, and therefore central chemoreceptive drive to breathe, rather than to CDO(2)

Severe hypoxaemic hypercapnia compounds cerebral oxidative–nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function

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 &gt; 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 &gt; v) and global cerebral blood flow (P = 0.034 to &lt;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

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 carbon dioxide 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, following a 30-second 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 the 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-minute steady state and transient 30-second hypercapnic tests (both +9mmHg CO2). Internal carotid artery dilation was lower in the transient, compared to the 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 the transient (time: 16.8±13.2s vs. 59.4±60.3s; P<0.01) and steady state (time: 18.2±14.2s vs. 110.3±79.6s; P<0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient (r(2)=0.44; P<0.01), but not steady state (r(2)=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

Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: implications for cerebral bioenergetic function

We examined to what extent apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox-regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (6 men, 4 women) performed two maximal dry apnoeas preceded by, [1] normoxic normoventilation resulting in severe end-apnoea hypoxaemic hypercapnia and [2] hyperoxic hyperventilation designed to ablate hypoxaemia resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (A·-, electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (NO, tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (gCBF, 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 = &lt;0.001). Apnoea generally increased gCBF (all P = &lt;0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015 to 0.044). This was associated with a general net cerebral output (v&gt;a) of A·- that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite (〖"NO" 〗_"2" ^"-" ) uptake (a&gt;v) and gCBF (P = 0.034 to &lt;0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of NO consistent with elevated cerebral oxidative-nitrosative stress (OXNOS). In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P = &gt;0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral OXNOS

Trans-cerebral HCO3- and PCO2 exchange during acute respiratory acidosis and exercise-induced metabolic acidosis in humans

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO(3)(−)]) and carbon dioxide tension (PCO(2)) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO(2) (PaCO(2)) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO(3)(−)] increased by 0.15 ± 0.05 mmol ⋅ l(−1) per mmHg elevation in PaCO(2) across a wide physiological range (35 to 60 mmHg PaCO(2); P < 0.001). The narrowing of the venous-arterial [HCO(3)(−)] and PCO(2) differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO(3)(−)] exchange (CBF × venous-arterial [HCO(3)(−)] difference) was reduced indicating a shift from net release toward net uptake of [HCO(3)(−)] (P = 0.004). Arterial [HCO(3)(−)] was reduced by −0.48 ± 0.15 mmol ⋅ l(−1) per nmol ⋅ l(−1) increase in arterial [H(+)] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO(3)(−)] difference and arterial [H(+)] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO(3)(−)] exchange was unaltered throughout exercise when indexed against arterial [H(+)] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO(3)(−)] – during acute respiratory/exercise-induced metabolic acidosis, respectively – differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO(3)(−)] exchange)

UBC‐nepal expedition: Phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude

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 nine‐day ascent to 5050m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400m (‐30.3 ± 21.6%; P < 0.01) and 4371m (‐14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modeling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximate 100 mL · min−1 (∼17‐34%) lower CBF 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 5050m. 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