Morten Overgaard

Blood flow in internal carotid and vertebral arteries during orthostatic stress

It remains unclear whether orthostatic stress evokes regional differences in cerebral blood flow. The present study compared blood flow in the internal carotid (ICA) and vertebral arteries (VA) during orthostatic stress (60 deg head‐up tilt; HUT) in six healthy young men. The ICA and VA blood flow were measured using Doppler ultrasonography. Dynamic cerebral autoregulation was also determined during supine (Supine) and HUT conditions, from the rate of regulation (RoR) in cerebrovascular conductance of the ICA and VA during acute hypotension induced by the release of bilateral thigh‐cuffs. The HUT decreased ICA blood flow by −9.4 ± 1.7% (P < 0.01 versus Supine), leaving ICA conductance unchanged. In contrast, there was no significant difference in VA blood flow between Supine and HUT, and VA conductance increased (+12.9 ± 0.8%, P < 0.01). In addition, dynamic cerebral autoregulation in both the ICA and VA was attenuated during HUT, and the magnitude of the attenuation in RoR was greater in the VA [0.25 ± 0.03 s−1 Supine versus 0.16 ± 0.02 s−1 HUT (−33.9 ± 5.8%); P < 0.05] compared with the ICA [0.23 ± 0.02 s−1 Supine versus 0.20 ± 0.03 s−1 HUT (−10.6 ± 13.4%); P > 0.05]. These data indicate that orthostatic stress evokes regional differences in cerebral blood flow and possible differences in dynamic cerebral autoregulation between two main brain vascular areas in response to an acute change in blood pressure during orthostatic stress.

The effect of phenylephrine on arterial and venous cerebral blood flow in healthy subjects

Aim:  Sympathetic regulation of the cerebral circulation remains controversial. Although intravenous phenylephrine (PE) infusion reduces the near‐infrared spectroscopy (NIRS)‐determined measure of frontal lobe oxygenation (ScO2) and increases middle cerebral artery mean blood velocity (MCA Vmean), suggesting α‐adrenergic‐mediated cerebral vasoconstriction, this remains unconfirmed by evaluation of arterial and venous cerebral blood flow.

Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain

Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1‐13C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (Fio2 10%, arterial oxygen saturation 72±10%, mean±sd). Whole‐body lactate turnover increased 3.5‐fold and 9‐fold at two workloads in normoxia and 18‐fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min−1 (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min−1 (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell‐cell lactate shuttle that may involve neurons and astrocytes.— Overgaard, M., Rasmussen, P., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P., Evans, K. A., Nielsen, H. B., Secher, N. H. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. FASEB J. 26, 3012–3020 (2012). www.fasebj.org

Non‐selective β‐adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans

Intense exercise decreases the cerebral metabolic ratio of oxygen to carbohydrates [O2/(glucose +½lactate)], but whether this ratio is influenced by adrenergic stimulation is not known. In eight males, incremental cycle ergometry increased arterial lactate to 15.3 ± 4.2 mm (mean ±s.d.) and the arterial–jugular venous (a–v) difference from −0.02 ± 0.03 mm at rest to 1.0 ± 0.5 mm (P < 0.05). The a–v difference for glucose increased from 0.7 ± 0.3 to 0.9 ± 0.1 mm (P < 0.05) at exhaustion and the cerebral metabolic ratio decreased from 5.5 ± 1.4 to 3.0 ± 0.3 (P < 0.01). Administration of a non‐selective β‐adrenergic (β1+β2) receptor antagonist (propranolol) reduced heart rate (69 ± 8 to 58 ± 6 beats min−1) and exercise capacity (239 ± 42 to 209 ± 31 W; P < 0.05) with arterial lactate reaching 9.4 ± 3.6 mm. During exercise with propranolol, the increase in a–v lactate difference (to 0.5 ± 0.5 mm; P < 0.05) was attenuated and the a–v glucose difference and the cerebral metabolic ratio remained at levels similar to those at rest. Together with the previous finding that the cerebral metabolic ratio is unaffected during exercise with administration of the β1‐receptor antagonist metropolol, the present results suggest that the cerebral metabolic ratio decreases in response to a β2‐receptor mechanism.

Effect of heat stress on cardiac output and systemic vascular conductance during simulated hemorrhage to presyncope in young men

During moderate actual or simulated hemorrhage, as cardiac output decreases, reductions in systemic vascular conductance (SVC) maintain mean arterial pressure (MAP). Heat stress, however, compromises the control of MAP during simulated hemorrhage, and it remains unknown whether this response is due to a persistently high SVC and/or a low cardiac output. This study tested the hypothesis that an inadequate decrease in SVC is the primary contributing mechanism by which heat stress compromises blood pressure control during simulated hemorrhage. Simulated hemorrhage was imposed via lower body negative pressure (LBNP) to presyncope in 11 passively heat-stressed subjects (increase core temperature: 1.2 ± 0.2°C; means ± SD). Cardiac output was measured via thermodilution, and SVC was calculated while subjects were normothermic, heat stressed, and throughout subsequent LBNP. MAP was not changed by heat stress but was reduced to 45 ± 12 mmHg at the termination of LBNP. Heat stress increased cardiac output from 7.1 ± 1.1 to 11.7 ± 2.2 l/min (P < 0.001) and increased SVC from 0.094 ± 0.018 to 0.163 ± 0.032 l·min(-1)·mmHg(-1) (P < 0.001). Although cardiac output at the onset of syncopal symptoms was 37 ± 16% lower relative to pre-LBNP, presyncope cardiac output (7.3 ± 2.0 l/min) was not different than normothermic values (P = 0.46). SVC did not change throughout LBNP (P > 0.05) and at presyncope was 0.168 ± 0.044 l·min(-1)·mmHg(-1). These data indicate that in humans a cardiac output adequate to maintain MAP while normothermic is no longer adequate during a heat-stressed-simulated hemorrhage. The absence of a decrease in SVC at a time of profound reductions in MAP suggests that inadequate control of vascular conductance is a primary mechanism compromising blood pressure control during these conditions.

Pulmonary Artery and Intestinal Temperatures during Heat Stress and Cooling

PURPOSE In humans, whole body heating and cooling are used to address physiological questions where core temperature is central to the investigated hypotheses. Core temperature can be measured in various locations throughout the human body. The measurement of intestinal temperature is increasingly used in laboratory settings as well as in athletics. However, it is unknown whether intestinal temperature accurately tracks pulmonary artery blood temperature, the gold standard, during thermal stimuli in resting humans, which is the investigated hypothesis. METHODS This study compared pulmonary artery blood temperature (via thermistor in a pulmonary artery catheter) with intestinal temperature (telemetry pill) during whole body heat stress (n = 8), followed by whole body cooling in healthy humans (mean ± SD; age = 24 ± 3 yr, height = 183 ± 8 cm, mass = 78.1 ± 8.2 kg). Heat stress and subsequent cooling were performed by perfusing warm followed by cold water through a tube-lined suit worn by each subject. RESULTS Before heat stress, blood temperature (36.69°C ± 0.25°C) was less than intestinal temperature (36.96°C ± 0.21°C, P = 0.004). The increase in blood temperature after 20 min of heat stress was greater than the intestinal temperature (0.70 ± 0.24 vs 0.47 ± 0.18, P = 0.001). However, the increase in temperatures at the end of heat stress was similar between sites (blood Δ = 1.32°C ± 0.20°C vs intestinal Δ = 1.21°C ± 0.36°C, P = 0.30). Subsequent cooling decreased blood temperature (Δ = -1.03°C ± 0.34°C) to a greater extent than intestinal temperature (Δ = -0.41°C ± 0.30°C, P = 0.04). CONCLUSIONS In response to the applied thermal provocations, early temperature changes in the intestine are less than the temperature changes in pulmonary artery blood.

Nitrite and S-nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation; Relationship to Basal and Exercise Blood Flow Responses to Hypoxia

Background: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite (![Graphic][1] ) and S -nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow ( P gradients reflecting consumption (arterial>venous; P arterial; P 0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated ![Graphic][3] reduction identified as the dominant mechanism underlying hypoxic vasodilation. # Clinical Perspective {#article-title-44} [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gifBackground: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite ( ) and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680–0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Nitrite and S -Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral CirculationClinical Perspective : Relationship to Basal and Exercise Blood Flow Responses to Hypoxia

Background: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite (![Graphic][1] ) and S -nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow ( P gradients reflecting consumption (arterial>venous; P arterial; P 0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated ![Graphic][3] reduction identified as the dominant mechanism underlying hypoxic vasodilation. # Clinical Perspective {#article-title-44} [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gifBackground: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite ( ) and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680–0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral CirculationClinical Perspective

Background: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite (![Graphic][1] ) and S -nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow ( P gradients reflecting consumption (arterial>venous; P arterial; P 0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated ![Graphic][3] reduction identified as the dominant mechanism underlying hypoxic vasodilation. # Clinical Perspective {#article-title-44} [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gifBackground: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite ( ) and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680–0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.