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Static apneas performed after an overnight fast as opposed to postprandially have been evinced to improve apneic performance. However, no study has explored the effect of dietary intake on apneic performance, cardiovascular or splenic responses over a series of repeated apneas. Ten healthy adults attended the laboratory on three separate occasions (≥48-h apart): after a 14-h fast (F14), 1 h postconsumption of a high-calorie, high-carbohydrate (HCHC) meal, or 1 h postconsumption of a low-calorie, low-carbohydrate (LCLC)-based meal. During each visit, the subjects performed a hyperoxic rebreathing trial and a series of three repeated maximal static apneas. Heart rate, peripheral oxyhemoglobin saturation (SpO2 ), and gas exchange were monitored continuously, whereas splenic volume (SV) and hematology were assessed after the rebreathing and apneas. At rest, after HCHC, the respiratory exchange ratio (0.87 ± 0.17, P ≤ 0.043), expired minute volume of carbon dioxide (CO2; HCHC, 0.35 ± 0.09 L/min, P ≤ 0.014), and SV (227 ± 45 mL, P ≤ 0.031) were higher compared with F14 (0.71 ± 0.08; 0.23 ± 0.04 L/min; 204 ± 49 mL) and LCLC (0.72 ± 0.07; 0.25 ± 0.03 L/min; 199 ± 49 mL). A faster CO2 accumulation was recorded during the HCHC (96 ± 35 s) rebreathing trial (F14, 162 ± 42 s, P = 0.001; LCLC, 151 ± 23 s, P = 0.002). Longer apneas were reported in F14 compared with HCHC (apneas 1-3, P ≤ 0.046) and LCLC (apneas 2-3, P ≤ 0.006). After the first apnea, SV was lower in F14 (141 ± 43 mL, P = 0.015) compared with HCHC (180 ± 34 mL). Moreover, after the third apnea, end-tidal partial pressure of oxygen and nadir SpO2 were lower in F14 (8.6 ± 2.2 kPa, P = 0.028; 77 ± 13%, P = 0.009) compared with HCHC (10.1 ± 1.7 kPa; 84 ± 9%). No differences were measured in end-apneic end-tidal partial pressure of CO2, heart rate nor hematology across diets. Fasting improved apneic performance with apneas being terminated at lower oxygen levels through altering the rate of CO2 accumulation but without affecting the cardiovascular responses. [ABSTRACT FROM AUTHOR]

Acclima(tiza)tion to heat or hypoxia enhances work capacity in hot and hypoxic environmental conditions, respectively; an acclimation response is considered to be mediated by stimuli-specific molecular/systemic adaptations and potentially facilitated by the addition of exercise sessions. Promising findings at the cellular level provided the impetus for recent studies investigating whether acclimation to one stressor will ultimately facilitate whole body performance when exercise is undertaken in a different environmental condition. The present critical Mini-Review examines the theory of cross-adaptation between heat and hypoxia with particular reference to the determinants of aerobic performance. Indeed, early functional adaptations (improved exercise economy and enhanced oxyhemoglobin saturation) succeeded by later morphological adaptations (increased hemoglobin mass) might aid acclimatized humans perform aerobic work in an alternative environmental setting. Longer-term acclimation protocols that focus on the specific adaptation kinetics (and further allow for the adaptation reversal) will elucidate the exact physiological mechanisms that might mediate gains in aerobic performance or explain the lack thereof. [ABSTRACT FROM AUTHOR]

Acute apnea is known to induce decreases in oxyhemoglobin desaturation (SpO2) and increases in erythropoietin concentration ([EPO]). This study examined the potential of an apnea training program to induce erythropoiesis and increase hematological parameters and exercise performance. Twenty-two male subjects were randomly divided into an apnea and control group. The apnea group performed a 6-wk apnea training program consisting of a daily series of five maximal static apneas. Before and after training, subjects visited the lab on 3 test days to perform 1) a ramp incremental test measuring VO2peak, 2) CO-rebreathing for Hbmass determination and a 3-km time trial, and 3) an apnea test protocol with continuous finger SpO2 registration. Venous blood samples were drawn before and 180 min after the apnea test for analysis of [EPO]. Minimal SpO2 reached during the apnea test protocol was 91 ± 7% pre and 82 ± 7% post apnea training. The apnea test protocol did not elicit an acute increase in [EPO] (P = 0.685) before nor after the training program. Consequently, resting [EPO] (P = 0.170), Hbmass (P = 0.134), V2peak (P = 0.796), and 3-km cycling time trial performance (P = 0.509) were not affected either. The apnea test and training protocol, consisting of five maximal static apneas, did not induce a sufficiently strong hypoxic stimulus to cause erythropoiesis and therefore did not result in an increase in resting [EPO], Hbmass, V2peak, or time trial performance. Longer and/or more intense training sessions inducing a stronger hypoxic stimulus are probably needed to obtain changes in hematological and exercise parameters. [ABSTRACT FROM AUTHOR]

Nearinfrared diffuse correlation spectroscopy (NIR-DCS) is an emerging technology for simultaneous measurement of skeletal muscle microvascular oxygen delivery and utilization during exercise. The extent to which NIR-DCS can track acute changes in oxygen delivery and utilization has not yet been fully established. To address this knowledge gap, 14 healthy men performed rhythmic handgrip exercise at 30% maximal voluntary contraction, with and without isolated brachial artery compression, designed to acutely reduce convective oxygen delivery to the exercising muscle. Radial artery blood flow (Duplex Ultrasound) and NIR-DCS derived variables [blood flow index (BFI), tissue oxygen saturation (StO2), and metabolic rate of oxygen (MRO2)] were simultaneously measured. During exercise, both radial artery blood flow (+51.6 ± 20.3 mL/min) and DCSderived BFI (+155.0 ± 82.2%) increased significantly (P < 0.001), whereas StO2 decreased -7.9 ± 6.2% (P = 0.002) from rest. Brachial artery compression during exercise caused a significant reduction in both radial artery blood flow (-32.0 ± 19.5 mL/min, P = 0.001) and DCS-derived BFI (-57.3 ± 51.1%, P = 0.01) and a further reduction of StO2 (-5.6 ± 3.8%, P = 0.001) compared with exercise without compression. MRO2 was not significantly reduced during arterial compression (P = 0.83) due to compensatory reductions in StO2, driven by increases in deoxyhemoglobin/myoglobin (+7.1 ± 6.1 ·M, P = 0.01; an index of oxygen extraction). Together, these proof-ofconcept data help to further validate NIR-DCS as an effective tool to assess the determinants of skeletal muscle oxygen consumption at the level of the microvasculature during exercise. [ABSTRACT FROM AUTHOR]

We hypothesize that noninvasive photoacoustic imaging can accurately measure cerebral venous oxyhemoglobin saturation (SO2) in a neonatal model of hypoxia-ischemia. In neonatal piglets, which have a skull thickness comparable to that of human neonates, we compared the photoacoustic measurement of sagittal sinus SO2 against that measured directly by blood sampling over a wide range of conditions. Systemic hypoxia was produced by decreasing inspired oxygen stepwise (i.e., 100, 21, 19, 17, 15, 14, 13, 12, 11, and 10%) with and without unilateral or bilateral ligation of the common carotid arteries to enhance hypoxiaischemia. Transcranial photoacoustic sensing enabled us to detect changes in sagittal sinus O2 saturation throughout the tested range of 5-80% without physiologically relevant bias. Despite lower cortical perfusion and higher oxygen extraction in groups with carotid occlusion at equivalent inspired oxygen, photoacoustic measurements successfully provided a robust linear correlation that approached the line of identity with direct blood sample measurements. Receiver-operating characteristic analysis for discriminating SO2 < 30% showed an area under the curve of 0.84 for the pooled group data, and 0.87, 0.91, and 0.92 for hypoxia alone, hypoxia plus unilateral occlusion, and hypoxia plus bilateral occlusion subgroups, respectively. The detection precision in this critical range was confirmed with sensitivity (87.0%), specificity (86.5%), accuracy (86.8%), positive predictive value (90.5%), and negative predictive value (81.8%) in the combined dataset. These results validate the capability of photoacoustic sensing technology to accurately monitor sagittal sinus SO2 noninvasively over a wide range and support its use for early detection of neonatal hypoxia-ischemia. NEW & NOTEWORTHY We present data to validate the noninvasive photoacoustic measurement of sagittal sinus oxyhemoglobin saturation. In particular, this paper demonstrates the robustness of this methodology during a wide range of hemodynamic and physiological changes induced by the stepwise decrease of fractional inspired oxygen to produce hypoxia and by unilateral and bilateral ligation of the common carotid arteries preceding hypoxia to produce hypoxiaischemia. This technique may be useful for diagnosing risk of neonatal hypoxic-ischemic encephalopathy. [ABSTRACT FROM AUTHOR]

Elevation of hemoglobin concentration, a common adaptive response to high-altitude hypoxia, occurs among Oromo but is dampened among Amhara highlanders of East Africa. We hypothesized that Amhara highlanders offset their smaller hemoglobin response with a vascular response. We tested this by comparing Amhara and Oromo highlanders at 3,700 and 4,000 m to their lowland counterparts at 1,200 and 1,700 m. To evaluate vascular responses, we assessed urinary levels of nitrate (NO3-) as a readout of production of the vasodilator nitric oxide and its downstream signal transducer cyclic guanosine monophosphate (cGMP), along with diastolic blood pressure as an indicator of vasomotor tone. To evaluate hematological responses, we measured hemoglobin and percent oxygen saturation of hemoglobin. Amhara highlanders, but not Oromo, had higher NO3- and cGMP compared with their lowland counterparts. NO3- directly correlated with cGMP (Amhara R² = 0.25, P < 0.0001; Oromo R² = 0.30, P < 0.0001). Consistent with higher levels of NO3- and cGMP, diastolic blood pressure was lower in Amhara highlanders. Both highland samples had apparent left shift in oxyhemoglobin saturation characteristics and maintained total oxyhemoglobin content similar to their lowland counterparts. However, deoxyhemoglobin levels were significantly higher, much more so among Oromo than Amhara. In conclusion, the Amhara balance minimally elevated hemoglobin with vasodilatory response to environmental hypoxia, whereas Oromo rely mainly on elevated hemoglobin response. These results point to different combinations of adaptive responses in genetically similar East African highlanders. [ABSTRACT FROM AUTHOR]

The purpose of this study was to analyze the cerebral oxygenation response to maximal self-paced and incremental exercise in elite Kenyan runners from the Kalenjin tribe. On two separate occasions, 15 elite Kenyan distance runners completed a 5-km time trial (TT) and a peak treadmill speed test (PTS). Changes in cerebral oxygenation were monitored via near-infrared spectroscopy through concentration changes in oxy- and deoxyhemoglobin (Δ[O2Hb] and Δ[HHb]), tissue oxygenation index (TOI), and total hemoglobin index (nTHI). During the 5-km TT (15.2 ± 0.2 min), cerebral oxygenation increased over the first half (increased Δ[O2Hb] and Δ[HHb]) and, thereafter, Δ[O2Hb] remained constant (effect size, ES = 0.33, small effect), whereas Δ[HHb] increased until the end of the trial (P < 0.05, ES = 3.13, large effect). In contrast, during the PTS, from the speed corresponding to the second ventilatory threshold, Δ[O2Hb] decreased (P < 0.05, ES = 1.51, large effect), whereas Δ[HHb] continued to increase progressively until exhaustion (P < 0.05, ES = 1.22, large effect). Last, the TOI was higher during the PTS than during the 5-km TT (P < 0.001, ES = 3.08; very large effect), whereas nTHI values were lower (P < 0.001, ES = 2.36, large effect). This study shows that Kenyan runners from the Kalenjin tribe are able to maintain their cerebral oxygenation within a stable range during a self-paced maximal 5-km time trial, but not during an incremental maximal test. This may contribute to their long-distance running success. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) is extensively applied to challenge cardiovascular and respiratory function, and to induce physiological acclimatization. The purpose of this study was to test the hypothesis that oxyhemoglobin equilibrium and tachycardiac responses during hypoxemia were enhanced after 14-day IH exposures. Normobaric-poikilocapnic hypoxia was induced with inhalation of 10% O2 for 5-6 min interspersed with 4 min recovery on eight nonsmokers. Heart rate (HR), arterial O2 saturation (SaO2), and end-tidal O2 (PETO2) were continuously monitored during cyclic normoxia and hypoxia. These variables were compared during the first and fifth hypoxic bouts between day 1 and day 14. There was a rightward shift in the oxyhemoglobin equilibrium response following 14-day IH exposures, as indicated by the greater PETO2 (an index of arterial PO2) at 50% of SaO2 on day 14 compared with day 1 [33.9 ± 1.5 vs. 28.2 ± 1.3 mmHg (P = 0.005) during the first hypoxic bout and 39.4 ± 2.4 vs. 31.4 ± 1.5 mmHg (P = 0.006) during the fifth hypoxic bout] and by the augmented gains of ΔSaO2/ΔPETO2 (i.e., deoxygenation) during PETO2 from 65 to 40 mmHg in the first (1.12 ± 0.08 vs. 0.80 ± 0.02%/mmHg, P = 0.001) and the fifth (1.76 ± 0.31 vs. 1.05 ± 0.06%/mmHg, P = 0.024) hypoxic bouts. Repetitive IH exposures attenuated (P = 0.049) the tachycardiac response to hypoxia while significantly enhancing normoxic R-R interval variability in low-frequency and high-frequency spectra without changes in arterial blood pressure at rest or during hypoxia. We conclude that 14-day IH exposures enhance arterial O2 delivery and improve vagal control of HR during hypoxic hypoxemia. [ABSTRACT FROM AUTHOR]

Central and peripheral neural regulation of swallowing and aerodigestive reflexes is unclear in human neonates. Functional near infrared spectroscopy (NIRS) is a noninvasive method to measure changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbD). Pharyngoesophageal manometry permits evaluation of aerodigestive reflexes. Modalities were combined to investigate feasibility and to test neonatal frontoparietal cortical changes during pharyngoesophageal (visceral) stimulation and/or swallowing. Ten neonates (45.6 ± 3.0 wk postmenstrual age, 4.1 ± 0.5 kg) underwent novel pharyngoesophageal manometry concurrent with NIRS. To examine esophagus-brain interactions, we analyzed cortical hemodynamic response (HDR) latency and durations during aerodigestive provocation and esophageal reflexes. Data are presented as means ± SE or percent. HDR rates were 8.84 times more likely with basal spontaneous deglutition compared with sham stimuli (P = 0.004). Of 182 visceral stimuli, 95% were analyzable for esophageal responses, 38% for HDR, and 36% for both. Of analyzable HDR (n = 70): 1) HbO concentration (μmol/l) baseline 1.5 ± 0.7 vs. 3.7 ± 0.7 poststimulus was significant (P = 0.02), 2) HbD concentration (μmol/l) between baseline 0.1 ± 0.4 vs. poststimulus -0.5 ± 0.4 was not significant (P = 0.73), and 3) hemispheric lateralization was 21% left only, 29% right only, and 50% bilateral. During concurrent esophageal and NIRS responses (n = 66): 1) peristaltic reflexes were present in 74% and HDR in 61% and 2) HDR was 4.75 times more likely with deglutition reflex vs. secondary peristaltic reflex (P = 0.016). Concurrent NIRS with visceral stimulation is feasible in neonates, and frontoparietal cortical activation is recognized. Deglutition contrasting with secondary peristalsis is related to cortical activation, thus implicating higher hierarchical aerodigestive protective functional neural networks. [ABSTRACT FROM AUTHOR]

Ultrasound Doppler and near-infrared spectroscopy (NIRS) are routinely used for noninvasive monitoring of peripheral hemodynamics in both clinical and experimental settings. However, the comparative ability of these methodologies to detect changes in microvascular and whole limb hemodynamics during pharmacological manipulation of vascular smooth muscle receptors located at varied locations within the arterial tree is unknown. Thus, in 10 healthy subjects (25 ± 2 yr), changes in resting leg blood flow (ultrasound Doppler; femoral artery) and muscle oxygenation (oxyhemoglobin oxymyoglobin; vastus lateralis) were simultaneously evaluated in response to intra-arterial infusions of phenylephrine (PE, 0.025- 0.8 μg·kg-1·min-1), BHT- 933 (2.5-40 μg·kg-1·min-1), and angiotensin II (ANG II, 0.5-8 ng·kg-1·min-1). All drugs elicited significant dose-dependent reductions in leg blood flow and oxyhemoglobin oxymyoglobin. Significant relationships were found between ultrasound Doppler and NIRS changes across doses of PE (r²=0.37±0.08), BHT-933 (r²=0.74±0.06), and ANG II (r² = 0.68 ± 0.13), with the strongest relationships evident with agonists for receptors located preferentially "downstream" in the leg microcirculation (BHT-933 and ANG II). Analyses of drug potency revealed similar EC50 between ultrasound Doppler and NIRS measurements for PE (0.06 ± 0.02 vs. 0.10 ± 0.01), BHT-933 (5.0 ± 0.9 vs. 4.5 ± 1.3), and ANG II (1.4 ± 0.8 vs. 1.3 ± 0.3). These data provide evidence that both ultrasound Doppler and NIRS track pharmacologically induced changes in peripheral hemodynamics and are equally capable of determining drug potency. However, considerable disparity was observed between agonist infusions targeting different levels of the arterial tree, suggesting that receptor landscape is an important consideration for proper interpretation of hemodynamic monitoring with these methodologies. [ABSTRACT FROM AUTHOR]

The modified Oxford maneuver is the reference standard for assessing arterial baroreflex function. The maneuver comprises a systemic bolus injection of 100 μg sodium nitroprusside (SNP) followed by 150 μg phenylephrine (PE). On the one hand, this results in an increase in oxyhemoglobin and total hemoglobin followed by a decrease within the cerebral sample volume illuminated by near-infrared spectroscopy (NIRS). On the other hand, it produces a decrease in cerebral blood flow velocity (CBFv) within the middle cerebral artery (MCA) during SNP and an increase in CBFv during PE as measured by transcranial Doppler ultrasound. To resolve this apparent discrepancy, we hypothesized that SNP dilates, whereas PE constricts, the MCA. We combined transcranial Doppler ultrasound of the right MCA with NIRS illuminating the right frontal cortex in 12 supine healthy subjects 18-24 yr old. Assuming constant O2 consumption and venous saturation, as estimated by partial venous occlusion plethysmography, we used conservation of mass (continuity) equations to estimate the changes in arterial inflow (▵ Qa) and venous outflow (▵ Qv) of the NIRS-illuminated area. Oxyhemoglobin and total hemoglobin, respectively, increased by 13.6 ± 1.6 and 15.2 ± 1.4 μmol/kg brain tissue with SNP despite hypotension and decreased by 6 ± 1 and 7 ± 1 μmol/kg with PE despite hypertension. SNP increased ▵ Qa by 0.36 ± .03 μmol.kg-1.s-1 (21.6 μmol.kg-1 .min-1), whereas CBFv decreased from 71 ± 2 to 62 ± 2 cm/s. PE decreased ▵ Qa by 0.27 ± .2 μmol.kg-1.s-1 (16.2 μmol.kg-1.min-1), whereas CBFv increased to 75 ± 3 cm/s. These results are consistent with dilation of the MCA by SNP and constriction by PE. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that acute isocapnic hypoxia results in persistent resetting of the baroreflex to higher levels of muscle sympathetic nerve activity (MSNA), which outlasts the hypoxic stimulus. Cardiorespiratory measures were recorded in humans (26 ± 1 yr; n = 14; 3 women) during baseline, exposure to 20 min of isocapnic hypoxia, and for 5 min following termination of hypoxia. The spontaneous baroreflex threshold technique was used to determine the change in baroreflex function during and following 20 min of isocapnic hypoxia (oxyhemoglobin saturation = 80%). From the spontaneous baroreflex analysis, the linear regression between diastolic blood pressure (DBP) and sympathetic burst occurrence, the T50 (DBP with a 50% likelihood of a burst occurring), and DBP error signal (DBP minus the T50) provide indexes of baroreflex function. MSNA and DBP increased in hypoxia and remained elevated during posthypoxia relative to baseline (P < 0.05). The DBP error signal became progressively less negative (i.e., smaller difference between DBP and T50) in the hypoxia and posthypoxia periods (baseline: -3.9 ± 0.8 mmHg; hypoxia: -1.4 ± 0.6 mmHg; posthypoxia: 0.2 ± 0.6 mmHg; P < 0.05). Hypoxia caused no change in the slope of the baroreflex stimulus-response curve; however, there was a shift toward higher pressures that favored elevations in MSNA, which persisted posthypoxia. Our results indicate that there is a resetting of the baroreflex in hypoxia that outlasts the stimulus and provide further explanation for the complex control of MSNA following acute hypoxia. [ABSTRACT FROM AUTHOR]

Vasomotion is defined as a spontaneous local oscillation in vascular tone whose function is unclear but may have a beneficial effect on tissue oxygenation. Optical reflectance spectroscopy and laser Doppler fluximetry provide unique insights into the possible mechanisms of vasomotion in the cutaneous microcirculation through the simultaneous measurement of changes in concentration of oxyhemoglobin ([HbO2]), deoxyhemoglobin ([Hb]), and mean blood saturation (SmbO2) along with blood volume and flux. The effect of vasomotion at frequencies <0.02 Hz attributed to endothelial activity was studied in the dorsal forearm skin of 24 healthy males. Fourier analysis identified periodic fluctuations in SmbO2 in 19 out of 24 subjects, predominantly where skin temperatures were >29.3°C (χ² = 6.19, P < 0.02). A consistent minimum threshold in SmbO2 (mean: 39.4%, range: 24.0-50.6%) was seen to precede a sudden transient surge in flux, inducing a fast rise in SmbO2. The integral increase in flux correlated with the integral increase in [HbO2] (Pearson's correlation r² = 0.50, P < 0.001) and with little change in blood volume suggests vasodilation upstream, responding to a low SmbO2 downstream. This transient surge in flux was followed by a sustained period where blood volume and flux remained relatively constant and a steady decrease in [HbO2] and equal and opposite increase in [Hb] was considered to provide a measure of oxygen extraction. A measure of this oxygen extraction has been approximated by the mean half-life of the decay in SmbO2 during this period. A comparison of the mean half-life in the 8 normal subjects [body mass index (BMI) <26.0 kg/m²] of 12.2 s and the 11 obese subjects (BMI >29.5 kg/m²) of 18.8 s was statistically significant (Mann Whitney, P < 0.004). The SmbO2 fluctuated spontaneously in this saw tooth manner by an average of 9.0% (range 4.0-16.2%) from mean SmbO2 values ranging from 30 to 52%. These observations support the hypothesis that red blood cells may act as sensors of local tissue hypoxia, through the oxygenation status of the hemoglobin, and initiate improved local perfusion to the tissue through hypoxic vasodilation. [ABSTRACT FROM AUTHOR]

The erythrocyte is proposed to play a key role in the control of local tissue perfusion via three O2-dependent signaling mechanisms: 1) reduction of circulating nitrite to vasoactive NO, 2) S-nitrosohemoglobin (SNO-Hb)-dependent vasodilatation, and 3) release of the vasodilator and sympatholytic ATP; however, their relative roles in vivo remain unclear. Here we evaluated each mechanism to gain insight into their roles in the regulation of human skeletal muscle blood flow during hypoxia and hyperoxia at rest and during exercise. Arterial and femoral venous hemoglobin O2 saturation (O2Hb), plasma and erythrocyte NO and ATP metabolites, and leg and systemic hemodynamics were measured in 10 healthy males exposed to graded hypoxia, normoxia, and graded hyperoxia both at rest and during submaximal one-legged knee-extensor exercise. At rest, leg blood flow and NO and ATP metabolites in plasma and erythrocytes remained unchanged despite large alterations in O2Hb. During exercise, however, leg and systemic perfusion and vascular conductance increased in direct proportion to decreases in arterial and venous O2Hb (r2 = 0.86-0.98; P = 0.01), decreases in venous plasma nitrite (r2 = 0.93; P < 0.01), increases in venous erythrocyte nitroso species (r2 = 0.74; P < 0.05), and to a lesser extent increases in erythrocyte SNO (r2 = 0.59; P = 0.07). No relationship was observed with plasma ATP (r2 = 0.01; P = 0.99) or its degradation compounds. These in vivo data indicate that, during low-intensity exercise and hypoxic stress, but not hypoxic stress alone, plasma nitrite consumption and formation of erythrocyte nitroso species are associated with limb vasodilatation and increased blood flow in the human skeletal muscle vasculature. [ABSTRACT FROM AUTHOR]

It was the purpose of this study to examine the effect of a priming contractile bout on oxygen uptake (Vo2) on-kinetics in highly oxidative skeletal muscle. Canine gastrocnemii (n = 12) were stimulated via their sciatic nerves (8 V, 0.2-ms duration, 50 Hz, 200-ms train) at a rate of 2 contractions/3 s (≈70% peak Vo2) for two 2-min bouts, separated by 2 mm of recovery. Blood flow was recorded with an ultrasonic flowmeter, and muscle oxygenation monitored via near-infrared spectroscopy. Compared with the first bout (bout 2 vs. bout 1), the Vo2 primary time constant (mean ± SD, 9.4 ± 2.3 vs. 12.0 ± 3.9 s) and slow component amplitude (5.9 ± 6.3 vs. 12.1 ± 9.0 ml O2∙kg wet wt-1.min-1) were significantly reduced (P <0.05) during the second bout. Blood flow on-kinetics were significantly speeded during the second bout (time constant = 7.7 ± 2.6 vs. 14.8 ± 5.8 s), and 02 extraction was greater at the onset of contractions (0.050 ± 0.030 vs. 0.020 ± 0.0 10 ml O2/ml blood). Kinetics of muscle deoxygenation were significantly slower at the onset of the second bout (7.2 ± 2.2 vs. 4.4 ± 1.2 s), while relative oxyhemoglobin concentration was elevated throughout the second bout. These results suggest that better matching of O2 delivery to Vo2 speeds Vo2 on-kinetics at this metabolic rate, but do not eliminate a potential role for enhanced metabolic activation. Additionally, altered motor unit recruitment at the onset of a second bout is not a prerequisite for reductions in the Vo2 slow-component amplitude after a priming contractile bout in canine muscle in situ. [ABSTRACT FROM AUTHOR]

A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by Nω-nitro-L-arginine methyl ester (LNAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation. [ABSTRACT FROM AUTHOR]

Rodent models of chronic intermittent hypoxia (IH) are commonly used to investigate the pathophysiological sequelae that result from hypoxic exposure in patients experiencing obstructive sleep apnea (OSA). Despite the widespread use of IH models, little attention has been paid to carefully defining the degree of oxyhemoglobin desaturation that occurs during each hypoxic period. Therefore, we developed a rapid blood sampling technique to determine the arterial blood gas changes that occur in conscious unrestrained mice during a single IH event and hypothesized that the arterial PO2 (PaO2) at the nadir level of the inspired oxygen profile causes oxyhemoglobin saturation to fall to between 80% and 90%. Mice were exposed to 120-180 cycles of IH at a rate of 60 cycles/h, and arterial blood samples were withdrawn (<3 s) at baseline and at 10-s time intervals over the course of a single IH cycle. The IH regimen caused a:decline in the fraction of inspired oxygen from room air levels to a transient nadir of 6.0 ± 0.2% over the 30-s hypoxic period. The PaO2 and arterial oxyhemoglobin saturation reached a nadir of 47 ± 2mmHg and 85 ± 2% at 30 s, respectively. Arterial PCO2 decreased to a nadir of 26 ± 2 mmHg at 30 s, associated with a rise in arterial pH to 7.46 ± 0.2. We conclude that the magnitude of oxyhemoglpbin desaturation that is induced in our murine model of IH is consistent with the degree of hypoxic stress that occurs in moderate to severe clinical OSA. [ABSTRACT FROM AUTHOR]

Thorn CE, Matcher Si, Meglinski IV, Shore AC. Is mean blood saturation a useful marker of tissue oxygenation?. Am J Physiol Heart Circ Physiol 296: H1289-Hl295, 2009. First published March 13, 2009; doi:10.1152/ajpheart.0l 192.2008.-Increasingly we are monitoring the distribution of oxygen through the microcirculation using optical techniques such as optical reflectance spectroScopy (ORS) and near-infrared spectroscopy. Mean blood oxygen saturation (SmbOZ) and tissue oxygenation index measured by these two techniques, respectively, evoke a concept of the measurement of oxygen delivery to tissue. This study aims to establish whether S[submb]O[sub2] is an appropriate indicator of tissue oxygenation. Spontaneous fluctuations in S[submb]O[sub2] observed as changes in concentration of oxyhemoglobin ([HbO[sub2]]) and. deoxyhemoglobin ([Hb]) were measured by ORS in the skin microcirculation of 30 healthy subjects (15 men, age 21-42 yr). Fourier analysis identified two distinctly different spontaneous falls in S[submb]O[sub2]. The first type of swing, thought to be induced by fluctuations in arterial blood volume, resulted from the effects of respiration, endothelial, sympathetic, and myogenic activity. There Was no apparent change in [Hbi. In contrast, a second type of swing resulted from a fall in [HbO[sub2]] accompanied by a rise in [Hb] and was only induced by endothelial and sympathetic activity. Thus the same fall in S[submb]O[sub2] can be induced by two distinct responses. A "type I" swing does not suggest an inadequacy in oxygen delivery whereas a "type II" swing may indicate a change in oxygen delivery from blood to tissue. S[submb]O[sub2] alone cannot therefore be accepted as a definitive marker of tissue oxygenation. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the, acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (S1) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in S1 [4.1 vs. 3.4 (mU/l)-1·min-1; p = 0.0179] and SG (1.9 vs. 1.3 min-1 × 10-2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition (P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion. [ABSTRACT FROM AUTHOR]

A decrease in hemoglobin affinity for oxygen is considered an adaptive mechanism against tissue hypoxia. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by recurrent episodes of apnea and hypopnea resulting in arterial oxygen desaturations during sleep. Maillard et al. (10) observed a right shift of the oxyhemoglobin dissociation curve (ODC) and an increase in 2,3-diphosphoglycerate (2,3-DPG) concentration ([2,3-DPG]) in 15 patients with severe OSAHS, but some had slight daytime arterial hypoxemia while breathing room air. The aim of our study was to measure the ODC and 2,3-DPG concentrations in a group of subjects normoxemic during daytime referred to our sleep laboratory for suspicion of snoring or OSAHS. The patients were recruited during a period of 6 mo. All arterial and venous blood samples were taken early in the morning within 1 h of awakening following a full-night polysomnography. ODC and 2,3-DPG were analyzed in 88 patients: 56 OSAHS (oxygen desaturation index: 27.5 ± 24.5) and 32 non-OSAHS. We found a significant correlation between the P50 and 2,3-DPG levels in the 88 patients: r = 0.502, P < 0.001. We observed no difference between OSAHS and non-OSAHS for the P50 and for [2,3-DPG]. There was no correlation between the severity of OSAHS and either P50 or [2,3-DPG]. Finally, there was no change in these parameters measured at baseline, after 3 days and after 1 mo of treatment by nasal continuous positive airway pressure in 7 patients with OSAHS. We conclude that patients with OSAHS who are normoxemic during daytime have comparable oxyhemoglobin affinity than nonapneic subjects. [ABSTRACT FROM AUTHOR]

Nitrite reacts with deoxyhemoglobin to generate nitric oxide (NO). This reaction has been proposed to contribute to nitrite-dependent vasodilation in vivo and potentially regulate physiological hypoxic vasodilation. Paradoxically, while deoxyhemoglobin can generate NO via nitrite reduction, both oxyhemoglobin and deoxyhemoglobin potently scavenge NO. Furthermore, at the very low O2 tensions required to deoxygenate cell-free hemoglobin solutions in aortic ring bioassays, surprisingly low doses of nitrite can be reduced to NO directly by the blood vessel, independent of the presence of hemoglobin; this makes assessments of the role of hemoglobin in the bioactivation of nitrite difficult to characterize in these systems. Therefore, to study the O2 dependence and ability of deoxhemoglobin to generate vasodilatory NO from nitrite, we performed full factorial experiments of oxyhemoglobin, deoxyhemoglobin, and nitrite and found a highly significant interaction between hemoglobin deoxygenation and nitrite-dependent vasodilation (P ⩽ 0.0002). Furthermore, we compared the effect of hemoglobin oxygenation on authentic NO-dependent vasodilation using a NONOate NO donor and found that there was no such interaction, i.e., both oxyhemoglobin and deoxyhemoglobin inhibited NO-mediated vasodilation. Finally, we showed that another NO scavenger, 2-carboxyphenyl-4,4-5,5-tetramethylimidazoline-1-oxyl-3-oxide, inhibits nitrite-dependent vasodilation under normoxia and hypoxia, illustrating the uniqueness of the interaction of nitrite with deoxyhemoglobin. While both oxyhemoglobin and deoxyhemoglobin potently inhibit NO, deoxyhemoglobin exhibits unique functional duality as an NO scavenger and nitrite-dependent NO generator, suggesting a model in which intravascular NO homeostasis is regulated by a balance between NO scavenging and NO generation that is dynamically regulated by hemoglobin's O2 fractional saturation and allosteric nitrite reductase activity. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that the extent of the decrement in VO2max and the respiratory response seen during maximal exercise in moderate hypobaric hypoxia (H; simulated 2,500 m) is affected by the hypoxia ventilatory and hypercapnia ventilatory responses (HVR and HCVR, respectively). Twenty men (5 untrained subjects, 7 long distance runners, 8 middle distance runners) performed incremental exhaustive running tests in H and normobaric normoxia (N) condition. During the running test; VO2, pulmonary ventilation (VE) and arterial oxyhemoglobin saturation (SaO2) were measured, and in two ventilatory response tests performed during N, a rebreathing method was used to evaluate HVR and HCVR. Mean HVR and HCVR were 0.36 ± 0.04 and 2.11 ± 0.2 l·min-1· mmHg-1, respectively. HVR correlated significantly with the percent decrements in VO2max (%dVO2max), SaO2 [%dSaO2 = (N—H)·N-1 100], and Ve/VO2 seen during H condition. By contrast, HCVR did not correlate with any of the variables tested. The increment in maximal VE between H and N significantly correlated with %dVO2max. Our findings suggest that O2 chemosensitivity plays a significant role in determining the level of exercise hyperventilation during moderate hypoxia; thus, a higher O2 chemosensitivity was associated with a smaller drop in VO2max and SaO2 under those conditions. [ABSTRACT FROM AUTHOR]

Oxyhemoglobin (OxyHb) can suppress voltage-dependent K+ channel (Kv) currents through protein tyrosine kinase activation, which may contribute to cerebral vasospasm following subarachnoid hemorrhage. Here we have tested the hypothesis that shedding of heparin-binding EGF-like growth factor (HB-EGF) and the resulting activation of the tyrosine kinase EGF receptor (EGFR) underlie OxyHb-induced Kv channel suppression in the cerebral vasculature. With the use of the conventional whole cell patch-clamp technique, two EGFR ligands, EGF and HB-EGF, were found to mimic OxyHb-induced Kv suppression in rabbit cerebral artery myocytes. Kv current suppression by OxyHb or EGF ligands was eliminated by a specific EGFR inhibitor, AG-1478, but was unaffected by PKC inhibition. Compounds (heparin and CRM-197) that specifically interfere with HB-EGF signaling eliminated OxyHb-induced Kv suppression, suggesting that HB-EGF is the EGFR ligand involved in this pathway. HB-EGF exists as a precursor protein that, when cleaved by matrix metalloproteases (MMPs), causes EGFR activation. MMP activation was detected in OxyHb-treated arteries by gelatin zymography. Furthermore, the MMP inhibitor (GM-6001) abolished OxyHb-induced Kv current suppression. We also observed Kv current suppression due to EGFR activation in human cerebral artery myocytes. In conclusion, these data demonstrate that OxyHb induces MMP activation, causing HB-EGF shedding and enhanced EGFR activity, ultimately leading to Kv channel suppression. We propose that EGFR-mediated Kv suppression contributes to vascular pathologies, such as cerebral vasospasm, and may play a more widespread role in the regulation of regional blood flow and peripheral resistance. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effects of assuming constant reduced scattering coefficient (μs′) on the muscle oxygenation response to incremental exercise and its recovery kinetics. Fifteen subjects (age: 24 ± 5 yr) underwent incremental cycling exercise. Frequency domain near-infrared spectroscopy (NIRS) was used to estimate deoxyhemoglobin concentration {[deoxy(Hb+Mb)]} (where Mb is myoglobin), oxyhemoglobin concentration {[oxy(Hb+Mb)]}, total Hb concentration (Total[Hb+Mb]), and tissue O2 saturation (StiO2), incorporating both continuous measurements of μs′ and assuming constant μs′. When measuring μs′, we observed significant changes in NIRS variables at peak work rate Δ[deoxy(Hb+Mb)] (15.0 ± 7.8 μM), Δ[oxy(Hb+Mb)] (-4.8 ± 5.8 μM), ΔTotal[Hb+Mb] (10.9 ± 8.4 μM), and ΔStiO2 (-11.8 ± 4.1%). Assuming constant μs′ resulted in greater (P < 0.01 vs. measured μs′) changes in the NIRS variables at peak work rate, where Δ[deoxy(Hb+Mb)] = 24.5 ± 15.6 μM, Δ[oxy(Hb+Mb)] = -9.7 ± 8.2 μM, ΔTotal[Hb+Mb] = 14.8 ± 8.7 μM, and ΔStiO2 = -18.7 ± 8.4%. Regarding the recovery kinetics, the large 95% confidence intervals (CI) for the difference between those determine measuring μs′ and assuming constant μs′ suggested poor agreement between methods. For the mean response time (MRT), which describes the overall kinetics, the 95% confidence intervals were MRT - [deoxy(Hb+Mb)] = 26.7 s; MRT - [oxy(Hb+Mb)] = 11.8 s, and MRT - StiO2 = 11.8 s. In conclusion, μs′ changed from light to peak exercise. Furthermore, assuming a constant μs′ led to an overestimation of the changes in NIRS variables during exercise and distortion of the recovery kinetics. [ABSTRACT FROM AUTHOR]

Describes the validation of carbon monoxide (CO)-oximeter for porcine-specific oxyhemoglobin saturation. Nonlinear mathematical model of the porcine oxyhemoglobin saturation curve; Correlation of the estimate between the mathematical model and the porcine-specific CO-oximeter measurements; Need for species-specific measurement methodology.

Evaluates charged coupled devices (CCD) imaging in cryospectrophotometric determination of microvascular oxyhemoglobin saturations. Determination of basic hemoglobin spectra; Selection of mathematical model for oxyhemoglobin saturation calculations; Application of the method to tissue samples.

Examines the effects of oxyhemoglobin dissociation kinetics and diffusion facilitation by myoglobin in muscle cells in athletic and nonathletic animals at maximum oxygen consumption (VO2max). Analysis of adaptive pairs; Tissue oxygen diffusivity and solubility; Effect of pH, partial carbon dioxide and temperature on oxyhemoglobin dissociation.

Studies the mechanisms responsible for the mediation of flow-induced dilation of isolated arterioles of rat gracilis muscle. Effect of endothelium removal, indomethacin, Nomega-nitro-L-arginine and oxyhemoglobin on arterioles; Changes in diameter of rat gracilis arterioles as a function of perfusate flow.

Elevation of hemoglobin concentration, a common adaptive response to high-altitude hypoxia, occurs among Oromo but is dampened among Amhara highlanders of East Africa. We hypothesized that Amhara highlanders offset their smaller hemoglobin response with a vascular response. We tested this by comparing Amhara and Oromo highlanders at 3,700 and 4,000 m to their lowland counterparts at 1,200 and 1,700 m. To evaluate vascular responses, we assessed urinary levels of nitrate (NO 3 - ) as a readout of production of the vasodilator nitric oxide and its downstream signal transducer cyclic guanosine monophosphate (cGMP), along with diastolic blood pressure as an indicator of vasomotor tone. To evaluate hematological responses, we measured hemoglobin and percent oxygen saturation of hemoglobin. Amhara highlanders, but not Oromo, had higher NO 3 - and cGMP compared with their lowland counterparts. NO 3 - and cGMP, diastolic blood pressure was lower in Amhara highlanders. Both highland samples had apparent left shift in oxyhemoglobin saturation characteristics and maintained total oxyhemoglobin content similar to their lowland counterparts. However, deoxyhemoglobin levels were significantly higher, much more so among Oromo than Amhara. In conclusion, the Amhara balance minimally elevated hemoglobin with vasodilatory response to environmental hypoxia, whereas Oromo rely mainly on elevated hemoglobin response. These results point to different combinations of adaptive responses in genetically similar East African highlanders.2 = 0.25, P < 0.0001; Oromo R 2 = 0.30, P < 0.0001). Consistent with higher levels of NO 3 - and cGMP, diastolic blood pressure was lower in Amhara highlanders. Both highland samples had apparent left shift in oxyhemoglobin saturation characteristics and maintained total oxyhemoglobin content similar to their lowland counterparts. However, deoxyhemoglobin levels were significantly higher, much more so among Oromo than Amhara. In conclusion, the Amhara balance minimally elevated hemoglobin with vasodilatory response to environmental hypoxia, whereas Oromo rely mainly on elevated hemoglobin response. These results point to different combinations of adaptive responses in genetically similar East African highlanders., (Copyright © 2017 the American Physiological Society.)