Four weeks of repetitive acute hypoxic preconditioning did not alleviate allergen-induced airway dysfunction in rats.

Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning (RAHP) during allergic inflammation. Brown Norway rats were sensitized to house dust mites (HDM) and exposed to 4-week RAHP or normoxia (SHAM), concurrent with weekly HDM or saline (SAL) challenges. We assessed methacholine responses and lung HIF-1α expression at endpoint, and weekly blood pressure (BP). RAHP relative to SHAM: 1) in HDM-challenged rats, showed no protection against HDM-induced airway dysfunction and did not significantly impact BP (week 4 mean BP difference = 10.51 mmHg, p = 0.09) or HIF-1α expression; 2) in SAL-challenged rats, attenuated airway responses to methacholine, reduced BP (week 4 mean BP average difference = -8.72 mmHg, p = 0.04) and amplified HIF-1α expression (p = 0.0086). Four weeks of RAHP did not mitigate the allergen-induced lower airway dysfunction and may detrimentally affect BP. However, it elicited beneficial cardiopulmonary responses in SAL-challenged rats, concurrent with increased HIF-1α expression.

Blunted cardiac output response to exercise in adolescents born preterm.

PURPOSE: Premature birth is associated with lasting effects, including lower exercise capacity and pulmonary function, and is acknowledged as a risk factor for cardiovascular disease. The aim was to evaluate factors affecting exercise capacity in adolescents born preterm, including the cardiovascular and pulmonary responses to exercise, activity level and strength. METHODS: 21 preterm-born and 20 term-born adolescents (age 12-14 years) underwent strength and maximal exercise testing with thoracic bioimpedance monitoring. Baseline variables were compared between groups and ANCOVA was used to compare heart rate, cardiac output (Q) and stroke volume (SV) during exercise between groups while adjusting for body surface area. RESULTS: Preterm-borns had lower maximal aerobic capacity than term-borns (2.0 ± 0.5 vs. 2.5 ± 0.5 L/min, p = 0.01) and lower maximal power (124 ± 26 vs. 153 ± 33 watts, p < 0.01), despite similar physical activity scores. Pulmonary function and muscular strength did not differ significantly. Although baseline Q and SV did not differ between groups, preterm adolescents had significantly lower cardiac index (Qi) at 50, 75 and 100% of maximal time to exhaustion, driven by SV volume index (SVi, 50% max time: 53.0 ± 9.0 vs. 61.6 ± 11.4; 75%: 51.7 ± 8.4 vs. 64.3 ± 11.1; 100%: 51.2 ± 9.3 vs. 64.3 ± 11.5 ml/m2, all p < 0.01), with similar heart rates. CONCLUSION: Otherwise healthy and physically active adolescents born very preterm exhibit lower exercise capacity than term-born adolescents. Despite similar baseline cardiovascular values, preterm-born adolescents demonstrate significantly reduced Qi and SVi during incremental and maximal exercise.

The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia.

KEY POINTS: The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end-organ responses. Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady-state eucapnic hypoxia were measured in a cohort of 82 middle-aged individuals. Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals. It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required. Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor-driven levels of sympathetic nervous system activity and respiratory drive. ABSTRACT: Hypersensitivity of the carotid chemoreceptor leading to sympathetic nervous system activation and ventilatory instability has been implicated in the pathogenesis and consequences of several common clinical conditions. A variety of treatment approaches aimed at lessening chemoreceptor-driven sympathetic overactivity are now under investigation; thus, the ability to quantify this outcome variable with specificity and precision is crucial. Accordingly, we measured ventilatory and neurocirculatory responses to chemoreflex inhibition elicited by transient hyperoxia and chemoreflex excitation produced by exposure to graded, steady-state eucapnic hypoxia in middle-aged men and women (n = 82) with continuous positive airway pressure-treated obstructive sleep apnoea. Progressive, eucapnic hypoxia produced robust and highly variable increases in ventilation (+83 ± 59%) and muscle sympathetic nerve activity (MSNA) burst frequency (+55 ± 31%), whereas transient hyperoxia caused marked reductions in these variables (-35 ± 14% and -42 ± 16%, respectively). Coefficients of variation for ventilatory and MSNA burst frequency responses, indicating test-retest reproducibility, were respectively 9% and 24% for hyperoxia and 35% and 28% for hypoxia. Based on statistical measures of rank correlation or even comparisons across quartiles of corresponding ventilatory and MSNA responses, we found that the magnitudes of ventilatory inhibition with hyperoxia or excitation with eucapnic hypoxia were not correlated with corresponding MSNA responses within individuals. We conclude that, in conscious, behaving humans, ventilatory sensitivities to progressive, steady-state, eucapnic hypoxia and transient hyperoxia do not predict MSNA responsiveness. Our findings also support the use of transient hyperoxia as a reliable, sensitive, measure of the carotid chemoreceptor contribution to tonic sympathetic nervous system activity and respiratory drive.

Early Pulmonary Vascular Disease in Young Adults Born Preterm.

Rationale: Premature birth affects 10% of live births in the United States and is associated with alveolar simplification and altered pulmonary microvascular development. However, little is known about the long-term impact prematurity has on the pulmonary vasculature.Objectives: Determine the long-term effects of prematurity on right ventricular and pulmonary vascular hemodynamics.Methods: Preterm subjects (n = 11) were recruited from the Newborn Lung Project, a prospectively followed cohort at the University of Wisconsin-Madison, born preterm with very low birth weight (≤1,500 g; average gestational age, 28 wk) between 1988 and 1991. Control subjects (n = 10) from the same birth years were recruited from the general population. All subjects had no known adult cardiopulmonary disease. Right heart catheterization was performed to assess right ventricular and pulmonary vascular hemodynamics at rest and during hypoxic and exercise stress.Measurements and Main Results: Preterm subjects had higher mean pulmonary arterial pressures (mPAPs), with 27% (3 of 11) meeting criteria for borderline pulmonary hypertension (mPAP, 19-24 mm Hg) and 18% (2 of 11) meeting criteria for overt pulmonary hypertension (mPAP ≥ 25 mm Hg). Pulmonary vascular resistance and elastance were higher at rest and during exercise, suggesting a stiffer vascular bed. Preterm subjects were significantly less able to augment cardiac index or right ventricular stroke work during exercise. Among neonatal characteristics, total ventilatory support days was the strongest predictor of adult pulmonary pressure.Conclusions: Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.

Inspiratory and expiratory resistance cause right-to-left bubble passage through the foramen ovale.

A patent foramen ovale (PFO) is linked to increased risk of decompression illness in divers. One theory is that venous gas emboli crossing the PFO can be minimized by avoiding lifting, straining and Valsalva maneuvers. Alternatively, we hypothesized that mild increases in external inspiratory and expiratory resistance, similar to that provided by a SCUBA regulator, recruit the PFO. Nine healthy adults with a Valsalva-proven PFO completed three randomized trials (inspiratory, expiratory, and combined external loading) with six levels of increasing external resistance (2-20 cmH2 O/L/sec). An agitated saline contrast echocardiogram was performed at each level to determine foramen ovale patency. Contrary to our hypothesis, there was no relationship between the number of subjects recruiting their PFO and the level of external resistance. In fact, at least 50% of participants recruited their PFO during 14 of 18 trials and there was no difference between the combined inspiratory, expiratory, or combined external resistance trials (P > 0.05). We further examined the relationship between PFO recruitment and intrathoracic pressure, estimated from esophageal pressure. Esophageal pressure was not different between participants with and without a recruited PFO. Intrasubject variability was the most important predictor of PFO patency, suggesting that some individuals are more likely to recruit their PFO in the face of even mild external resistance. Right-to-left bubble passage through the PFO occurs in conditions that are physiologically relevant to divers. Transthoracic echocardiography with mild external breathing resistance may be a tool to identify divers that are at risk of PFO-related decompression illness.

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea.

NEW FINDINGS: What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensin II and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea. ABSTRACT: Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT1 R) blockade. Both AT1 R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25 events h-1 and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6 weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O2 tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.

Impaired autonomic function in adolescents born preterm.

Preterm birth temporarily disrupts autonomic nervous system (ANS) development, and the long-term impacts of disrupted fetal development are unclear in children. Abnormal cardiac ANS function is associated with worse health outcomes, and has been identified as a risk factor for cardiovascular disease. We used heart rate variability (HRV) in the time domain (standard deviation of RR intervals, SDRR; and root means squared of successive differences, RMSSD) and frequency domain (high frequency, HF; and low frequency, LF) at rest, as well as heart rate recovery (HRR) following maximal exercise, to assess autonomic function in adolescent children born preterm. Adolescents born preterm (less than 36 weeks gestation at birth) in 2003 and 2004 and healthy age-matched full-term controls participated. Wilcoxon Rank Sum tests were used to compare variables between control and preterm groups. Twenty-one adolescents born preterm and 20 term-born controls enrolled in the study. Preterm-born subjects had lower time-domain HRV, including SDRR (69.1 ± 33.8 vs. 110.1 ± 33.0 msec, respectively, P = 0.008) and RMSSD (58.8 ± 38.2 vs. 101.5 ± 36.2 msec, respectively, P = 0.012), with higher LF variability in preterm subjects. HRR after maximal exercise was slower in preterm-born subjects at 1 min (30 ± 12 vs. 39 ± 9 bpm, respectively, P = 0.013) and 2 min (52 ± 10 vs. 60 ± 10 bpm, respectively, P = 0.016). This study is the first report of autonomic dysfunction in adolescents born premature. Given prior association of impaired HRV with adult cardiovascular disease, additional investigations into the mechanisms of autonomic dysfunction in this population are warranted.

Chronic intermittent hypoxia worsens bleomycin-induced lung fibrosis in rats.

Obstructive sleep apnea (OSA) has been linked to increased mortality in pulmonary fibrosis. Its key feature, chronic intermittent hypoxia (CIH), can lead to oxidative stress and inflammation, known to lead to fibrotic pathology in other organs. We tested the effects of CIH in an animal model of bleomycin-induced lung fibrosis. Sprague Dawley rats were instilled intratracheally with bleomycin (Blm) or saline (Sal), and exposed to CIH or normal air (Norm) for 9 or 30 days. Pulmonary function was tested and lungs were harvested for histological and molecular analyses. In Blm-treated animals, 30days of CIH compared to Norm increased total lung collagen content (p=0.008) and reduced Quasi-static lung compliance (p=0.04). CIH upregulated lipid peroxidation and increased NF-κB activation, IL-17 mRNA and Col1α1 mRNA expression. Our results indicate that following Blm-induced lung injury, CIH amplifies collagen deposition via oxidative and inflammatory pathways, culminating in stiffer lungs. Thus, OSA may augment fibrosis in patients with interstitial lung disease.

Pulmonary Gas Exchange and Exercise Capacity in Adults Born Preterm.

RATIONALE: Preterm birth, and its often-required medical interventions, can result in respiratory and gas exchange deficits into childhood. However, the long-term sequelae into adulthood are not well understood. OBJECTIVES: To determine exercise capacity and pulmonary gas exchange efficiency during exercise in adult survivors of preterm birth. METHODS: Preterm (n = 14), very low birth weight (<1,500 g) adults (20-23 yr) and term-born, age-matched control subjects (n = 16) performed incremental exercise on a cycle ergometer to volitional exhaustion while breathing one of two oxygen concentrations: normoxia (fraction of inspired oxygen, 0.21) or hypoxia (fraction of inspired oxygen, 0.12). MEASUREMENTS AND MAIN RESULTS: Ventilation, mixed expired gases, arterial blood gases, power output, and oxygen consumption were measured during rest and exercise. We calculated the alveolar-to-arterial oxygen difference to determine pulmonary gas exchange efficiency. Preterm subjects had lower power output at volitional exhaustion than did control subjects in normoxia (150 ± 10 vs. 180 ± 10 W; P = 0.01), despite similar normoxic oxygen consumption. However, during hypoxic exercise, there was no difference in power output at volitional exhaustion between the two groups (116 ± 10 vs. 135 ± 10 W; P = 0.11). Preterm subjects also exhibited a more acidotic, acid-base balance throughout exercise compared with control subjects. In contrast to other studies, adults born preterm, as a group developed a wider alveolar-to-arterial oxygen difference and lower PaO2 than did control subjects during normoxic but not hypoxic exercise. CONCLUSIONS: This study demonstrates that pulmonary gas exchange efficiency is lower in some adult survivors of preterm birth during exercise compared with control subjects. The gas exchange inefficiency, when present, is accompanied by low arterial blood oxygen tension. Preterm subjects also exhibit reduced power output. Overall, our findings suggest potential long-term consequences of extreme preterm birth and very low birth weight on cardiopulmonary function.

Effect of body position and oxygen tension on foramen ovale recruitment.

While there is an increased prevalence of stroke at altitude in individuals who are considered to be low risk for thrombotic events, it is uncertain how venous thrombi reach the brain. The patent foramen ovale (PFO) is a recruitable intracardiac shunt between the right and left atrium. We aimed to determine whether body position and oxygen tension affect blood flow through the PFO in healthy adults. We hypothesized that hypoxia and body positions that promote right atrial filling would independently recruit the PFO. Subjects with a PFO (n = 11) performed 11 trials, combining four different fractions of inhaled oxygen (FiO2) (1.0, 0.21, 0.15, and 0.10) and three positions (upright, supine, and 45° head down), with the exception of FiO2 = 0.10, while 45° head down. After 5 min in each position, breathing the prescribed oxygen tension, saline bubbles were injected into an antecubital vein and a four-chamber echocardiogram was obtained to evaluate PFO recruitment. We observed a high incidence of PFO recruitment in all conditions, with increased recruitment in response to severe hypoxia and some contribution of body position at moderate levels of hypoxia. We suspect that increased pulmonary vascular pressure, secondary to hypoxia-induced pulmonary vasoconstriction, increased right atrial pressure enough to recruit the PFO. Additionally, we hypothesize that the minor increase in breathing resistance that was added by the mouthpiece, used during experimental trials, affected intrathoracic pressure and venous return sufficiently to recruit the PFO.

Effects of chronic intermittent hypoxia on allergen-induced airway inflammation in rats.

Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma.

Effects of stabilizing or increasing respiratory motor outputs on obstructive sleep apnea.

To determine how the obstructive sleep apnea (OSA) patient's pathophysiological traits predict the success of the treatment aimed at stabilization or increase in respiratory motor outputs, we studied 26 newly diagnosed OSA patients [apnea-hypopnea index (AHI) 42 ± 5 events/h with 92% of apneas obstructive] who were treated with O2 supplementation, an isocapnic rebreathing system in which CO2 was added only during hyperpnea to prevent transient hypocapnia, and a continuous rebreathing system. We also measured each patient's controller gain below eupnea [change in minute volume/change in end-tidal Pco2 (ΔVe/ΔPetCO2)], CO2 reserve (eupnea-apnea threshold PetCO2), and plant gain (ΔPetCO2/ΔVe), as well as passive upper airway closing pressure (Pcrit). With isocapnic rebreathing, 14/26 reduced their AHI to 31 ± 6% of control (P < 0.01) (responder); 12/26 did not show significant change (nonresponder). The responders vs. nonresponders had a greater controller gain (6.5 ± 1.7 vs. 2.1 ± 0.2 l·min(-1)·mmHg(-1), P < 0.01) and a smaller CO2 reserve (1.9 ± 0.3 vs. 4.3 ± 0.4 mmHg, P < 0.01) with no differences in Pcrit (-0.1 ± 1.2 vs. 0.2 ± 0.9 cmH2O, P > 0.05). Hypercapnic rebreathing (+4.2 ± 1 mmHg PetCO2) reduced AHI to 15 ± 4% of control (P < 0.001) in 17/21 subjects with a wide range of CO2 reserve. Hyperoxia (SaO2 ∼95-98%) reduced AHI to 36 ± 11% of control in 7/19 OSA patients tested. We concluded that stabilizing central respiratory motor output via prevention of transient hypocapnia prevents most OSA in selected patients with a high chemosensitivity and a collapsible upper airway, whereas increasing respiratory motor output via moderate hypercapnia eliminates OSA in most patients with a wider range of chemosensitivity and CO2 reserve. Reducing chemosensitivity via hyperoxia had a limited and unpredictable effect on OSA.

Hypoxia recruits intrapulmonary arteriovenous pathways in intact rats but not isolated rat lungs.

Intrapulmonary arteriovenous anastomoses (IPAVS) directly connect the arterial and venous circulations in the lung, bypassing the capillary network. Here, we used solid, latex microspheres and isolated rat lung and intact, spontaneously breathing rat models to test the hypothesis that IPAVS are recruited by alveolar hypoxia. We found that hypoxia recruits IPAVS in the intact rat, but not the isolated lung. IPAVS are at least 70 µm in the rat and, interestingly, appear to be recruited when the mixed venous Po(2) falls below 22 mmHg. These data provide evidence that large-diameter, direct arteriovenous connections exist in the lung and are recruitable by hypoxia in the intact animal.

Effect of obesity and metabolic syndrome on hypoxic vasodilation.

This study was designed to test whether obese adults and adults with metabolic syndrome (MetSyn) exhibit altered hyperemic responses to hypoxia at rest and during forearm exercise when compared with lean controls. We hypothesized blood flow responses due to hypoxia would be lower in young obese subjects (n = 11, 24 ± 2 years, BMI 36 ± 2 kg m(-2)) and subjects with MetSyn (n = 8, 29 ± 3 years BMI 39 ± 2 kg m(-2)) when compared with lean adults (n = 13, 29 ± 2 years, BMI 24 ± 1 kg m(-2)). We measured forearm blood flow (FBF, Doppler Ultrasound) and arterial oxygen saturation (pulse oximetry) during rest and steady-state dynamic forearm exercise (20 contractions/min at 8 and 12 kg) under two conditions: normoxia (0.21 F(i)O(2), ~98% S(a)O(2)) and hypoxia (~0.10 F(i)O(2), 80% S(a)O(2)). Forearm vascular conductance (FVC) was calculated as FBF/mean arterial blood pressure. At rest, the percent change in FVC with hypoxia was greater in adults with MetSyn when compared with lean controls (p = 0.02); obese and lean adult responses were not statistically different. Exercise increased FVC from resting levels in all groups (p < 0.05). Hypoxia caused an additional increase in FVC (p < 0.05) that was not different between groups; responses to hypoxia were heterogeneous within and between groups. Reporting FVC responses as absolute or percent changes led to similar conclusions. These results suggest adults with MetSyn exhibit enhanced hypoxic vasodilation at rest. However, hypoxic responses during exercise in obese adults and adults with MetSyn were not statistically different when compared with lean adults. Individual hypoxic vasodilatory responses were variable, suggesting diversity in vascular control.

Heterogeneous vascular responses to hypoxic forearm exercise in young and older adults.

We aimed to assess age-related differences in compensatory hypoxic vasodilation during moderate-to-high dynamic exercise at absolute workloads. We hypothesized healthy older adults (n = 12, 61 ± 1 years) would exhibit impaired hypoxic vasodilation at a moderate absolute workload, and this effect would be exaggerated at a higher workload when compared to young adults (n = 17, 27 ± 2 years). Forearm blood flow (FBF) was measured with Doppler ultrasound. Dynamic forearm exercise (20 contractions/min) was completed at two absolute workloads (8 and 12 kg) under normoxic (0.21 FiO2, ~98% SpO2) and isocapnic hypoxic (~0.10 FiO2, 80% SpO2) conditions performed in random order. FBF was normalized as forearm vascular conductance (FBF / mean arterial blood pressure = FVC) to control for differences in blood pressure and to assess vasodilation. FVC increased with exercise and hypoxia (main effects, p < 0.05); vascular responses were not different between young and older adults (interaction effect exercise × group p = 0.37 and hypoxia × group p = 0.96). Results were confirmed when analyzed as either an absolute or relative change in FVC (ΔFVC and %ΔFVC, respectively). Although group responses to hypoxia were not different, individual results were highly variable (i.e., some adults constricted and others dilated to hypoxia). These data suggest (1) compensatory hypoxic vasodilation in older adults is not impaired during forearm exercise at both moderate and higher absolute exercise intensities, and (2) vascular responses to hypoxia are heterogeneous in both young and older adults. Results suggest unique individual differences exist in factors regulating vascular responses to hypoxia.

Implications of group III and IV muscle afferents for high-intensity endurance exercise performance in humans.

We investigated the influence of group III/IV muscle afferents on peripheral fatigue, central motor drive (CMD) and endurance capacity during high-intensity leg-cycling. In a double-blind, placebo-controlled design, seven males performed constant-load cycling exercise (318 ± 9 W; 80% of peak power output (W(peak))) to exhaustion under placebo conditions and with lumbar intrathecal fentanyl impairing spinal µ-opioid receptor-sensitive group III/IV muscle afferents. Peripheral fatigue was assessed via changes in pre- vs. post-exercise quadriceps force in response to supramaximal magnetic femoral nerve stimulation (ΔQ(tw,pot)). CMD was estimated via quadriceps electromyogram. To rule out a direct central effect of fentanyl, we documented unchanged resting cardioventilatory responses. Compared to placebo, significant hypoventilation during the fentanyl trial was indicated by the 9% lower V(E)/V(CO(2)), causing a 5 mmHg increase in end-tidal P(CO(2)) and a 3% lower haemoglobin saturation. Arterial pressure and heart rate averaged 8 and 10% lower, respectively, during the fentanyl trial and these differences progressively diminished towards end-exercise. Although initially similar, the percent change in CMD was 9 ± 3% higher at end-exercise with fentanyl vs. placebo (P < 0.05). Time to exhaustion was shorter (6.8 ± 0.3 min vs. 8.7 ± 0.3 min) and end-exercise ΔQ(tw,pot) was about one-third greater (-44 ± 2% vs. -34 ± 2%) following fentanyl vs. placebo. The rate of peripheral fatigue development was 67 ± 10% greater during the fentanyl trial (P < 0.01). Our findings suggest that feedback from group III/IV muscle afferents limits CMD but also minimizes locomotor muscle fatigue development by stimulating adequate ventilatory and circulatory responses to exercise. In the face of blocked group III/IV muscle afferents, CMD is less inhibited but O(2) transport compromised and locomotor muscle fatigability is exacerbated with a combined net effect of a reduced endurance performance.

Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans.

We investigated the role of somatosensory feedback on cardioventilatory responses to rhythmic exercise in five men. In a double-blind, placebo-controlled design, subjects performed the same leg cycling exercise (50/100/150/325 ± 19 W, 3 min each) under placebo conditions (interspinous saline, L(3)-L(4)) and with lumbar intrathecal fentanyl impairing central projection of spinal opioid receptor-sensitive muscle afferents. Quadriceps strength was similar before and after fentanyl administration. To evaluate whether a cephalad migration of fentanyl affected cardioventilatory control centers in the brain stem, we compared resting ventilatory responses to hypercapnia (HCVR) and cardioventilatory responses to arm vs. leg cycling exercise after each injection. Similar HCVR and minor effects of fentanyl on cardioventilatory responses to arm exercise excluded direct medullary effects of fentanyl. Central command during leg exercise was estimated via quadriceps electromyogram. No differences between conditions were found in resting heart rate (HR), ventilation [minute ventilation (VE)], or mean arterial pressure (MAP). Quadriceps electromyogram, O(2) consumption (VO(2)), and plasma lactate were similar in both conditions at the four steady-state workloads. Compared with placebo, a substantial hypoventilation during fentanyl exercise was indicated by the 8-17% reduction in VE/CO(2) production (VCO(2)) secondary to a reduced breathing frequency, leading to average increases of 4-7 Torr in end-tidal PCO(2) (P < 0.001) and a reduced hemoglobin saturation (-3 ± 1%; P < 0.05) at the heaviest workload (∼90% maximal VO(2)) with fentanyl. HR was reduced 2-8%, MAP 8-13%, and ratings of perceived exertion by 13% during fentanyl vs. placebo exercise (P < 0.05). These findings demonstrate the essential contribution of muscle afferent feedback to the ventilatory, cardiovascular, and perceptual responses to rhythmic exercise in humans, even in the presence of unaltered contributions from other major inputs to cardioventilatory control.

Impact of pulmonary system limitations on locomotor muscle fatigue in patients with COPD.

We examined the effects of respiratory muscle work [inspiratory (W(r-insp)); expiratory (W(r-exp))] and arterial oxygenation (Sp(O(2))) on exercise-induced locomotor muscle fatigue in patients with chronic obstructive pulmonary disease (COPD). Eight patients (FEV, 48 +/- 4%) performed constant-load cycling to exhaustion (Ctrl; 9.8 +/- 1.2 min). In subsequent trials, the identical exercise was repeated with 1) proportional assist ventilation + heliox (PAV); 2) heliox (He:21% O(2)); 3) 60% O(2) inspirate (hyperoxia); or 4) hyperoxic heliox mixture (He:40% O(2)). Five age-matched healthy control subjects performed Ctrl exercise at the same relative workload but for 14.7 min ( approximately best COPD performance). Exercise-induced quadriceps fatigue was assessed via changes in quadriceps twitch force (Q(tw,pot)) from before to 10 min after exercise in response to supramaximal femoral nerve stimulation. During Ctrl, absolute workload (124 +/- 6 vs. 62 +/- 7 W), W(r-insp) (207 +/- 18 vs. 301 +/- 37 cmH(2)O x s x min(-1)), W(r-exp) (172 +/- 15 vs. 635 +/- 58 cmH(2)O x s x min(-1)), and Sp(O(2)) (96 +/- 1% vs. 87 +/- 3%) differed between control subjects and patients. Various interventions altered W(r-insp), W(r-exp), and Sp(O(2)) from Ctrl (PAV: -55 +/- 5%, -21 +/- 7%, +6 +/- 2%; He:21% O(2): -16 +/- 2%, -25 +/- 5%, +4 +/- 1%; hyperoxia: -11 +/- 2%, -17 +/- 4%, +16 +/- 4%; He:40% O(2): -22 +/- 2%, -27 +/- 6%, +15 +/- 4%). Ten minutes after Ctrl exercise, Q(tw,pot) was reduced by 25 +/- 2% (P < 0.01) in all COPD and 2 +/- 1% (P = 0.07) in healthy control subjects. In COPD, DeltaQ(tw,pot) was attenuated by one-third after each interventional trial; however, most of the exercise-induced reductions in Q(tw,pot) remained. Our findings suggest that the high susceptibility to locomotor muscle fatigue in patients with COPD is in part attributable to insufficient O(2) transport as a consequence of exaggerated arterial hypoxemia and/or excessive respiratory muscle work but also support a critical role for the well-known altered intrinsic muscle characteristics in these patients.

Opioid-mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans.

We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development of peripheral fatigue during high-intensity endurance exercise. In a double-blind, placebo-controlled design, eight cyclists randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5K(Plac), L3-L4) or intrathecal fentanyl (5K(Fent), L3-L4) to impair cortical projection of opioid-mediated muscle afferents. Peripheral quadriceps fatigue was assessed via changes in force output pre- versus postexercise in response to supramaximal magnetic femoral nerve stimulation (DeltaQ(tw)). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5K(Fent) versus 5K(Plac) by 12 +/- 3% (P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 +/- 2% higher during the first and 11 +/- 2% lower during the second 2.5 km of 5K(Fent) versus 5K(Plac) (both P < 0.05). Capillary blood lactate was higher (16.3 +/- 0.5 versus 12.6 +/- 1.0%) and arterial haemoglobin O(2) saturation was lower (89 +/- 1 versus 94 +/- 1%) during 5K(Fent) versus 5K(Plac). Exercise-induced DeltaQ(tw) was greater following 5K(Fent) versus 5K(Plac) (-46 +/- 2 versus -33 +/- 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive development of peripheral muscle fatigue.

Somatosensory feedback from the limbs exerts inhibitory influences on central neural drive during whole body endurance exercise.

We investigated whether somatosensory feedback from contracting limb muscles exerts an inhibitory influence on the determination of central command during closed-loop cycling exercise in which the subject voluntarily determines his second-by-second central motor drive. Eight trained cyclists performed two 5-km time trials either without (5K(Ctrl)) or with lumbar epidural anesthesia (5K(Epi); 24 ml of 0.5% lidocaine, vertebral interspace L(3)-L(4)). Percent voluntary quadriceps muscle activation was determined at rest using a superimposed twitch technique. Epidural lidocaine reduced pretime trial maximal voluntary quadriceps strength (553 +/- 45 N) by 22 +/- 3%. Percent voluntary quadriceps activation was also reduced from 97 +/- 1% to 81 +/- 3% via epidural lidocaine, and this was unchanged following the 5K(Epi), indicating the presence of a sustained level of neural impairment throughout the trial. Power output was reduced by 9 +/- 2% throughout the race (P < 0.05). We found three types of significant effects of epidural lidocaine that supported a substantial role for somatosensory feedback from the exercising limbs as a determinant of central command throughout high-intensity closed-loop cycling exercise: 1) significantly increased relative integrated EMG of the vastus lateralis; 2) similar pedal forces despite the reduced number of fast-twitch muscle fibers available for activation; 3) and increased ventilation out of proportion to a reduced carbon dioxide production and heart rate and increased blood pressure out of proportion to power output and oxygen consumption. These findings demonstrate the inhibitory influence of somatosensory feedback from contracting locomotor muscles on the conscious and/or subconscious determination of the magnitude of central motor drive during high intensity closed-loop endurance exercise.