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Spaceflight-associated neuro-ocular syndrome (SANS) involves unilateral or bilateral optic disc edema, widening of the optic nerve sheath, and posterior globe flattening. Owing to posterior globe flattening, it is hypothesized that microgravity causes a disproportionate change in intracranial pressure (ICP) relative to intraocular pressure. Countermeasures capable of reducing ICP include thigh cuffs and breathing against inspiratory resistance. Owing to the coupling of central venous pressure (CVP) and intracranial pressure, we hypothesized that both ICP and CVP will be reduced during both countermeasures. In four male participants (32 ± 13 yr) who were previously implanted with Ommaya reservoirs for treatment of unrelated clinical conditions, ICP was measured invasively through these ports. Subjects were healthy at the time of testing. CVP was measured invasively by a peripherally inserted central catheter. Participants breathed through an impedance threshold device (ITD, -7 cmH

The effects of iron stores and supplementation on erythropoietic responses to moderate altitude in endurance athletes were examined. In a retrospective study, red cell compartment volume (RCV) responses to 4 wk at 2,500 m were assessed in athletes with low ( n = 9, ≤20 and ≤30 ng/mL for women and men, respectively) and normal ( n = 10) serum ferritin levels ([Ferritin]) without iron supplementation. In a subsequent prospective study, the same responses were assessed in athletes ( n = 26) with a protocol designed to provide sufficient iron before and during identical altitude exposure. The responses to a 4-wk training camp at sea level were assessed in another group of athletes ( n = 13) as controls. RCV and maximal oxygen uptake (V̇o2max) were determined at sea level before and after intervention. In the retrospective study, athletes with low [Ferritin] did not increase RCV (27.0 ± 2.9 to 27.5 ± 3.8 mL/kg, mean ± SD, P = 0.65) or V̇o2max (60.2 ± 7.2 to 62.2 ± 7.5 mL·kg−1·min−1, P = 0.23) after 4 wk at altitude, whereas athletes with normal [Ferritin] increased both (RCV: 27.3 ± 3.1 to 29.8 ± 2.4 mL/kg, P = 0.002; V̇o2max: 62.0 ± 3.1 to 66.2 ± 3.7 mL·kg−1·min−1, P = 0.003). In the prospective study, iron supplementation normalized low [Ferritin] observed in athletes exposed to altitude ( n = 14) and sea level ( n = 6) before the altitude/sea-level camp and maintained [Ferritin] within normal range in all athletes during the camp. RCV and V̇o2max increased in the altitude group but remained unchanged in the sea-level group. Finally, the increase in RCV correlated with the increase in V̇o2max [( r = 0.368, 95% confidence interval (CI): 0.059–0.612, P = 0.022]. Thus, iron deficiency in athletes restrains erythropoiesis to altitude exposure and may preclude improvement in sea-level athletic performance. NEW & NOTEWORTHY Hypoxic exposure increases iron requirements and utilization for erythropoiesis in athletes. This study clearly demonstrates that iron deficiency in athletes inhibits accelerated erythropoiesis to a sojourn to moderate high altitude and may preclude a potential improvement in sea-level athletic performance with altitude training. Iron replacement therapy before and during altitude exposure is important to maximize performance gains after altitude training in endurance athletes.

This study aimed to assess the efficacy of acute subanesthetic dosages of xenon inhalation to cause erythropoiesis and determine the effect of chronic xenon dosing on hematological parameters and athletic performance. To assess the acute effects, seven subjects breathed three subanesthetic concentrations of xenon: 30% fraction of inspired xenon (FiXe) for 20 min, 50% FiXe for 5 min, and 70% FiXe for 2 min. Erythropoietin (EPO) was measured at baseline, during, and after xenon inhalation. To determine the chronic effects, eight subjects breathed 70% FiXe for 2 min on 7 consecutive days, and EPO, total blood, and plasma volume were measured. Phase II involved assessment of 12 subjects for EPO, total blood volume, maximal oxygen uptake, and 3-km time before and after random assignment to 4 wk of xenon or sham gas inhalation. FiXe 50% and 70% stimulated an increase in EPO at 6 h [+2.3 mIU/mL; 95% confidence interval (CI) 0.1–4.5; P = 0.038] and at 192 h postinhalation (+2.9 mIU/mL; 95% CI 0.6–5.1; P = 0.017), respectively. Seven consecutive days of dosing significantly elevated plasma volume (+491 mL; 95% CI 194–789; P = 0.002). Phase II showed no significant effect on EPO, hemoglobin mass, plasma volume, maximal oxygen uptake, or 3-km time. Acute exposure to subanesthetic doses of xenon caused a consistent increase in EPO, and 7 consecutive days of xenon inhalation significantly expanded plasma volume. However, this physiological response appeared to be transient, and 4 wk of xenon inhalation did not stimulate increases in plasma volume or erythropoiesis, leaving cardiorespiratory fitness and athletic performance unchanged. NEW & NOTEWORTHY This is the first study to examine each element of the cascade by which xenon inhalation is purported to take effect, starting with measurement of the hypoxia-inducible factor effector, erythropoietin, to hemoglobin mass and blood volume and athletic performance. We found that acute exposure to xenon increased serum erythropoietin concentration, although major markers of erythropoiesis remained unchanged. While daily dosing significantly expanded plasma volume, no physiological or performance benefits were apparent following 4 wk of dosing.

This study aimed to quantify the sedative effects, detection rates, and cardiovascular responses to xenon. On 3 occasions, participants breathed xenon (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) in a nonblinded design. Sedation was monitored by a board-certified anesthesiologist. During 70% xenon, participants were also verbally instructed to operate a manual value with time-to-task failure being recorded. Beat-by-beat hemodynamics were measured continuously by ECG, photoplethysmography, and transcranial Doppler. Over 48 h postadministration, xenon was measured in blood and urine by gas chromatography-mass spectrometry. Xenon caused variable levels of sedation and restlessness. Task failure of the self-operating value occurred at 60–90 s in most individuals. Over the first minute, 50% and 70% xenon caused a substantial reduction in total peripheral resistance ( P < 0.05). All dosages caused an increase in cardiac output ( P < 0.05). By the end of xenon inhalation, slight hypertension was observed after all three doses ( P < 0.05), with an increase in middle cerebral artery velocity ( P < 0.05). Xenon was consistently detected, albeit in trace amounts, up to 3 h after all three doses of xenon inhalation in blood and urine with variable results thereafter. Xenon inhalation caused sedation incompatible with self-operation of a breathing apparatus, thus causing a potential life-threatening condition in the absence of an anesthesiologist. Yet, xenon can only be reliably detected in blood and urine up to 3 h postacute dosing. NEW & NOTEWORTHY Breathing xenon in dosages conceivable for doping purposes (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) causes an initial rapid fall in total peripheral resistance with tachycardia and thereafter a mild hypertension with elevated middle cerebral artery velocity. These dose duration intervals cause sedation that is incompatible with operating a breathing apparatus and can only be detected in blood and urine samples with a high probability for up to ~3 h.

Cerebral vasomotor reactivity (CVMR) and dynamic cerebral autoregulation (CA) are measured extensively in clinical and research studies. However, the relationship between these measurements of cerebrovascular function is not well understood. In this study, we measured changes in cerebral blood flow velocity (CBFV) and arterial blood pressure (BP) in response to stepwise increases in inspired CO2 concentrations of 3 and 6% to assess CVMR and dynamic CA in 13 healthy young adults [2 women, 32 ± 9 (SD) yr]. CVMR was assessed as percentage changes in CBFV (CVMRCBFV) or cerebrovascular conductance index (CVCi, CVMRCVCi) in response to hypercapnia. Dynamic CA was estimated by performing transfer function analysis between spontaneous oscillations in BP and CBFV. Steady-state CBFV and CVCi both increased exponentially during hypercapnia; CVMRCBFV and CVMRCVCi were greater at 6% (3.85 ± 0.90 and 2.45 ± 0.79%/mmHg) than at 3% CO2 (2.09 ± 1.47 and 0.21 ± 1.56%/mmHg, P = 0.009 and 0.005, respectively). Furthermore, CVMRCBFV was greater than CVMRCVCi during either 3 or 6% CO2 ( P = 0.017 and P < 0.001, respectively). Transfer function gain and coherence increased in the very low frequency range (0.02-0.07 Hz), and phase decreased in the low-frequency range (0.07–0.20 Hz) when breathing 6%, but not 3% CO2. There were no correlations between the measurements of CVMR and dynamic CA. These findings demonstrated influences of inspired CO2 concentrations on assessment of CVMR and dynamic CA. The lack of correlation between CVMR and dynamic CA suggests that cerebrovascular responses to changes in arterial CO2 and BP are mediated by distinct regulatory mechanisms.

The pathophysiology of acute mountain sickness and high-altitude cerebral edema, the cerebral forms of high-altitude illness, remain uncertain and controversial. Persistently elevated or pathological fluctuations in intracranial pressure are thought to cause symptoms similar to those reported by individuals suffering cerebral forms of high-altitude illness. This review first focuses on the basic physiology of the craniospinal system, including a detailed discussion of the long-term and dynamic regulation of intracranial pressure. Thereafter, we critically examine the available literature, based primarily on invasive pressure monitoring, that suggests intracranial pressure is acutely elevated at altitude due to brain swelling and/or elevated sagittal sinus pressure, but normalizes over time. We hypothesize that fluctuations in intracranial pressure occur around a slightly elevated or normal mean intracranial pressure, in conjunction with oscillations in arterial Po2 and arterial blood pressure. Then these modest fluctuations in intracranial pressure, in concert with direct vascular stretch due to dilatation and/or increased blood pressure transmission, activate the trigeminal vascular system and cause symptoms of acute mountain sickness. Elevated brain water (vasogenic edema) may be due to breakdown of the blood-brain barrier. However, new information suggests cerebral spinal fluid flux into the brain may be an important factor. Regardless of the source (or mechanisms responsible) for the excess brain water, brain swelling occurs, and a “tight fit” brain would be a major risk factor to produce symptoms; activities that produce large changes in brain volume and cause fluctuations in blood pressure are likely contributing factors.

Cross-sectional studies in athletes suggest that endurance training augments cardiovascular structure and function with apparently different phenotypes in athletic males and females. It is unclear whether the longitudinal response to endurance training leads to similar cardiovascular adaptations between sexes. We sought to determine whether males and females demonstrate similar cardiovascular adaptations to 1 yr of endurance training, matched for training volume and intensity. Twelve previously sedentary males (26 ± 7, n = 7) and females (31 ± 6, n = 5) completed 1 yr of progressive endurance training. All participants underwent a battery of tests every 3 mo to determine maximal oxygen uptake (V̇o2max) and left ventricle (LV) function and morphology (cardiac magnetic resonance imaging). Pulmonary artery catheterization was performed before and after 1 yr of training, and pressure-volume and Starling curves were constructed during decreases (lower-body negative pressure) and increases (saline infusion) in cardiac volume. Males progressively increased V̇o2max, LV mass, and mean wall thickness, before reaching a plateau from month 9 to 12 of training. In contrast, despite exactly the same training, the response in females was markedly blunted, with V̇o2max, LV mass, and mean wall thickness plateauing after only 3 mo of training. The response of LV end-diastolic volume was not influenced by sex (males +20% and females +18%). After training Starling curves were shifted upward and left, but the effect was greatest in males (interaction P = 0.06). We demonstrate for the first time clear sex differences in response to 1 yr of matched endurance training, such that the development of ventricular hypertrophy and increase in V̇o2maxin females is markedly blunted compared with males.

to the editor: We appreciate the letter by Dr. Safer and colleagues ([2][1]) and are pleased to respond. First, we would like to inform the readers that the volunteers in our study are the exact same subjects as described by Hastings et al. ([1][2]), participating in exactly the same study

While a number of published studies exist to guide endurance athletes with the best practices regarding implementation of altitude training, a key unanswered question concerns the proper timing of return to sea level prior to major competitions. Evidence reviewed here suggests that, altogether, the deacclimatization responses of hematological, ventilatory, and biomechanical factors with return to sea level likely interact to determine the best timing for competitive performance.

Item does not contain fulltext Cerebral blood flow (CBF) is stably maintained through the combined effects of blood pressure (BP) regulation and cerebral autoregulation. Previous studies suggest that aerobic exercise training improves cardiac baroreflex function and beneficially affects BP regulation, but may negatively affect cerebral autoregulation. The purpose of this study was to reveal the impact of lifelong exercise on cardiac baroreflex function and dynamic cerebral autoregulation (CA) in older adults. Eleven Masters athletes (MA) (8 men, 3 women; mean age 73 +/- 6 yr; aerobic training >15 yr) and 12 healthy sedentary elderly (SE) (7 men, 5 women; mean age 71 +/- 6 yr) participated in this study. BP, CBF velocity (CBFV), and heart rate were measured during resting conditions and repeated sit-stand maneuvers to enhance BP variability. Baroreflex gain was assessed using transfer function analysis of spontaneous changes in systolic BP and R-R interval in the low frequency range (0.05-0.15 Hz). Dynamic CA was assessed during sit-stand-induced changes in mean BP and CBFV at 0.05 Hz (10 s sit, 10 s stand). Cardiac baroreflex gain was more than doubled in MA compared with SE (MA, 7.69 +/- 7.95; SE, 3.18 +/- 1.29 ms/mmHg; P = 0.018). However, dynamic CA was similar in the two groups (normalized gain: MA, 1.50 +/- 0.56; SE, 1.56 +/- 0.42% CBFV/mmHg; P = 0.792). These findings suggest that lifelong exercise improves cardiac baroreflex function, but does not alter dynamic CA. Thus, beneficial effects of exercise training on BP regulation can be achieved in older adults without compromising dynamic regulation of CBF.

Sedentary aging leads to increased cardiovascular stiffening, which can be ameliorated by sufficient amounts of lifelong exercise training. An even more extreme form of cardiovascular stiffening can be seen in heart failure with preserved ejection fraction (HFpEF), which comprises ∼40∼50% of elderly patients diagnosed with congestive heart failure. There are two major interrelated hypotheses proposed to explain heart failure in these patients: 1) increased left ventricular (LV) diastolic stiffness and 2) increased arterial stiffening. The beat-to-beat dynamic Starling mechanism, which is impaired with healthy human aging, reflects the interaction between ventricular and arterial stiffness and thus may provide a link between these two mechanisms underlying HFpEF. Spectral transfer function analysis was applied between beat-to-beat changes in LV end-diastolic pressure (LVEDP; estimated from pulmonary artery diastolic pressure with a right heart catheter) and stroke volume (SV) index. The dynamic Starling mechanism (transfer function gain between LVEDP and the SV index) was impaired in HFpEF patients ( n = 10) compared with healthy age-matched controls ( n = 12) (HFpEF: 0.23 ± 0.10 ml·m−2·mmHg−1 and control: 0.37 ± 0.11 ml·m−2·mmHg−1, means ± SD, P = 0.008). There was also a markedly increased (3-fold) fluctuation of LV filling pressures (power spectral density of LVEDP) in HFpEF patients, which may predispose to pulmonary edema due to intermittent exposure to higher pulmonary capillary pressure (HFpEF: 12.2 ± 10.4 mmHg2 and control: 3.8 ± 2.9 mmHg2, P = 0.014). An impaired dynamic Starling mechanism, even more extreme than that observed with healthy aging, is associated with marked breath-by-breath LVEDP variability and may reflect advanced ventricular and arterial stiffness in HFpEF, possibly contributing to reduced forward output and pulmonary congestion.

Bed rest deconditioning leads to physiological cardiac atrophy, which may compromise left ventricular (LV) filling during orthostatic stress by reducing diastolic untwisting and suction. To test this hypothesis, myocardial-tagged magnetic resonance imaging (MRI) was performed, and maximal untwisting rates of the endocardium, midwall, and epicardium were calculated by Harmonic Phase Analysis (HARP) before and after -6 degrees head-down tilt bed rest for 18 days with (n = 14) and without exercise training (n = 10). LV mass and LV end-diastolic volume were measured using cine MRI. Exercise subjects cycled on a supine ergometer for 30 min, three times per day at 75% maximal heart rate (HR). After sedentary bed rest, there was a significant reduction in maximal untwisting rates of the midwall (-46.8 +/- 14.3 to -35.4 +/- 12.4 degrees /s; P = 0.04) where untwisting is most reliably measured, and to a lesser degree of certainty in the endocardium (-50.3 +/- 13.8 to -40.1 +/- 18.5 degrees /s; P = 0.09); the epicardium was unchanged. In contrast, when exercise was performed in bed, untwisting rates were enhanced at the endocardium (-48.4 +/- 20.8 to -72.3 +/- 22.3 degrees /ms; P = 0.05) and midwall (-39.2 +/- 12.2 to -59.0 +/- 19.6 degrees /s; P = 0.03). The differential response was significant between groups at the endocardium (interaction P = 0.02) and the midwall (interaction P = 0.004). LV mass decreased in the sedentary group (156.4 +/- 30.3 to 149.5 +/- 27.9 g; P = 0.07), but it increased slightly in the exercise-trained subjects (156.4 +/- 34.3 to 162.3 +/- 40.5 g; P = 0.16); (interaction P = 0.03). We conclude that diastolic untwisting is impaired following sedentary bed rest. However, exercise training in bed can prevent the physiological cardiac remodeling associated with bed rest and preserve or even enhance diastolic suction.

To evaluate the effect of intermittent hypobaric hypoxia combined with sea level training on exercise economy, 23 well-trained athletes (13 swimmers, 10 runners) were assigned to either hypobaric hypoxia (simulated altitude of 4,000–5,500 m) or normobaric normoxia (0–500 m) in a randomized, double-blind design. Both groups rested in a hypobaric chamber 3 h/day, 5 days/wk for 4 wk. Submaximal economy was measured twice before (Pre) and after (Post) the treatment period using sport-specific protocols. Economy was estimated both from the relationship between oxygen uptake (V̇o2) and speed, and from the absolute V̇o2at each speed using sport-specific protocols. V̇o2was measured during the last 60 s of each (3–4 min) stage using Douglas bags. Ventilation (V̇e), heart rate (HR), and capillary lactate concentration ([La−]) were measured during each stage. Velocity at maximal V̇o2(velocity at v̇o2max) was used as a functional indicator of changes in economy. The average V̇o2for a given speed of the Pre values was used for Post test comparison using a two-way, repeated-measures ANOVA. Typical error of measurement of V̇o2was 4.7% (95% confidence limits 3.6–7.1), 3.6% (2.8–5.4), and 4.2% (3.2–6.9) for speeds 1, 2, and 3, respectively. There was no change in economy within or between groups (ANOVA interaction P = 0.28, P = 0.23, and P = 0.93 for speeds 1, 2, and 3). No differences in submaximal HR, [La−], V̇e, or velocity at V̇o2maxwere found between groups. It is concluded that 4 wk of intermittent hypobaric hypoxia did not improve submaximal economy in this group of well-trained athletes.

This double-blind, randomized, placebo-controlled trial examined the effects of 4 wk of resting exposure to intermittent hypobaric hypoxia (IHE, 3 h/day, 5 days/wk at 4,000–5,500 m) or normoxia combined with training at sea level on performance and maximal oxygen transport in athletes. Twenty-three trained swimmers and runners completed duplicate baseline time trials (100/400-m swims, or 3-km run) and measures for maximal oxygen uptake (V̇O2max), ventilation (V̇Emax), and heart rate (HRmax) and the oxygen uptake at the ventilatory threshold (V̇O2at VT) during incremental treadmill or swimming flume tests. Subjects were matched for sex, sport, performance, and training status and divided randomly between hypobaric hypoxia (Hypo, n = 11) and normobaric normoxia (Norm, n = 12) groups. All tests were repeated within the first (Post1) and third weeks (Post2) after the intervention. Time-trial performance did not improve in either group. We could not detect a significant difference between groups for a change in V̇O2max, V̇Emax, HRmax, or V̇O2at VT after the intervention (group × test interaction P = 0.31, 0.24, 0.26, and 0.12, respectively). When runners and swimmers were considered separately, Hypo swimmers appeared to increase V̇O2max(+6.2%, interaction P = 0.07) at Post2 following a precompetition taper and increased V̇O2at VT (+8.9 and +12.1%, interaction P = 0.007 and 0.006, at Post1 and Post2). We conclude that this “dose” of IHE was not sufficient to improve performance or oxygen transport in this heterogeneous group of athletes. Whether there are potential benefits of this regimen for specific sports or training/tapering strategies may require further study.

Foreign and soluble gas rebreathing methods are attractive for determining cardiac output (Q̇c) because they incur less risk than traditional invasive methods such as direct Fick and thermodilution. We compared simultaneously obtained Q̇c measurements during rest and exercise to assess the accuracy and precision of several rebreathing methods. Q̇c measurements were obtained during rest (supine and standing) and stationary cycling (submaximal and maximal) in 13 men and 1 woman (age: 24 ± 7 yr; height: 178 ± 5 cm; weight: 78 ± 13 kg; V̇o2max: 45.1 ± 9.4 ml·kg−1·min−1; mean ± SD) using one-N2O, four-C2H2, one-CO2 (single-step) rebreathing technique, and two criterion methods (direct Fick and thermodilution). CO2 rebreathing overestimated Q̇c compared with the criterion methods (supine: 8.1 ± 2.0 vs. 6.4 ± 1.6 and 7.2 ± 1.2 l/min, respectively; maximal exercise: 27.0 ± 6.0 vs. 24.0 ± 3.9 and 23.3 ± 3.8 l/min). C2H2 and N2O rebreathing techniques tended to underestimate Q̇c (range: 6.6–7.3 l/min for supine rest; range: 16.0–19.1 l/min for maximal exercise). Bartlett's test indicated variance heterogeneity among the methods ( P < 0.05), where CO2 rebreathing consistently demonstrated larger variance. At rest, most means from the noninvasive techniques were ±10% of direct Fick and thermodilution. During exercise, all methods fell outside the ±10% range, except for CO2 rebreathing. Thus the CO2 rebreathing method was accurate over a wider range (rest through maximal exercise), but was less precise. We conclude that foreign gas rebreathing can provide reasonable Q̇c estimates with fewer repeat trials during resting conditions. During exercise, these methods remain precise but tend to underestimate Q̇c. Single-step CO2 rebreathing may be successfully employed over a wider range but with more measurements needed to overcome the larger variability.

This study tested the hypothesis that athletes exposed to 4 wk of intermittent hypobaric hypoxia exposure (3 h/day, 5 days/wk at 4,000–5,500 m) or double-blind placebo increase their red blood cell volume (RCV) and hemoglobin mass (Hbmass) secondary to an increase in erythropoietin (EPO). Twenty-three collegiate level athletes were measured before (Pre) and after (Post) the intervention for RCV via Evans blue (EB) dye and in duplicate for Hbmassusing CO rebreathing. Hematological indexes including EPO, soluble transferrin receptor, and reticulocyte parameters were measured on 8–10 occasions spanning the intervention. The subjects were randomly divided among hypobaric hypoxia (Hypo, n = 11) and normoxic (Norm, n = 12) groups. Apart from doubling EPO concentration 3 h after hypoxia there was no increase in any of the measures for either Hypo or Norm groups. The mean change in RCV from Pre to Post for the Hypo group was 2.3% (95% confidence limits = −4.8 to 9.5%) and for the Norm group was −0.2% (−5.7 to 5.3%). The corresponding changes in Hbmasswere 1.0% (−1.3 to 3.3%) for Hypo and −0.3% (−2.6 to 3.1%) for Norm. There was good agreement between blood volume (BV) from EB and CO: EB BV = 1.03 × CO BV + 142, r2= 0.85, P < 0.0001. Overall, evidence from four independent techniques (RCV, Hbmass, reticulocyte parameters, and soluble transferrin receptor) suggests that INTERMITTENT HYPOBARIC HYPOXIA EXPOSURE did not accelerate erythropoiesis despite the increase in serum EPO.

To engage in this debate we will address the following questions: what is the change in performance after adaptation to living high and training low (LHTL); what physiological mechanisms could be responsible; what is the evidence that a change in red cell volume (RCV) is one such mechanism; and what

Aging results in marked abnormalities of cardiovascular regulation. Regular exercise can improve many of these age-related abnormalities. However, it remains unclear how much exercise is optimal to achieve this improvement or whether the elderly can ever improve autonomic control by exercise training to a degree similar to that observed in healthy young individuals. Ten healthy sedentary seniors [71 ± 3 (SD) yr] trained for 12 mo; training involved progressive increases in volume and intensity. Static hemodynamics were measured, and R-wave-R-wave interval (RRI), beat-to-beat blood pressure (BP) variability, and transfer function gain between systolic BP and RRI were calculated at baseline and every 3 mo during training. Data were compared with those obtained in 12 Masters athletes (68 ± 3 yr) and 11 healthy sedentary young individuals (29 ± 6 yr) at baseline. Additionally, the adaptation of these variables after completion of identical training loads was compared between the seniors and the young. Indexes of RRI variability and baroreflex gain were decreased in the sedentary seniors but preserved in the Masters athletes compared with the young at baseline. With training in the seniors, baroreflex gain and resting BP showed a peak adaptation after moderate doses of training following 3–6 mo. Indexes of RRI variability continued to improve with increasing doses of training and increased to the same magnitude as the young at baseline after heavy doses of training for 12 mo; however, baroreflex gain never achieved values equivalent to the young at baseline, even after a year of training. The magnitude of the adaptation of these variables to identical training loads was similar (no interaction effects of age × training) between the seniors and the young. Thus RRI variability in seniors improves with increasing “dose” of exercise over 1 yr of training. In contrast, more moderate doses of training for 3–6 mo may optimally improve baroreflex sensitivity, associated with a modest hypotensive effect; however, higher doses of training do not lead to greater enhancement of these changes. Seniors retain a similar degree of “trainability” as young subjects for cardiac autonomic function to dynamic exercise.

This study was designed to test the hypothesis that intermittent normobaric hypoxia at rest is a sufficient stimulus to elicit changes in physiological measures associated with improved performance in highly trained distance runners. Fourteen national-class distance runners completed a 4-wk regimen (5:5-min hypoxia-to-normoxia ratio for 70 min, 5 times/wk) of intermittent normobaric hypoxia (Hyp) or placebo control (Norm) at rest. The experimental group was exposed to a graded decline in fraction of inspired O2: 0.12 ( week 1), 0.11 ( week 2), and 0.10 ( weeks 3 and 4). The placebo control group was exposed to the same temporal regimen but breathed fraction of inspired O2of 0.209 for the entire 4 wk. Subjects were matched for training history, gender, and baseline measures of maximal O2uptake and 3,000-m time-trial performance in a randomized, balanced, double-blind design. These parameters, along with submaximal treadmill performance (economy, heart rate, lactate, and ventilation), were measured in duplicate before, as well as 1 and 3 wk after, the intervention. Hematologic indexes, including serum concentrations of erythropoietin and soluble transferrin receptor and reticulocyte parameters (flow cytometry), were measured twice before the intervention, on days 1, 5, 10, and 19 of the intervention, and 10 and 25 days after the intervention. There were no significant differences in maximal O2uptake, 3,000-m time-trial performance, erythropoietin, soluble transferrin receptor, or reticulocyte parameters between groups at any time. Four weeks of a 5:5-min normobaric hypoxia exposure at rest for 70 min, 5 days/wk, is not a sufficient stimulus to elicit improved performance or change the normal level of erythropoiesis in highly trained runners.

This study tested the hypothesis that head-down tilt bed rest (HDBR) reduces adrenergic and nonadrenergic cutaneous vasoconstrictor responsiveness. Additionally, an exercise countermeasure group was included to identify whether exercise during bed rest might counteract any vasoconstrictor deficits that arose during HDBR. Twenty-two subjects underwent 14 days of strict 6° HDBR. Eight of these 22 subjects did not exercise during HDBR, while 14 of these subjects exercised on a supine cycle ergometer for 90 min a day at 75% of pre-bed rest heart rate maximum. To assess α-adrenergic vasoconstrictor responsiveness, intradermal microdialysis was used to locally administer norepinephrine (NE), while forearm skin blood flow (SkBF; laser-Doppler flowmetry) was monitored over microdialysis membranes. Nonlinear regression modeling was used to identify the effective drug concentration that caused 50% of the cutaneous vasoconstrictor response (EC50) and minimum values from the SkBF-NE dose-response curves. In addition, the effects of HDBR on nonadrenergic cutaneous vasoconstriction were assessed via the venoarteriolar response of the forearm and leg. HDBR did not alter EC50 or the magnitude of cutaneous vasoconstriction to exogenous NE administration regardless of whether the subjects exercised during HDBR. Moreover, HDBR did not alter the forearm venoarteriolar response in either the control or exercise groups during HDBR. However, HDBR significantly reduced the magnitude of cutaneous vasoconstriction due to the venoarteriolar response in the leg, and this response was similarly reduced in the exercise group. These data suggest that HDBR does not alter cutaneous vasoconstrictor responses to exogenous NE administration, whereas cutaneous vasoconstriction of the leg due to the venoarteriolar response is reduced after HDBR. It remains unclear whether attenuated venoarteriolar responses in the lower limbs contribute to reduced orthostatic tolerance after bed rest and spaceflight.

Animal studies suggest that nitric oxide (NO) plays an important role in buffering short-term arterial pressure variability, but data from humans addressing this hypothesis are scarce. We evaluated the effects of NO synthase (NOS) inhibition on arterial blood pressure (BP) variability in eight healthy subjects in the supine position and during 60° head-up tilt (HUT). Systemic NOS was blocked by intravenous infusion of N G-monomethyl-l-arginine (l-NMMA). Electrocardiogram and beat-by-beat BP in the finger (Finapres) were recorded continuously for 6 min, and brachial cuff BP was recorded before and after l-NMMA in each body position. BP and R-R variability and their transfer functions were quantified by power spectral analysis in the low-frequency (LF; 0.05–0.15 Hz) and high-frequency (HF; 0.15–0.35 Hz) ranges.l-NMMA infusion increased supine BP (systolic, 109 ± 4 vs. 122 ± 3 mmHg, P = 0.03; diastolic, 68 ± 2 vs. 78 ± 3 mmHg, P = 0.002), but it did not affect supine R-R interval or BP variability. Beforel-NMMA, HUT decreased HF R-R variability ( P= 0.03), decreased transfer function gain (LF, 12 ± 2 vs. 5 ± 1 ms/mmHg, P = 0.007; HF, 18 ± 3 vs. 3 ± 1 ms/mmHg, P = 0.002), and increased LF BP variability ( P < 0.0001). After l-NMMA, HUT resulted in similar changes in BP and R-R variability compared with tilt without l-NMMA. Increased supine BP afterl-NMMA with no effect on BP variability during HUT suggests that tonic release of NO is important for systemic vascular tone and thus steady-state arterial pressure, but NO does not buffer dynamic BP oscillations in humans.

Unlike quadrupeds, the legs of humans are regularly exposed to elevated pressures relative to the arms. We hypothesized that this “dependent hypertension” would be associated with altered adrenergic responsiveness. Isoproterenol (0.75–24 ng · 100 ml limb volume−1 · min−1) and phenylephrine (0.025–0.8 μg · 100 ml limb volume−1 · min−1) were infused incrementally in the brachial and femoral arteries of 12 normal volunteers; changes in limb blood flow were quantified by using strain-gauge plethysmography. Compared with the forearm, baseline calf vascular resistance was greater (38.8 ± 2.5 vs. 26.9 ± 2.0 mmHg · 100 ml · min · ml−1; P < 0.001) and maximal conductance was lower (46.1 ± 11.9 vs. 59.4 ± 13.4 ml · ml−1 · min−1 · mmHg−1; P < 0.03). Vascular conductance did not differ between the two limbs during isoproterenol infusions, whereas decreases in vascular conductance were greater in the calf than the forearm during phenylephrine infusions ( P < 0.001). With responses normalized to maximal conductance, the half-maximal response for phenylephrine was significantly less for the calf than the forearm ( P < 0.001), whereas the half-maximal response for isoproterenol did not differ between limbs. We conclude that α1- but not β-adrenergic-receptor responsiveness in human limbs is nonuniform. The relatively greater response to α1-adrenergic-receptor stimulation in the calf may represent an adaptive mechanism that limits blood pooling and capillary filtration in the legs during standing.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 ( n = 5) and 12 ( n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 ± 2.2% ( P = 0.005) after 6 wk with an additional atrophy of 7.6 ± 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 ± 12.2 vs. 153.4 ± 12.1 g, P = 0.81). Mean wall thickness decreased (4 ± 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 ± 1.7% ( P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 ± 2.7% ( P = 0.06) and RV end-diastolic volume by 16 ± 7.9% ( P = 0.06). After spaceflight, LV mass decreased by 12 ± 6.9% ( P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.

Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 ± 0.16 ml · 100 ml−1 · min−1) relative to 1-G supine conditions (1.94 ± 0.19 ml · 100 ml−1 · min−1, P = 0.01), and arterial pressure tended to increase ( P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 ± 4 units; in-flight: 83 ± 13 units; P < 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight ( P > 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the “upright set-point” hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance.

Whole body heating in humans increases skin blood flow (SkBF) and decreases central venous pressure (CVP). This study sought to identify whether elevations in SkBF are augmented during passive heating if CVP is increased during the heat stress. Seven subjects were exposed to passive heating. Once SkBF was substantially elevated, 15 ml/kg warm saline were rapidly infused intravenously. Whole body heating significantly increased cutaneous vascular conductance and decreased CVP from 7.7 ± 0.6 to 4.9 ± 0.5 mmHg ( P < 0.05). Saline infusion returned CVP to pre-heat-stress pressures (7.9 ± 0.6 mmHg; P > 0.05) and significantly increased cutaneous vascular conductance relative to the period before saline administration. Moreover, saline infusion did not alter mean arterial pressure, pulse pressure, or esophageal temperature (all P > 0.05). To serve as a volume control, 15 ml/kg saline were rapidly infused intravenously in normothermic subjects. Saline infusion increased CVP ( P < 0.05) without affecting mean arterial pressure, pulse pressure, or cutaneous vascular conductance (all P > 0.05). These data suggest that cardiopulmonary baroreceptor unloading during passive heating may attenuate the elevation in SkBF in humans, whereas loading cardiopulmonary baroreceptors in normothermia has no effect on SkBF.

Zhang, Rong, Julie H. Zuckerman, James A. Pawelczyk, and Benjamin D. Levine. Effects of head-down-tilt bed rest on cerebral hemodynamics during orthostatic stress. J. Appl. Physiol. 83(6): 2139–2145, 1997.—Our aim was to determine whether the adaptation to simulated microgravity (μG) impairs regulation of cerebral blood flow (CBF) during orthostatic stress and contributes to orthostatic intolerance. Twelve healthy subjects (aged 24 ± 5 yr) underwent 2 wk of −6° head-down-tilt (HDT) bed rest to simulate hemodynamic changes that occur when humans are exposed to μG. CBF velocity in the middle cerebral artery (transcranial Doppler), blood pressure, cardiac output (acetylene rebreathing), and forearm blood flow were measured at each level of a ramped protocol of lower body negative pressure (LBNP; −15, −30, and −40 mmHg × 5 min, −50 mmHg × 3 min, then −10 mmHg every 3 min to presyncope) before and after bed rest. Orthostatic tolerance was assessed by using the cumulative stress index (CSI; mmHg × minutes) for the LBNP protocol. After bed rest, each individual’s orthostatic tolerance was reduced, with the group CSI decreased by 24% associated with greater decreases in cardiac output and greater increases in systemic vascular resistance at each level of LBNP. Before bed rest, mean CBF velocity decreased by 14, 10, and 45% at −40 mmHg, −50 mmHg, and maximal LBNP, respectively. After bed rest, mean velocity decreased by 16% at −30 mmHg and by 21, 35, and 39% at −40 mmHg, −50 mmHg, and maximal LBNP, respectively. Compared with pre-bed rest, post-bed-rest mean velocity was less by 11, 10, and 21% at −30, −40, and −50 mmHg, respectively. However, there was no significant difference at maximal LBNP. We conclude that cerebral autoregulation during orthostatic stress is impaired by adaptation to simulated μG as evidenced by an earlier and greater fall in CBF velocity during LBNP. We speculate that impairment of cerebral autoregulation may contribute to the reduced orthostatic tolerance after bed rest.

The cardiovascular system appears to adapt well to microgravity but is compromised on reestablishment of gravitational forces leading to orthostatic intolerance and a reduction in work capacity. However, maximal systemic oxygen uptake (Vo2) and transport, which may be viewed as a measure of the functional integrity of the cardiovascular system and its regulatory mechanisms, has not been systematically measured in space or immediately after return to Earth after spaceflight. We studied six astronauts (4 men and 2 women, age 35–50 yr) before, during, and immediately after 9 or 14 days of microgravity on two Spacelab Life Sciences flights (SLS-1 and SLS-2). Peak Vo2 (Vo2peak) was measured with an incremental protocol on a cycle ergometer after prolonged submaximal exercise at 30 and 60% of Vo2peak. We measured gas fractions by mass spectrometer and ventilation via turbine flowmeter for the calculation of breath-by-breath Vo2, heart rate via electrocardiogram, and cardiac output (Qc) via carbon dioxide rebreathing. Peak power and Vo2 were well maintained during spaceflight and not significantly different compared with 2 wk preflight. Vo2peak was reduced by 22% immediately postflight (P < 0.05), entirely because of a decrease in peak stroke volume and Qc. Peak heart rate, blood pressure, and systemic arteriovenous oxygen difference were unchanged. We conclude that systemic Vo2peak is well maintained in the absence of gravity for 9–14 days but is significantly reduced immediately on return to Earth, most likely because of reduced intravascular blood volume, stroke volume, and Qc.

Orthostatic intolerance occurs commonly after spaceflight, and important aspects of the underlying mechanisms remain unclear. We studied 14 individuals supine and standing before and after three space shuttle missions of 9-14 days. After spaceflight, 9 of the 14 (64%) crew members could not complete a 10-min stand test that all completed preflight. Pre- and postflight supine hemodynamics were similar in both groups except for slightly higher systolic and mean arterial pressures preflight in the finishers [15 +/- 3.7 and 8 +/- 1.2 (SE) mmHg, respectively; P < 0.05]. Postflight, finishers and nonfinishers had equally large postural reductions in stroke volume (-47 +/- 3.7 and -48 +/- 3.3 ml, respectively) and increases in heart rate (35 +/- 6.6 and 51 +/- 5.2 beats/min, respectively). Cardiac output during standing was also similar (3.6 +/- 0.4 and 4.1 +/- 0.3 l/min, respectively). However, the finishers had a greater postflight vasoconstrictor response with higher total peripheral resistance during standing (22.3 +/- 1.2 units preflight and 29.4 +/- 2.3 units postflight) than did the nonfinishers (20.1 +/- 1.1 units preflight and 19.9 +/- 1.4 units postflight). We conclude that 1) the primary systemic hemodynamic event, i.e., the postural decrease in stroke volume, was similar in finishers and nonfinishers and 2) the heart rate response and cardiac output during standing were not significantly different, but 3) the postural vasoconstrictor response was significantly greater among the finishers (P < 0.01).

To examine the role of barometric pressure in high-altitude pulmonary edema, we randomly exposed five unanesthetized chronically instrumented sheep with lung lymph fistulas in a decompression chamber to each of three separate conditions: hypobaric hypoxia, normobaric hypoxia, and normoxic hypobaria. A combination of slow decompression and/or simultaneous adjustment of inspired PO2 provided three successive stages of simulated altitudes of 2,600, 4,600, and 6,600 m during which hemodynamics and lymph flow were monitored. Under both hypoxic conditions we noted significant and equivalent elevations in pulmonary arterial pressure (Ppa), cardiac output, and heart rate, with left atrial and systemic pressures remaining fairly constant. Normoxic hypobaria was also accompanied by a smaller but significant rise in Ppa. Lymph flow increased to a highly significant maximum of 73% above base line, accompanied by a slight but significant decrease in lung lymph-to-plasma protein ratio, only under conditions of combined hypobaric hypoxia but not under equivalent degrees of alveolar hypoxia or hypobaria alone. Arterial hypoxemia was noted under all three conditions, with arterial PO2 being uniformly lower under hypobaric conditions than when identical amounts of inspired PO2 were delivered at normal atmospheric pressure. We therefore hypothesize that alveolar pressure significantly alters the Starling forces governing transcapillary fluid flux in the lung and may affect the alveolar-arterial gradient for O2 as well.