Erythropoietin response to acute normobaric hypoxia in humans.

Hypoxia causes an increased production of erythropoietin (EPO), but the time course of the EPO response in humans has not been well characterized. This study examines the relationship between the duration of normobaric hypoxic exposure and plasma EPO levels in healthy human subjects. Six volunteers breathed a gas mixture of 10.5% O2-89.5% N2 continuously for 5, 60, and 120 or intermittently for 240 min. O2 saturations were maintained between 75 and 85% during the exposure. Arterial pH was 7.467 +/- 0.019, PO2 37.05 +/- 2.43 Torr, and PCO2 36.69 +/- 2.05 Torr. O2 half-saturation pressures of hemoglobin were normal for all subjects. Plasma EPO was measured every 30 min for 360 min by radioimmunoassay. No increase in EPO was seen after the 5- and 60-min exposures. However, a 50% increase was seen 240 min after the initiation of the 120-min hypoxic exposure (P less than 0.01). Intermittent exposure resulted in an increase of EPO by 52% 360 min after the onset of exposure (P less than 0.05). Therefore, exposing humans continuously to an inspiratory O2 fraction of 0.105 for 120 min or intermittently for 240 min provides a sufficient stimulus to increase production of EPO.     

Plasma atriopeptin response to prolonged cycling in humans.

The exercise-induced increase in plasma atriopeptin (ANP) has been related to exercise intensity. The independent effect of duration on the ANP response to dynamic exercise remains incompletely documented. The purpose of this study was to describe the time course of plasma ANP concentration during a 90-min cycling exercise protocol and to examine this in light of concurrent variations in plasma arginine vasopressin (AVP), aldosterone (ALD), and catecholamine (norepinephrine and epinephrine) concentrations as well as plasma renin activity (PRA). Seven male and four female healthy college students (23 +/- 2 yr) completed a prolonged exercise protocol on a cycle ergometer at an intensity of 67% of maximal O2 uptake. Venous blood was sampled through an indwelling catheter at rest, after 15, 30, 45, 60, and 90 min of exercise, and after 30 min of passive upright recovery. Results (means +/- SE) indicate an increase in ANP from rest (22 +/- 2.6 pg/ml) at 15 min of exercise (45.3 +/- 7.4 pg/ml) with a further increase at 30 min (59.4 +/- 9.8 pg/ml) and a leveling-off thereafter until completion of the exercise protocol (51.7 +/- 10.7 pg/ml). In plasma ALD and PRA, a significant increase was found from rest (ALD, 21.4 +/- 6.4 ng/dl), PRA, 2.5 +/- 0.5 ng.ml-1.h-1 after 30 min of cycling, which continued to increase until completion of the exercise (ALD 46.6 +/- 8.7 ng/dl, PRA 9.5 +/- 0.9 ng.ml-1.h-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Skeletal muscle proteolysis in response to short-term unloading in humans.

Skeletal muscle atrophy is evident after muscle disuse, unloading, or spaceflight and results from decreased protein content as a consequence of decreased protein synthesis, increased protein breakdown or both. At this time, there are essentially no human data describing proteolysis in skeletal muscle undergoing atrophy on Earth or in space, primarily due to lack of valid and accurate methodology. This particular study aimed at assessing the effects of short-term unloading on the muscle contractile proteolysis rate. Eight men were subjected to 72-h unilateral lower limb suspension (ULLS) and intramuscular interstitial levels of the naturally occurring proteolytic tracer 3-methylhistidine (3MH) were measured by means of microdialysis before and on completion of this intervention. The 3MH concentration following 72-h ULLS (2.01 +/- 0.22 nmol/ml) was 44% higher (P < 0.05) than before ULLS (1.56 +/- 0.20 nmol/ml). The present experimental model and the employed method determining 3MH in microdialysates present a promising tool for monitoring skeletal muscle proteolysis or metabolism of specific muscles during conditions resulting in atrophy caused by, e.g., disuse and real or simulated microgravity. This study provides evidence that the atrophic processes are evoked rapidly and within 72 h of unloading and suggests that countermeasures should be employed in the early stages of space missions to offset or prevent muscle loss during the period when the rate of muscle atrophy is the highest.     

Antioxidants attenuate the plasma cytokine response to exercise in humans.

Exercise increases plasma TNF-alpha, IL-1beta, and IL-6, yet the stimuli and sources of TNF-alpha and IL-1beta remain largely unknown. We tested the role of oxidative stress and the potential contribution of monocytes in this cytokine (especially IL-1beta) response in previously untrained individuals. Six healthy nonathletes performed two 45-min bicycle exercise sessions at 70% of Vo(2 max) before and after a combination of antioxidants (vitamins E, A, and C for 60 days; allopurinol for 15 days; and N-acetylcysteine for 3 days). Blood was drawn at baseline, end-exercise, and 30 and 120 min postexercise. Plasma cytokines were determined by ELISA and monocyte intracellular cytokine level by flow cytometry. Before antioxidants, TNF-alpha increased by 60%, IL-1beta by threefold, and IL-6 by sixfold secondary to exercise (P < 0.05). After antioxidants, plasma IL-1beta became undetectable, the TNF-alpha response to exercise was abolished, and the IL-6 response was significantly blunted (P < 0.05). Exercise did not increase the percentage of monocytes producing the cytokines or their mean fluorescence intensity. We conclude that in untrained humans oxidative stress is a major stimulus for exercise-induced cytokine production and that monocytes play no role in this process.     

Ventilatory response to high-frequency airway oscillation in humans

To investigate respiratory control during high-frequency oscillation (HFO), ventilation was monitored in conscious humans by respiratory inductive plethysmography during application at the mouth of high-frequency pressure oscillations. Studies were conducted before and after airway and pharyngeal anesthesia. During HFO, breathing became slow and deep with an increase in tidal volume (VT) of 37% (P less than 0.01) and inspiratory duration (TI) of 34% (P less than 0.01). Timing ratio (TI/TT) increased 14% (P less than 0.05) and respiratory frequency (f) decreased 12% (P less than 0.01). Mean inspiratory flow (VT/TI) did not change during HFO. Following airway anesthesia, VT increased only 26% during HFO (P less than 0.01), whereas significant changes in TI, TI/TT, and f were not observed. Pharyngeal anesthesia failed to diminish the effect of HFO on TI, TT, or f, although the increase in VT was reduced. These results indicate that 1) HFO presented in this manner alters inspiratory timing without affecting the level of inspiratory activity, and 2) receptors in the larynx and/or lower airways may in part mediate the response.     

Immediate response to resistive loading in anesthetized humans

In eight spontaneously breathing anesthetized subjects (halothane: approximately 1 minimal alveolar concn; 70% N2O-30% O2), we determined 1) the inspiratory driving pressure by analysis of the pressure developed at the airway opening (Poao) during inspiratory efforts against airways occluded at end expiration; 2) the active inspiratory impedance; and 3) the immediate (first loaded breath) response to added inspiratory resistive loads (delta R). Based on these data we made model predictions of the immediate tidal volume response to delta R. Such predictions closely fitted the experimental results. The present investigation indicates that 1) in halothane-anesthetized humans the shape of the Poao wave differs from that in anesthetized animals, 2) the immediate response to delta R is not associated with appreciable changes in intensity, shape, and timing of inspiratory neural drive but depends mainly on intrinsic (nonneural) mechanisms; 3) the flow-dependent resistance of endotracheal tubes must be taken into account in studies dealing with increased neuromuscular drive in intubated subjects; and 4) in anesthetized humans Poao reflects the driving pressure available to produce the breathing movements.     

Respiratory response to sinusoidal work load in humans

Present study was undertaken to elucidate possible distortion of phase response and amplitude response of various respiratory parameter such as VO2, VCO2 and VE to sinusoidal work load by comparing model analysis with manual analysis. Also, an attempt was made to determine whether there is any relationship between the characteristics of response of these parameters and the aerobic capacity of subjects. Six healthy male subjects were performed exercise on an electrically braked bicycle ergometer for 32 min. The work load was varied sinusoidally between 30 watts and 60% VO2max being under anaerobic threshold with periods from 1 to 16 min. These parameters were determined in breath-by-breath mode with a computer system and mass spectrometer. In model analysis, amplitude and phase responses were well described by first order exponential model, and strong correlations were observed between magnitude of phase response or time constant of amplitude response and aerobic capacity. Manual analysis revealed that respiratory responses to sinusoidal work load are not completely sinusoidal but somewhat distorted forming saw-tooth waves with steeper downslopes.     

Biomechanical response to changes in natural turf during running and turning

Integrated biomechanical and engineering assessments were used to determine how humans responded to variations in turf during running and turning. Ground reaction force (AMTI, 960 Hz) and kinematic data (Vicon Peak Motus, 120 Hz) were collected from eight participants during running (3.83 m/s) and turning (10 trials per condition) on three natural turf surfaces in the laboratory. Surface hardness (Clegg hammer) and shear strength (cruciform shear vane) were measured before and after participant testing. Peak loading rate during running was significantly higher (p < .05) on the least hard surface (sandy; 101.48 BW/s ± 23.3) compared with clay (84.67 BW/s ± 22.9). There were no significant differences in running kinematics. Compared with the "medium" condition, fifth MTP impact velocities during turning were significantly (RM-ANOVA, p < .05) lower on clay (resultant: 2.30 m/s [± 0.68] compared with 2.64 m/s [± 0.70]), which was significantly (p < .05) harder "after" and had the greatest shear strength both "before" and "after" participant testing. This unique finding suggests that further study of foot impact velocities are important to increase understanding of overuse injury mechanisms.     

Ventilatory acclimatization in response to very small changes in PO2 in humans.

Ventilatory acclimatization to hypoxia (VAH) consists of a progressive increase in ventilation and decrease in end-tidal Pco(2) (Pet(CO(2))). Underlying VAH, there are also increases in the acute ventilatory sensitivities to hypoxia and hypercapnia. To investigate whether these changes could be induced with very mild alterations in end-tidal Po(2) (Pet(O(2))), two 5-day exposures were compared: 1) mild hypoxia, with Pet(O(2)) held at 10 Torr below the subject's normal value; and 2) mild hyperoxia, with Pet(O(2)) held at 10 Torr above the subject's normal value. During both exposures, Pet(CO(2)) was uncontrolled. For each exposure, the entire protocol required measurements on 13 consecutive mornings: 3 mornings before the hypoxic or hyperoxic exposure, 5 mornings during the exposure, and 5 mornings postexposure. After the subjects breathed room air for at least 30 min, measurements were made of Pet(CO(2)), Pet(O(2)), and the acute ventilatory sensitivities to hypoxia and hypercapnia. Ten subjects completed both protocols. There was a significant increase in the acute ventilatory sensitivity to hypoxia (Gp) after exposure to mild hypoxia, and a significant decrease in Gp after exposure to mild hyperoxia (P < 0.05, repeated-measures ANOVA). No other variables were affected by mild hypoxia or hyperoxia. The results, when combined with those from other studies, suggest that Gp varies linearly with Pet(O(2)), with a sensitivity of 3.5%/Torr (SE 1.0). This sensitivity is sufficient to suggest that Gp is continuously varying in response to normal physiological fluctuations in Pet(O(2)). We conclude that at least some of the mechanisms underlying VAH may have a physiological role at sea level.     

Methodological and physiological variability within the ventilatory response to hypoxia in humans.

Measurement of the acute hypoxic ventilatory response (AHVR) requires careful choice of the hypoxic stimulus. If the stimulus is too brief, the response may be incomplete; if the stimulus is too long, hypoxic ventilatory depression may ensue. The purpose of this study was to compare three different techniques for assessing AHVR, using different hypoxic stimuli, and also to examine the between-day variability in AHVR. Ten subjects were studied, each on six different occasions, which were >/=1 wk apart. On each occasion, AHVR was assessed using three different protocols: 1) protocol SW, which uses square waves of hypoxia; 2) protocol IS, which uses incremental steps of hypoxia; and 3) protocol RB, which simulates an isocapnic rebreathing test. Mean values for hypoxic sensitivity were 1.02 +/- 0.48, 1.15 +/- 0.55, and 0.93 +/- 0.60 (SD) l. min(-1). %(-1) for protocols SW, IS, and RB, respectively. These differed significantly (P < 0.01). The coefficients of variation for measurement of AHVR were 20, 23, and 36% for the three protocols, respectively. These were not significantly different. There was a significant physiological variation in AHVR (F (50,100) = 3.9, P < 0. 001), with a coefficient of variation of 26%. We conclude that there was relatively little systematic variation between the three protocols but that AHVR varies physiologically over time.     

Nasal glandular secretory response to cholinergic stimulation in humans and guinea pigs.

A guinea pig model of nasal secretory responses was developed to assess the contributions of vascular permeability and glandular secretion responsible for the production of cholinergically stimulated nasal secretions. The nasal secretory responses to provocation with saline, methacholine, and atropine on the ipsilateral (challenged) side and contralateral (reflex) side were analyzed by measurement of total protein (Lowry method), guinea pig albumin (enzyme-linked immunosorbent assay), 125I-labeled bovine serum albumin after intravenous injection, and alkaline phosphatase enzyme activity in nasal fluid. Alkaline phosphatase was found to be localized to submucosal glands by zymography. Topical methacholine challenge increased the secretion of total protein, alkaline phosphatase activity, and albumin on the ipsilateral challenged side, whereas the percentage of total protein represented by albumin was not increased. This response was totally prevented by atropine pretreatment. Serial provocation with methacholine resulted in progressively reduced amounts of both the total protein and alkaline phosphatase in secretions. The observation that repeated challenges produced progressively smaller responses was also examined employing human nasal provocation. Repeating methacholine (25 mg) challenges four times at 10-min intervals in six human volunteers revealed that the initial challenge produced the largest response as reflected in total protein, albumin, lysozyme, lactoferrin, immunoglobulin (Ig) G, IgA, and secretory IgA secretion. When the constituents in secretions were analyzed in relationship to the total protein, the two vascular proteins, IgG and albumin, demonstrated the greatest decrements with repeated methacholine challenges. The glandular proteins, lactoferrin, lysozyme, and secretory IgA, either remained constant or increased in their relative proportion to total protein. Thus, cholinergic stimulation causes glandular secretion from both the guinea pig and human nasal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of chest wall strapping on mechanical response to methacholine in humans.

We examined the effects of chest wall strapping (CWS) on the response to inhaled methacholine (MCh) and the effects of deep inspiration (DI). Eight subjects were studied on 1 day with MCh inhaled without CWS (CTRL), 1 day with MCh inhaled during CWS (CWSon/on), and 1 day with MCh inhaled during temporary removal of CWS (CWSoff/on). On the CWSon/on day, MCh caused greater increases in pulmonary resistance, upstream resistance, dynamic elastance, residual volume, and greater decreases in maximal expiratory flow than on the CTRL day. On the CWSoff/on day, the changes in these parameters with MCh were not different from the CTRL day. Six of the subjects were again studied using the same protocol on CTRL and CWSon/on days, except that, on a third day, MCh was given after applying the CWS, but the measurements before and after the inhalation were made without CWS (CWSon/off). The latter sequence was associated with more severe airflow obstruction than during CTRL, but less than with CWSon/on. The bronchodilator effects of a DI were blunted when CWS was applied during measurements (CWSon/on and CWSoff/on) but not after it was removed (CWSon/off). We conclude that CWS is capable of increasing airway responsiveness only when it is applied during the inhalation of the constrictor agent. We speculate that breathing at low lung volumes induced by CWS enhances airway narrowing because the airway smooth muscle is adapted at a length at which the contractile apparatus is able to generate a force greater than normal.     

Pancreatic polypeptide response to ethanol in humans and dogs

We studied the effect of a drink of various concentrations of pure ethanol and several commonly ingested alcoholic beverages on plasma levels of immunoreactive pancreatic polypeptide in six healthy human volunteers and compared the results to a protein-rich meal. A drink of distilled water (250 ml) and of pure ethanol (250 ml or 125 ml in the case of 40% v/v ethanol) in concentrations (4, 10, 20, and 40%, v/v) normally present in beer, wine, liquor and whisky did not stimulate plasma pancreatic polypeptide levels above basal. Neither beer, red and white wine (250 ml each) nor whisky (125 ml) caused an increase in basal plasma pancreatic polypeptide levels. The 90-min integrated plasma pancreatic polypeptide response to the protein-rich meal was significantly reduced by an additional drink of 250 ml of white wine ($\text{5987 ± 1315}$ versus $\text{4126 ± 809}\text{pmol · min}{}^{\mathrm{?1}}\text{· 1}{}^{\mathrm{?1}}$). An intravenous infusion of ethanol (300 mg · kg^?1 over 30 min) did not increase plasma pancreatic polypeptide levels above basal.In six dogs with gastric and duodenal fistulas the infusion of pure ethanol into a peripheral vein, into the stomach or into the duodenum did not alter plasma pancreatic polypeptide levels. When ethanol (200 ml of either 1.8, 10 or 40%, v/v) was given as an intragastric bolus injection, only 40% ethanol caused an increase in the mean 90-min integrated plasma pancreatic polypeptide response which was only one-twelfth of the pancreatic polypeptide response to an oral mixed meat meal (35 g · kg^?1). We conclude that in man neither an intravenous infusion nor a drink of ethanol in concentrations normally present in beer, wine and whisky, release pancreatic polypeptide. Also, beer, red and white wine and whisky have no effect on plasma pancreatic polypeptide concentrations. In dogs, a large amount of intragastric ethanol was needed to produce a very small rise in plasma pancreatic polypeptide levels. These results do not favour the hypothesis that, in man and dog, pancreatic polypeptide is the hormonal mediator of the ethanol induced inhibition of exocrine pancreatic secretion.     

Somatostatin inhibits the ventilatory response to hypoxia in humans

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.     

Nasal mucosal vasodilatation in response to passive hyperthermia in humans

The present study was conducted to measure nasal mucosal blood flow (NMBF) during body warming. Five subjects [mean (SD) 24 (2) years], wearing only shorts and a thick felt hat with ear flaps, were immersed to the neck in a bath at 40 (0.5)°C. Tympanic (T _ty), esophageal (T _es), mean unweighted skin (T _sk), nose skin and ear pinna skin were recorded at 1-min intervals. NMBF on the lower septal wall was estimated using a laser Doppler flow meter. At rest T _ty and T _es were both 36.5°C. T _ty dropped significantly below T _es during body warming, despite impeded heat loss from the head due to the felt hat. T _ty increased to 37.3°C and T _es increased to 37.5°C during the immersion. During the immersion all skin temperatures were steady or increasing, ruling out the possibility of a contamination of T _ty from (T _sk), Body warming significantly (P = 0.001) increased NMBF by approximately three times from resting values at the end of immersion. During the period of increasing core temperatures NMBF was significantly correlated to T _ty (r = 0.93, P = 0.0001) and T _es (r = 0.97, P = 0.0001), suggesting the blood flow change in this tissue was a thermo-regulatory response. The increased NMBF during hyperthermia supports the hypothesis of respiratory cooling involvement in selective brain cooling of humans.