Smaller lungs in women affect exercise hyperpnea

We subjected 29 healthy young women (age: 27 +/- 1 yr) with a wide range of fitness levels [maximal oxygen uptake (VO2 max): 57 +/- 6 ml . kg-1 . min-1; 35-70 ml . kg-1 . min-1] to a progressive treadmill running test. Our subjects had significantly smaller lung volumes and lower maximal expiratory flow rates, irrespective of fitness level, compared with predicted values for age- and height-matched men. The higher maximal workload in highly fit (VO2 max > 57 ml . kg-1 . min-1, n = 14) vs. less-fit (VO2 max < 56 ml . kg-1 . min-1, n = 15) women caused a higher maximal ventilation (VE) with increased tidal volume (VT) and breathing frequency (fb) at comparable maximal VT/vital capacity (VC). More expiratory flow limitation (EFL; 22 +/- 4% of VT) was also observed during heavy exercise in highly fit vs. less-fit women, causing higher end-expiratory and end-inspiratory lung volumes and greater usage of their maximum available ventilatory reserves. HeO2 (79% He-21% O2) vs. room air exercise trials were compared (with screens added to equalize external apparatus resistance). HeO2 increased maximal expiratory flow rates (20-38%) throughout the range of VC, which significantly reduced EFL during heavy exercise. When EFL was reduced with HeO2, VT, fb, and VE (+16 +/- 2 l/min) were significantly increased during maximal exercise. However, in the absence of EFL (during room air exercise), HeO2 had no effect on VE. We conclude that smaller lung volumes and maximal flow rates for women in general, and especially highly fit women, caused increased prevalence of EFL during heavy exercise, a relative hyperinflation, an increased reliance on fb, and a greater encroachment on the ventilatory "reserve." Consequently, VT and VE are mechanically constrained during maximal exercise in many fit women because the demand for high expiratory flow rates encroaches on the airways' maximum flow-volume envelope.     

Changes in corticosteroid sensitivity of peripheral blood lymphocytes after strenuous exercise in humans

Although plasma corticosteroid concentrations can be measured accurately, the biological effect on the target tissue is uncertain. The availability of an accurate measure of corticosteroid sensitivity would potentially clarify the putative roles of endogenous glucocorticoids in illnesses such as inflammatory disease and obesity and allow evaluation of an additional regulatory level of glucocorticoid action. To measure corticosteroid sensitivity, we developed an assay based on the inhibition by dexamethasone (Dex) of lipopolysaccharide (LPS)-induced Interleukin-6 (IL-6) production and release in whole unseparated blood in vitro. LPS induced a dose-dependent increase in IL-6 concentrations up to 34 +/- 6.6 ng/mL, reaching plateau levels after 8 h, whereas Dex dose dependently inhibited LPS-induced IL-6 production. Involvement of the glucocorticoid receptor in this response was supported by abrogation of Dex (10(-7) mol/L) inhibition of IL-6 production by the glucocorticoid receptor antagonist RU 38486. To determine whether corticosteroid sensitivity is a dynamic phenomenon, we subjected healthy males to a graded quantifiable exercise associated with increases in plasma ACTH and cortisol. Before exercise, 3 x 10(-8) mol/L Dex inhibited LPS-induced IL-6 production in vitro; after exercise, 3 x 10(-8) and 10(-7) mol/L Dex were unable to inhibit IL-6 production. We conclude that Dex suppression of LPS-induced IL-6 production is an effective means of determining corticosteroid sensitivity, and that corticosteroid sensitivity in human subjects is a dynamic, rather than a static, phenomenon.     

NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

N-methyl-D-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (VE) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (VT) decreased while frequency increased, resulting in a modest reduction in VE. Inspiratory time (TI) decreased, whereas expiratory time remained unchanged. The VE responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (VT/TI) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas VT was unaffected. Sodium cyanide doses associated with significant VE increases were 5 and 50 microg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reduced VE during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.     

Thermal drive contributes to hyperventilation during exercise in sheep

The etiology of exercise hypocapnia is unknown. The contributions of exercise intensity (ExInt), lactic acid, environmental temperature, rectal temperature (Tre), and physical conditioning to the variance in arterial CO2 tension (PaCO2) in the exercising sheep were quantified. We hypothesized that thermal drive contributes to hyperventilation. Four unshorn sheep were exercised at approximately 30, 50, and 70% of maximal O2 consumption for 30 min, or until exhaustion, both before and after 5 wk of physical conditioning. In addition, two of the sheep were shorn and exercised at each intensity in a cold (<15 degrees C) environment. Tre and O2 consumption were measured continuously. Lactic acid and PaCO2 were measured at 5- to 10-min intervals. Data were analyzed by multiple regression on PaCO2. During exercise, Tre rose and PaCO2 fell, except at the lowest ExInt in the cold environment. Tre explained 77% of the variance in PaCO2, and ExInt explained 5%. All other variables were insignificant. We conclude that, in sheep, thermal drive contributes to hyperventilation during exercise.     

Acetazolamide reduces peripheral afferent transmission in humans

Carbonic anhydrase has been localized in skeletal muscle and nerve, thus, inhibition with acetazolamide (ACZ) may alter nerve and/or muscle function in healthy humans. ACZ (3 oral doses 14, 8, and 2 h prior to testing) reduced isometric force (37%) and peak to peak electromyographic (EMG) amplitude (1.38 mV to 0.83 mV), while increasing EMG latency associated with a unilateral Achilles tendon-tap. Reflex recovery profiles, following a contralateral conditioning tap, were similar in both placebo and ACZ experiments. ACZ led to significant changes in Hmax/Mmax ratio (52.19/14.42 to 45.73/15.65) and H-reflex latency (34.18 +/- 2.54 ms to 35.24 +/- 2.74 ms). Motor nerve conduction velocity and maximal voluntary isometric torque (knee extensors) were unaltered by ACZ. These data suggest that inhibition of the tendon-tap reflex and associated isometric force, following ACZ, is related to impairment of synaptic integrity between la fibers of the muscle spindle and the alpha motor neuron and not impairment of the muscle spindle or force-generating capacity.     

Pivalic acid-induced carnitine deficiency and physical exercise in humans

To study the effect of carnitine depletion on physical working capacity, healthy subjects were administered pivaloyl-conjugated antibiotics for 54 days. The mean carnitine concentration in serum decreased from 35.0 to 3.5 mmicromol/L, and in muscle from 10 to 4.3 micromol/g noncollagen protein (NCP). Exercise tests were performed before and after 54 days' administration of the drug. At submaximal exercise, there was a slight increase in the concentration of 3-hydroxybutyrate in serum, presumably caused by decreased fatty acid oxidation in the liver. There was also a decreased consumption of muscle glycogen, indicating decreased glycolysis in the skeletal muscle. The muscle presumably had enough energy available, since there was no significant decrease in the concentration of adenosine triphosphate (ATP) and creatine phosphate during exercise. The work at maximal oxygen uptake (VO2max) and the maximal heart rate were reduced. Since VO2max is considered dependent on heart function, carnitine depletion seemed to affect cardiac function.     

Urea kinetics in humans at two levels of exercise intensity

A primed constant infusion of [15N2]urea was used to quantify the response of urea production to exercise at 40 and 70% maximal oxygen consumption on a treadmill. Total urea production, urea production from recycled N, urea production from nonrecycled N, and urea N recycled back into body protein were calculated. Most components of urea kinetics were unaffected by exercise at either intensity. The rate of urea reincorporated into protein was significantly increased during exercise and recovery at both levels of exercise. We conclude that exercise does not stimulate urea production but that there may be an accelerated reincorporation of urea N back into body protein.     

Effects of prior arm exercise on pulmonary gas exchange kinetics during high-intensity leg exercise in humans

The activation of MAPKs is controlled by the balance between MAPK kinase and MAPK phosphatase activities. The latter is mediated by a subset of phosphatases with dual specificity (VH-1 family). Here, we describe a new member of this family encoded by the puckered gene of Drosophila. Mutations in this gene lead to cytoskeletal defects that result in a failure in dorsal closure related to those associated with mutations in basket, the Drosophila JNK homolog. We show that puckered mutations result in the hyperactivation of DJNK, and that overexpression of puc mimics basket mutant phenotypes. We also show that puckered expression is itself a consequence of the activity of the JNK pathway and that during dorsal closure, JNK signaling has a dual role: to activate an effector, encoded by decapentaplegic, and an element of negative feedback regulation encoded by puckered.     

Rib cage mechanics during quiet breathing and exercise in humans

During exercise, large pleural, abdominal, and transdiaphragmatic pressure swings might produce substantial rib cage (RC) distortions. We used a three-compartment chest wall model (J. Appl. Physiol. 72: 1338-1347, 1992) to measure distortions of lung- and diaphragm-apposed RC compartments (RCp and RCa) along with pleural and abdominal pressures in five normal men. RCp and RCa volumes were calculated from three-dimensional locations of 86 markers on the chest wall, and the undistorted (relaxation) RC configuration was measured. Compliances of RCp and RCa measured during phrenic stimulation against a closed airway were 20 and 0%, respectively, of their values during relaxation. There was marked RC distortion. Thus nonuniform distribution of pressures distorts the RC and markedly stiffens it. However, during steady-state ergometer exercise at 0, 30, 50, and 70% of maximum workload, RC distortions were small because of a coordinated action of respiratory muscles, so that net pressures acting on RCp and RCa were nearly the same throughout the respiratory cycle. This maximizes RC compliance and minimizes the work of RC displacement. During quiet breathing, plots of RCa volume vs. abdominal pressure were to the right of the relaxation curve, indicating an expiratory action on RCa. We attribute this to passive stretching of abdominal muscles, which more than counterbalances the insertional component of transdiaphragmatic pressure.     

Hemodynamic patterns and duration of post-dynamic exercise hypotension in hypertensive humans

It has been shown, that smoking results in a lower yield of surfactant associated phospholipids in bronchoalveolar lavage (BAL). Indirect evidence suggests impaired secretion. In the present study, we investigated the influence of cigarette smoke on surfactant secretion in cultured rat alveolar type II cells. Smoke exposure was achieved by bubbling the smoke of four cigarettes through Dulbecco's modified Eagle's medium (DMEM) which was adjusted to a reference absorption value of 1.36 at 320 nm. Cells were preincubated with various dilutions of cigarette smoke-treated medium for 30 min, and were then exposed to this medium for 2 h. After this time, secretion of 3H-choline-labelled phosphatidylcholine (PC) was measured as a marker of surfactant secretion. A 10 fold dilution of cigarette smoke-treated medium inhibited PC secretion stimulated by a combination of terbutaline, adenosine triphosphate and 12-O-tetradecanoylphorbol-13-acetate by over 50%, but did not alter basal secretion. Exposure to less concentrated cigarette smoke-treated medium resulted in less inhibition. Cellular injury was not observed with the concentrations of cigarette smoke-treated medium used in this study. The gas phase of cigarette smoke was not inhibitory at comparable concentrations. Longer exposure to cigarette smoke-treated medium resulted in increased inhibition of PC secretion. The cigarette smoke ingredients, nicotine and benzo[a]pyrene, failed to inhibit PC secretion. Secretion of type II cells exposed to cigarette smoke-treated medium at lower temperatures was not affected. Addition of antioxidants to medium and cells during the preincubation and secretion period did not alter cigarette smoke-treated medium-induced inhibition of stimulated PC secretion. These results demonstrate a direct inhibitory effect of cigarette smoke constituents on surfactant secretion in type II cells. Inhibition is mediated by compounds contained predominantly in the particulate phase of cigarette smoke. Inactivation of the inhibitory effect by lower temperatures suggests involvement of processes such as enzymatic bioactivation or active transport mechanisms.     

The contribution of the reflex hypoxic drive to the hyperpnoea of exercise

Oxygen breath tests have been applied to six normal subjects at rest and during steady state exercise on a bicycle ergometer (200, 400 and 600 kpm) to estimate the contribution of the reflex hypoxic drive to total ventilation. The subjects were changed without their knowledge from air to 100% oxygen for 4--5 breaths, the fall in ventilation was recorded and expressed as a percentage of total ventilation (hypoxic drive). The average reflex hypoxic drive was 16.2% (SE +/- 2.6; n = 35) this remianed unaltered during all levels of steady state exercise. The maximum fall in ventilation occurred earlier in exercise (P less than 0.0005). At rest the maximum fall occurred on average 31.2 s (SE +/- 2.6) from the start of the first breath of oxygen. During the first level of steady state exercise the maximum fall occurred 19.4 s (SE +/- 0.5) from the start of the first breath of oxygen. It is concluded that the contribution of the reflex hypoxic drive to the total ventilation is unaltered by exercise although a substantial part of the hyperpnoea can be accounted for by the presence of this drive.     

Alanine and glutamine kinetics at rest and during exercise in humans

PURPOSE: The purpose of this study was to quantify both alanine and glutamine kinetics during exercise of moderate intensity to determine the sum total of alanine and glutamine flux. METHODS: Tracer methods were used to quantify alanine and glutamine rates of appearance (Ra) in plasma at rest and during 180 min of approximately 45% VO2max treadmill exercise in six normal volunteers (25 +/- 2 yr, 68 +/- 2.5 kg, VO2max 43 +/- 2.4 mL.min-1.kg-1; means +/- SE). Bolus injections (N = 3) or primed-constant infusions (N = 3) of 2H5-glutamine and 3-13C-alanine were given at rest on 1 d and 10-15 min after the onset of exercise on a separate day less than 2 wk later. Plasma enrichment decay curves and plateau enrichments were used to estimate alanine and glutamine kinetics. RESULTS: Whereas alanine Ra increased significantly from rest to exercise (5.72 +/- 0.31 vs 13.5 +/- 1.9 mumol.min-1.kg-1, respectively; P < 0.01), glutamine Ra was not significantly altered by exercise (6.11 +/- 0.44 and 6.40 +/- 0.69 mumol.min-1.kg-1 at rest and during exercise, respectively). The total of alanine and glutamine flux increased from 17.93 +/- 0.88 to 25.98 +/- 3.04 (P < 0.05). CONCLUSIONS: Since most muscle amino-N is released as alanine and glutamine, these findings provide strong evidence that amino-N delivery from muscle to the liver is increased during exercise. In addition, it appears that alanine, rather than glutamine, is the predominant N carrier involved in the transfer of N from muscle to the liver during moderate intensity exercise.     

Skeletal muscle blood flow in humans and its regulation during exercise

Regional limb blood flow has been measured with dilution techniques (cardio-green or thermodilution) and ultrasound Doppler. When applied to the femoral artery and vein at rest and during dynamical exercise these methods give similar reproducible results. The blood flow in the femoral artery is approximately 0.3 L min(-1) at rest and increases linearly with dynamical knee-extensor exercise as a function of the power output to 6-10 L min[-1] (Q= 1.94 + 0.07 load). Considering the size of the knee-extensor muscles, perfusion during peak effort may amount to 2-3 L kg(-1) min(-1), i.e. approximately 100-fold elevation from rest. The onset of hyperaemia is very fast at the start of exercise with T 1/2 of 2-10 s related to the power output with the muscle pump bringing about the very first increase in blood flow. A steady level is reached within approximately 10-150 s of exercise. At all exercise intensities the blood flow fluctuates primarily due to the variation in intramuscular pressure, resulting in a phase shift with the pulse pressure as a superimposed minor influence. Among the many vasoactive compounds likely to contribute to the vasodilation after the first contraction adenosine is a primary candidate as it can be demonstrated to (1) cause a change in limb blood flow when infused i.a., that is similar in time and magnitude as observed in exercise, and (2) become elevated in the interstitial space (microdialysis technique) during exercise to levels inducing vasodilation. NO appears less likely since NOS blockade with L-NMMA causing a reduced blood flow at rest and during recovery, it has no effect during exercise. Muscle contraction causes with some delay (60 s) an elevation in muscle sympathetic nerve activity (MSNA), related to the exercise intensity. The compounds produced in the contracting muscle activating the group IIl-IV sensory nerves (the muscle reflex) are unknown. In small muscle group exercise an elevation in MSNA may not cause vasoconstriction (functional sympatholysis). The mechanism for functional sympatholysis is still unknown. However, when engaging a large fraction of the muscle mass more intensely during exercise, the MSNA has an important functional role in maintaining blood pressure by limiting blood flow also to exercising muscles.     

Contribution of abdomen and legs to central blood volume expansion in humans during immersion

Collagen-induced arthritis (CIA) is a T cell-dependent disease in which susceptibility is controlled by genes both within and outside the major histocompatibility complex (MHC). In the present study, we compared the humoral responses and kinetics of cytokine secretion patterns in the draining lymph nodes of arthritis-susceptible DA rats and arthritis-resistant F344 and DA MHC congenic PVG.1AV1 rats immunized with rat type II collagen (RCII) in incomplete Freund's adjuvant. The results demonstrate a marked humoral RCII response and a Th1 cytokine profile, with expression of interferon-gamma and interleukin (IL)-2 mRNA in DA rats; a limited humoral RCII response and a Th2 cytokine profile, with expression of IL-4 mRNA in arthritis-resistant F344 rats; and a marked humoral RCII response in arthritis-resistant PVG.1AV1 rats. However, in contrast to DA rats, PVG.1AV1 rats produce IgG1 autoantibodies which, together with strong expression of IL-4 mRNA, indicates the involvement of Th2 subsets. From these data, we conclude that non-MHC gene(s) determines the direction of the anti-RCII response towards a Th1 disease-promoting, or a Th2 disease-limiting response.     

Evidence for two differentially regulated populations of peripheral beta-endorphin-releasing cells in humans

In the current study we tested the hypothesis that human plasma beta-endorphin (beta E) is derived from at least two subpopulations of beta E-releasing cells: one sensitive to glucocorticoids as well as to dopamine (DA; regulated analogously to the corticotrophs of the rat pituitary), and one insensitive to glucocorticoids but sensitive to DA (regulated analogously to the melanotrophs of the rat pituitary). To test this hypothesis, human plasma levels of ACTH, cortisol, and beta E-like immunoreactivity were measured at baseline and after haloperidol treatment (0.05 mg/kg, i.v.) in two experimental groups, one pretreated with dexamethasone (1.5 mg) and one pretreated with placebo. Plasma PRL levels were also measured in both groups as an indicator of DA receptor blockade. Dexamethasone partially suppressed both baseline and haloperidol-stimulated levels of human plasma beta E-like immunoreactivity, whereas it completely suppressed both basal and haloperidol-stimulated levels of ACTH and cortisol and had no statistically significant effect on either basal or haloperidol-stimulated PRL levels. These data support a negative feedback effect of glucocorticoids on one DA-sensitive cell population that releases both ACTH and beta E (corticotroph like), but not on a second cell population that releases beta E but not ACTH.     

Muscle fiber composition and blood ammonia levels after intense exercise in humans

The relationship between fiber type composition and the increase in blood ammonia was examined following a maximal O2 consumption (VO2max) test. Muscle biopsies were taken from the middle portion of the vastus lateralis for determination of fiber type percentages. Two subject groups were selected on the basis of a high (HST) or low (LST) percentage of slow-twitch fibers and compared for blood ammonia and lactate levels after exercise at work loads of approximately 85 and 110% of VO2max. An inverse relationship was found between the percentage of slow-twitch fibers and the increase in blood ammonia. Blood ammonia increased after exercise at both 85 and 110% of VO2max. However, the increase was twofold greater for the LST group following the 110% work effort. The increases in blood ammonia and lactate were positively correlated for both groups following exercise. The results suggest that the proportion of slow-twitch fibers plays an important role in determining the magnitude of the increase in blood ammonia after intense exercise.     

Respiratory effort sensation during exercise with induced expiratory-flow limitation in healthy humans

Nine healthy subjects (age 31 +/- 4 yr) exercised with and without expiratory-flow limitation (maximal flow approximately 1 l/s). We monitored flow, end-tidal PCO2, esophageal (Pes) and gastric pressures, changes in end-expiratory lung volume, and perception (sensation) of difficulty in breathing. Subjects cycled at increasing intensity (+25 W/30 s) until symptom limitation. During the flow-limited run, exercise performance was limited in all subjects by maximum sensation. Sensation was equally determined by inspiratory and expiratory pressure changes. In both runs, 90% of the variance in sensation could be explained by the Pes swings (difference between peak inspiratory and peak expiratory Pes). End-tidal PCO2 did not explain any variance in sensation in the control run and added only 3% to the explained variance in the flow-limited run. We conclude that in healthy subjects, during normal as well as expiratory flow-limited exercise, the pleural pressure generation of the expiratory muscles is equally related to the perception of difficulty in breathing as that of the inspiratory muscles.     

Haemodynamic and metabolic responses of the lower limb after high intensity exercise in humans

Beta-galactosidase activity is known to exist in Drosophila melanogaster, but a detailed analysis of the tissue-specific patterns of activity has not previously been reported. Such an analysis is of particular interest because Drosophila is commonly used for making transformants that carry fusion genes in which the E. coli beta-galactosidase gene, lacZ, is used as a reporter gene. When these transformants are analyzed for beta-galactosidase activity by using chromogen X-gal staining, the method does not distinguish true fusion-gene activity from endogenous beta-galactosidase activity or from the beta-galactosidase activity of bacterial contaminants. Therefore, detailed maps of endogenous beta-galactosidase activity in this organism would help to prevent errors in data interpretation and would indicate which stages were most appropriate for experiments with the lacZ transformants. We have constructed such maps by applying X-gal staining methods to serial frozen sections and whole mounts of larval, prepupal, pupal, and adult stages of D. melanogaster reared under axenic conditions. Results showed endogenous beta-galactosidase activity in a variety of organs including the larval intestine, spiracles, lymph glands, cellular epidermis, and eye-antenna imaginal discs; the pupal cellular epidermis, lymph glands, imaginal tissues, fat body, and spiracle; and the adult pericardial cells, thoracic nephrocytes, ventriculus, and reproductive system. The good correlation between staining and metamorphic remodeling and phagocytic activity indicates that endogenous beta-galactosidase is physiologically interesting.