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Lactate is an important energy intermediate and metabolic buffer, and may be ergogenic. We investigated if lactate supplementation is an effective approach to enhance the exercise performance and acid–base balance of trained cyclists during exercise devised to simulate the demands of endurance road race cycling. Sixteen endurance-trained male cyclists ( V · O2max 59 ± 7 mL·kg−1·min−1) consumed 120 mg·kg−1 body mass of lactate or a placebo 70 min prior to performing an exercise performance test, comprising five repeated blocks consisting of 1 km and 4 km time trials interspersed with 10 min of moderate-intensity exercise. Blood acid–base balance (including [H+] and [HCO3−]), heart rate, perceived exertion, and gastro-intestinal tolerance were assessed. There was no effect of lactate supplementation on exercise performance (p = 0.320), despite a reduction in RPE (p = 0.012) and increases in [SID] (p = 0.026) and [HCO3−] (p = 0.041). In addition, gastro-intestinal side effects were observed, but there was no effect on heart rate. Lactate supplementation did not improve exercise performance, despite positive changes in acid–base balance and RPE. This suggests that the alkalising effects of the supplement can reduce perceived effort, but these benefits do not translate into performance improvements. [ABSTRACT FROM AUTHOR]

The respiratory muscle pressure generation and inspiratory and expiratory neuromuscular recruitment patterns in younger and older men were compared during exercise, alongside descriptors of dyspnea. Healthy younger (n = 8, 28 ± 5 years) and older (n = 8, 68 ± 4 years) men completed a maximal incremental cycling test. Esophageal, gastric (Pga) and transdiaphragmatic pressures, and electromyography (EMG) of the crural diaphragm were measured using a micro‐transducer and EMG catheter. EMG of the parasternal intercostals, sternocleidomastoids, and rectus abdominis were measured using skin surface electrodes. After the exercise test, participants completed a questionnaire to evaluate descriptors of dyspnea. Pga at end‐expiration, Pga expiratory tidal swings, and the gastric pressure–time product (PTPga) at absolute and relative minute ventilation were higher (p < 0.05) for older compared to younger men. There were no differences in EMG responses between older and younger men. Younger men were more likely to report shallow breathing (p = 0.005) than older men. Our findings showed younger and older men had similar respiratory neuromuscular activation patterns and reported different dyspnea descriptors, and that older men had greater expiratory muscle pressure generation during exercise. Greater expiratory muscle pressures in older men may be due to compensatory mechanisms designed to offset increasing airway resistance due to aging. These results may have implications for exercise‐induced expiratory muscle fatigue in older men. [ABSTRACT FROM AUTHOR]

Introduction: The ergogenic effects of respiratory alkalosis induced by prior voluntary hyperventilation (VH) are controversial. This study examined the effects of prior VH on derived parameters from the 3-min all-out cycling test (3MT). Methods: Eleven men (...O2max = 46 ± 8 mL⋅kg-1⋅min-1) performed a 3MT preceded by 15 min of rest (CONT) or VH (...E = 38 ± 5 L⋅min-1) with PETCO2 reduced to 21 ± 1 mm Hg (HYP). End-test power (EP; synonymous with critical power) was calculated as the mean power output over the last 30 s of the 3MT, and the work done above EP (WEP; synonymous with W') was calculated as the power--time integral above EP. Results: At the start of the 3MT, capillary blood PCO2 and [H+] were lower in HYP (25.2 ± 3.0 mm Hg, 27.1 ± 2.6 nmol⋅L-1) than CONT (43.2 ± 2.0 mm Hg, 40.0 ± 1.5 nmol⋅L-1) (P < 0.001). At the end of the 3MT, blood PCO2 was still lower in HYP (35.7 ± 5.4 mm Hg) than CONT (40.6 ± 5.0 mm Hg) (P < 0.001). WEP was 10% higher in HYP (19.4 ± 7.0 kJ) than CONT (17.6 ± 6.4 kJ) (P = 0.006), whereas EP was 5% lower in HYP (246 ± 69 W) than CONT (260 ± 74 W) (P = 0.007). The ΔWEP (J⋅kg-1) between CONT and HYP correlated positively with the PCO2 immediately before the 3MT in HYP (r = 0.77, P = 0.006). Conclusion: These findings suggest that acid--base changes elicited by prior VH increaseWEP but decrease EP during the all-out 3MT. [ABSTRACT FROM AUTHOR]

Respiratory pressure responses to cervical magnetic stimulation are important measurements in monitoring the mechanical function of the respiratory muscles. Pressures can be measured using balloon catheters or a catheter containing integrated micro‐transducers. However, no research has provided a comprehensive analysis of their pressure measurement characteristics. Accordingly, the aim of this study was to provide a comparative analysis of these characteristics in two separate experiments: (1) in vitro with a reference pressure transducer following a controlled pressurization; and (2) in vivo following cervical magnetic stimulations. In vitro the micro‐transducer catheter recorded pressure amplitudes and areas which were in closer agreement to the reference pressure transducer than the balloon catheter. In vivo there was a main effect for stimulation power and catheter for esophageal (Pes), gastric (Pga), and transdiaphragmatic (Pdi) pressure amplitudes (p < 0.001) with the micro‐transducer catheter recording larger pressure amplitudes. There was a main effect of stimulation power (p < 0.001) and no main effect of catheter for esophageal (p = 0.481), gastric (p = 0.923), and transdiaphragmatic (p = 0.964) pressure areas. At 100% stimulator power agreement between catheters for Pdi amplitude (bias =6.9 cmH2O and LOA −0.61 to 14.27 cmH2O) and pressure areas (bias = −0.05 cmH2O·s and LOA −1.22 to 1.11 cmH2O·s) were assessed. At 100% stimulator power, and compared to the balloon catheters, the micro‐transducer catheter displayed a shorter 10–90% rise time, contraction time, latency, and half‐relaxation time, alongside greater maximal rates of change in pressure for esophageal, gastric, and transdiaphragmatic pressure amplitudes (p < 0.05). These results suggest that caution is warranted if comparing pressure amplitude results utilizing different catheter systems, or if micro‐transducers are used in clinical settings while applying balloon catheter‐derived normative values. However, pressure areas could be used as an alternative point of comparison between catheter systems. [ABSTRACT FROM AUTHOR]

We questioned whether the respiratory muscles of humans contribute to systemic oxidative stress following inspiratory flow-resistive breathing, whether the amount of oxidative stress is influenced by the level of resistive load, and whether the amount of oxidative stress is related to the degree of diaphragm fatigue incurred. Eight young and healthy participants attended the laboratory for four visits on separate days. During the first visit, height, body mass, lung function, and maximal inspiratory mouth and transdiaphragmatic pressure (Pdimax) were assessed. During visits 2-4, participants undertook inspiratory flow-resistive breathing with either no resistance (control) or resistive loads equivalent to 50 and 70% of their Pdimax (Pdimax50% and Pdimax70%) for 30 min. Participants undertook one resistive load per visit, and the order in which they undertook the loads was randomized. Inspiratory muscle pressures were higher (P < 0.05) during the 5th and Final min of Pdimax50% and Pdimax70% compared with control. Plasma F2-isoprostanes increased (P < 0.05) following inspiratory flow-resistive breathing at Pdimax70%. There were no increases in plasma protein carbonyls or total antioxidant capacity. Furthermore, although we evidenced small reductions in transdiapragmaic twitch pressures (PdiTW) after inspiratory flow-resistive breathing at Pdimax50% and Pdimax70%, this was not related to the increase in plasma F2-isoprostanes. Our novel data suggest that it is only when sufficiently strenuous that inspiratory flow-resistive breathing in humans elicits systemic oxidative stress evidenced by elevated plasma F2-isoprostanes, and based on our data, this is not related to a reduction in PdiTW. NEW & NOTEWORTHY We examined whether the respiratory muscles of humans contribute to systemic oxidative stress following inspiratory flow-resistive breathing, whether the amount of oxidative stress is influenced by the level of resistive load, and whether the amount of oxidative stress is related to the degree of diaphragm fatigue incurred. It is only when sufficiently strenuous that inspiratory flow-resistive breathing elevates plasma F2-isoprostanes, and our novel data show that this is not related to a reduction in transdiaphragmatic twitch pressure. [ABSTRACT FROM AUTHOR]

Although high dose n-3 PUFA supplementation reduces exercise- and hyperpnoea-induced bronchoconstriction (EIB/HIB), there are concurrent issues with cost, compliance and gastrointestinal discomfort. It is thus pertinent to establish the efficacy of lower n-3 PUFA doses. Eight male adults with asthma and HIB and eight controls without asthma were randomly supplemented with two n-3 PUFA doses (6·2 g/d (3·7 g EPA and 2·5 g DHA) and 3·1 g/d (1·8 g EPA and 1·3 g DHA)) and a placebo, each for 21 d followed by 14 d washout. A eucapnic voluntary hyperpnoea (EVH) challenge was performed before and after treatments. Outcome measures remained unchanged in the control group. In the HIB group, the peak fall in forced expiratory volume in 1 s (FEV1) after EVH at day 0 (−1005 (sd 520) ml, −30 (sd 18) %) was unchanged after placebo. The peak fall in FEV1 was similarly reduced from day 0 to day 21 of 6·2 g/d n-3 PUFA (−1000 (sd 460) ml, −29 (sd 17) % v. −690 (sd 460) ml, −20 (sd 15) %) and 3·1 g/d n-3 PUFA (−970 (sd 480) ml, −28 (sd 18) % v. −700 (sd 420) ml, −21 (sd 15) %) (P<0·001). Baseline fraction of exhaled nitric oxide was reduced by 24 % (P=0·020) and 31 % (P=0·018) after 6·2 and 3·1 g/d n-3 PUFA, respectively. Peak increases in 9α, 11β PGF2 after EVH were reduced by 65 % (P=0·009) and 56 % (P=0·041) after 6·2 and 3·1 g/d n-3 PUFA, respectively. In conclusion, 3·1 g/d n-3 PUFA supplementation attenuated HIB and markers of airway inflammation to a similar extent as a higher dose. Lower doses of n-3 PUFA thus represent a potentially beneficial adjunct treatment for adults with asthma and EIB. [ABSTRACT FROM PUBLISHER]

Gut microbes have a substantial influence on systemic immune function and allergic sensitisation. Manipulation of the gut microbiome through prebiotics may provide a potential strategy to influence the immunopathology of asthma. This study investigated the effects of prebiotic Bimuno-galactooligosaccharide (B-GOS) supplementation on hyperpnoea-induced bronchoconstriction (HIB), a surrogate for exercise-induced bronchoconstriction, and airway inflammation. A total of ten adults with asthma and HIB and eight controls without asthma were randomised to receive 5·5 g/d of either B-GOS or placebo for 3 weeks separated by a 2-week washout period. The peak fall in forced expiratory volume in 1 s (FEV1) following eucapnic voluntary hyperpnoea (EVH) defined HIB severity. Markers of airway inflammation were measured at baseline and after EVH. Pulmonary function remained unchanged in the control group. In the HIB group, the peak post-EVH fall in FEV1 at day 0 (−880 (sd 480) ml) was unchanged after placebo, but was attenuated by 40 % (−940 (sd 460) v. −570 (sd 310) ml, P=0·004) after B-GOS. In the HIB group, B-GOS reduced baseline chemokine CC ligand 17 (399 (sd 140) v. 323 (sd 144) pg/ml, P=0·005) and TNF-α (2·68 (sd 0·98) v. 2·18 (sd 0·59) pg/ml, P=0·040) and abolished the EVH-induced 29 % increase in TNF-α. Baseline C-reactive protein was reduced following B-GOS in HIB (2·46 (sd 1·14) v. 1·44 (sd 0·41) mg/l, P=0·015) and control (2·16 (sd 1·02) v. 1·47 (sd 0·33) mg/l, P=0·050) groups. Chemokine CC ligand 11 and fraction of exhaled nitric oxide remained unchanged. B-GOS supplementation attenuated airway hyper-responsiveness with concomitant reductions in markers of airway inflammation associated with HIB. [ABSTRACT FROM PUBLISHER]

The influence of oxidative stress, diaphragm fatigue, and inspiratory muscle training (IMT) on the cytokine response to maximum sustainable voluntary ventilation (MSVV) is unknown. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1 h of (1) passive rest and (2) MSVV, whereby participants undertook volitional hyperpnea at rest that mimicked the breathing and respiratory muscle recruitment patterns commensurate with heavy cycling exercise. Plasma cytokines remained unchanged during passive rest. There was a main effect of time (P < 0.01) for plasma interleukin-1β (IL-1β) and interleukin-6 (IL-6) concentrations and a strong trend (P = 0.067) for plasma interleukin-1 receptor antagonist concentration during MSVV. Plasma IL-6 concentration was reduced after IMT by 27 ± 18% (main effect of intervention, P = 0.029), whereas there was no change after PLA (P = 0.753). There was no increase in a systemic marker of oxidative stress [DNA damage in peripheral blood mononuclear cells (PBMC)], and diaphragm fatigue was not related to the increases in plasma IL-1β and IL-6 concentrations. A dose-response relationship was observed between respiratory muscle work and minute ventilation and increases in plasma IL-6 concentration. In conclusion, increases in plasma IL-ip and IL-6 concentrations during MSVV were not due to diaphragm fatigue or DNA damage in PBMC. Increases in plasma IL-6 concentration during MSVV are attenuated following IMT, and the plasma IL-6 response is dependent upon the level of respiratory muscle work and minute ventilation. [ABSTRACT FROM AUTHOR]

It is unknown whether the respiratory muscles contribute to exercise-induced increases in plasma interleukin-6 (IL-6) concentration, if this is related to diaphragm fatigue, and whether inspiratory muscle training (IMT) attenuates the plasma IL-6 response to whole body exercise and/or a volitional mimic of the exercise hyperpnea. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1 h of 1) passive rest, 2) cycling exercise at estimated maximal lactate steady state power (EX), and 3) volitional hyperpnea at rest, which mimicked the breathing and respiratory muscle recruitment patterns achieved during EX (HYPEX). Plasma IL-6 concentration remained unchanged during passive rest. The plasma IL-6 response to EX was reduced following IMT (main effect of intervention, P = 0.039) but not PLA (P = 0.272). Plasma IL-6 concentration increased during HYPEX (main effect of time, P < 0.01) and was unchanged postintervention. There was no evidence of diaphragm fatigue (measured by phrenic nerve stimulation) following each trial. In conclusion, plasma IL-6 concentration is increased during EX and HYPEX and this occurred in the absence of diaphragm fatigue. Furthermore, IMT reduced the plasma IL-6 response to EX but not HYPEX. These findings suggest that the respiratory muscles contribute to exercise-induced increases in plasma IL-6 concentration in the absence of diaphragm fatigue and that IMT can reduce the magnitude of the response to exercise but not a volitional mimic of the exercise hyperpnea. [ABSTRACT FROM AUTHOR]

We examined whether inspiratory muscle training (IMT) improved cycling time-trial performance and changed the relationship between limit work (W (lim)) and limit time (T (lim)), which is described by the parameters critical power (CP) and anaerobic work capacity (AWC). Eighteen male cyclists were assigned to either a pressure-threshold IMT or sham hypoxic-training placebo (PLC) group. Prior to and following a 6 week intervention subjects completed a 25-km cycling time-trial and three constant-power tests to establish the W (lim)-T (lim) relationship. Constant-power tests were prescribed to elicit exercise intolerance within 3-10 (Ex1), 10-20 (Ex2), and 20-30 (Ex3) min. Maximal inspiratory mouth pressure increased by (mean +/- SD) 17.1 +/- 12.2% following IMT (P < 0.01) and was accompanied by a 2.66 +/- 2.51% improvement in 25-km time-trial performance (P < 0.05); there were no changes following PLC. Constant-power cycling endurance was unchanged following PLC, as was CP (pre vs. post: 249 +/- 32 vs. 250 +/- 32 W) and AWC (30.7 +/- 12.7 vs. 30.1 +/- 12.5 kJ). Following IMT Ex1 and Ex3 cycling endurance improved by 18.3 +/- 15.1 and 15.3 +/- 19.1% (P < 0.05), respectively, CP was unchanged (264 +/- 62 vs. 263 +/- 61 W), but AWC increased from 24.8 +/- 5.6 to 29.0 +/- 8.4 kJ (P < 0.05). In conclusion, these data provide novel evidence that improvements in constant-power and cycling time-trial performance following IMT in cyclists may be explained, in part, by an increase in AWC. [ABSTRACT FROM AUTHOR]

In the epidermis, local and systemic factors including extracellular nucleotides and parathyroid hormone-related protein (PTHrP) regulate keratinocyte proliferation and differentiation. Extracellular nucleotides increase proliferation via activation of P2 receptors and induction of calcium transients, while endoproteases cleave PTHrP, resulting in fragments with different cellular functions. We investigated the effects of adenosine 5′-triphosphate (ATP) alone and in combination with synthetic PTHrP peptides on calcium transients in HaCaT cells. ATP induced calcium transients, while PTHrP peptides did not. C-terminal and mid-molecule PTHrP peptides (1–100 pM) potentiated ATP-induced calcium transients independently of calcium influx. 3-isobutyl-1-methylxanthine potentiated ATP-induced calcium transients, suggesting that a cyclic monophosphate is responsible. Cyclic AMP is not involved, but cyclic GMP is a likely candidate since the protein kinase G inhibitor, KT5823, inhibited potentiation. Co-stimulation with ATP and either PTHrP (43–52) or PTHrP (70–77) increased proliferation, suggesting that this is important in the regulation of cell turnover and wound healing and may be a mechanism for hyperproliferation in skin disorders such as psoriasis. Finally, PTHrP fragments potentiated bradykinin-induced calcium transients, suggesting a role in inflammation in the skin. Since PTHrP is found in many normal and malignant cells, potentiation is likely to have a wider role in modulating signal transduction events.Journal of Investigative Dermatology (2008) 128, 1107–1115; doi:10.1038/sj.jid.5701159; published online 15 November 2007 [ABSTRACT FROM AUTHOR]

Extracellular nucleotides are agonists at the family of receptors known as the P2 receptors, and in keratinocytes the P2Y[SUB2] subtype is known to elevate the intracellular free calcium concentration (Ca[SUBi]) and stimulate proliferation. In this study, we have investigated the presence of other functional members of the P2Y subgroup in both normal human keratinocytes and the HaCaT cell line. Using reverse transcription polymerase chain reaction, the expression of mRNA for P2Y[SUB1], P2Y[SUB2], P2Y[SUB4], and P2Y[SUB6] receptors was demonstrated in HaCaT cells and differentiated and undifferentiated normal human keratinocytes. Ca[SUBi] was monitored in response to a panel of P2Y receptor agonists. To couple mobilized Ca[SUBi] to a downstream cellular response, cell proliferation was also addressed. In both cell types, adenosine 5'-triphosphate and uridine 5'-triphosphate induced Ca[SUBi] transients of approximately equal duration, magnitude, and shape, confirming the presence of functional P2Y[SUB2] receptors. In HaCaT cells, additional characteristic responses were observed in a subpopulation of cells; adenosine 5'-triphosphate failed to elevate Ca[SUBi] in some cells responding to uridine 5'-triphosphate, indicating the presence of P2Y[SUB4] receptors, whereas the P2Y[SUBl]-specific agonist 2-methylthio-5'-adenosine diphosphate was, again, only effective in a small subpopulation. Uridine 5'-diphosphate was ineffective, indicating the absence of functional P2Y[SUB6] receptors. Adenosine 5'-triphosphate and uridine 5'-triphosphate equally promoted cell growth in normal human keratinocytes in comparison with the control. In HaCaT cells, adenosine 5'-triphosphate, uridine 5'-triphosphate, and adenosine 5'-diphosphate significantly increased proliferation in comparison to the controls, with a 30% higher response to uridine 5'-triphosphate than with adenosine 5'-triphosphate. These data demonstrate that multiple P2Y receptors (P2Y[SUB1], P2Y[SUB2], and P2Y[SUB4]... [ABSTRACT FROM AUTHOR]