Identification of maximal steady-state metabolic rate by the change in muscle oxygen saturation.

We tested the hypothesis that a %SmO2 (muscle O2 saturation) slope can distinguish the heavy-severe exercise domain boundary and the highest steady-state metabolic rate. Thirteen participants (5 women) performed a graded exercise test (GXT) to determine peak oxygen consumption (V̇o2peak) and lactate turn point (LTP). On a separate study day, a %SmO2 zero-slope prediction trial included completing 5-min cycling bouts in an estimated heavy domain, at an estimated critical power, and in an estimated severe domain. Linear regression then determined the work rate at the predicted %SmO2 zero-slope, before a fourth 5-min confirmation trial. Two separate validation study days included confirmed steady-state (heavy domain) and nonsteady-state (severe domain) constant work rate trials. The power at the predicted %SmO2 zero-slope was 204 ± 36 W and occurred at a %SmO2 slope of 0.7 ± 1.4%/min (P = 0.12 relative to zero). There was no difference between the power at LTP (via GXT) and the predicted %SmO2 zero-slope linked power (P = 0.74). From validation study days, the %SmO2 slope was 0.32 ± 0.73%/min during confirmed heavy-domain constant work rate exercise and -0.75 ± 1.94%/min during confirmed severe-domain exercise (P < 0.05). The %SmO2 zero-slope consistently delineated steady state from nonsteady-state metabolic parameters (V̇o2 and blood lactate) and the heavy-severe domain boundary. Our data suggest the %SmO2 slope can identify the highest steady-state metabolic rate and the physiological boundary between the heavy-severe domain, independent of work rate.NEW & NOTEWORTHY Muscle O2 saturation (%SmO2) rate can be used to not only identify sustainable from unsustainable exercise intensities but also delineate the transition from heavy to severe exercise domains. This report is the first to identify, and then validate, that the highest steady-state metabolic rate is related to a zero-slope muscle O2 saturation and is therefore dependent on muscle oxygen supply-demand balance.

Transcutaneous delivery of sodium bicarbonate increases intramuscular pH.

Introduction: Oral bicarbonate loading improves the buffering of metabolic acidosis and may improve exercise performance but can also result in gastric distress. Momentous' PR Lotion contains a novel composition intended to provide a transdermal delivery vehicle for sodium bicarbonate which could allow the same ergogenic effect without the gastric distress. The present study explored the effect of transdermal delivery of sodium bicarbonate in a resting condition. Methods: We measured the pH from intramuscular dialysate, via microdialysis, of the vastus lateralis during a 2 h application of PR Lotion (40 g of lotion per leg) in 9 subjects (3 women, 6 men). Venous blood samples were obtained for serum pH before and after application. A placebo time control was also performed in 4 subjects (2 women, 2 men). We hypothesized that PR Lotion application would increase pH of intramuscular dialysate. Results: PR Lotion resulted in a rise in pH of 0.13 ± 0.04 units (p < 0.05), which translates to a 28% reduction in [H+]. Increases in serum pH were smaller (∼9%) yet consistent (p < 0.05). In contrast, placebo time control pH tended to decrease (p = 0.08). The effect of PR Lotion on pH tended to correlate with the dose per kg body weight of each individual (r = 0.70, p = 0.08). Conclusion: These observations support the idea of transdermal bicarbonate delivery impacting pH buffering both systemically and intramuscularly. Further work investigating these potential benefits in an exercising model would be critical to establishing PR Lotion's utility as an ergogenic aid.

Interaction of exercise bioenergetics with pacing behavior predicts track distance running performance.

The best possible finishing time for a runner competing in distance track events can be estimated from their critical speed (CS) and the finite amount of energy that can be expended above CS (D´). During tactical races with variable pacing, the runner with the "best" combination of CS and D´ and, therefore, the fastest estimated finishing time prior to the race, does not always win. We hypothesized that final race finishing positions depend on the relationships between the pacing strategies used, the athletes' initial CS, and their instantaneous D´ (i.e., D´ balance) as the race unfolds. Using publicly available data from the 2017 International Association of Athletics Federations (IAAF) World Championships men's 5,000-m and 10,000-m races, race speed, CS, and D´ balance were calculated. The correlation between D´ balance and actual finishing positions was nonsignificant using start-line values but improved to R2 > 0.90 as both races progressed. The D´ balance with 400 m remaining was strongly associated with both final 400-m split time and proximity to the winner. Athletes who exhausted their D´ were unable to hold pace with the leaders, whereas a high D´ remaining enabled a fast final 400 m and a high finishing position. The D´ balance model was able to accurately predict finishing positions in both a "slow" 5,000-m and a "fast" 10,000-m race. These results indicate that although CS and D´ can characterize an athlete's performance capabilities prior to the start, the pacing strategy that optimizes D´ utilization significantly impacts the final race outcome.NEW & NOTEWORTHY We show that the interaction between exercise bioenergetics and real-time pacing strategy predicts track distance running performance. Critical speed (CS) and the finite energy expended above CS (D´) can characterize an athlete's capabilities prior to the race start, but the pacing strategy that optimizes D´ utilization ultimately impacts whether a runner is in contention to win and whether a runner will have a fast final 400 m. Accordingly, D´ balance predicts final race finishing order.

The impact of elevated body core temperature on critical power as determined by a 3-min all-out test.

Critical power (CP) delineates the heavy and severe exercise intensity domains, and sustained work rates above CP result in an inexorable progression of oxygen uptake to a maximal value and, subsequently, the limit of exercise tolerance. The finite work capacity above CP, W', is defined by the curvature constant of the power-duration relationship. Heavy or severe exercise in a hot environment generates additional challenges related to the rise in body core temperature (Tc) that may impact CP and W'. The purpose of this study was to determine the effect of elevated Tc on CP and W'. CP and W' were estimated by end-test power (EP; mean of final 30 s) and work above end-test power (WEP), respectively, from 3-min "all-out" tests performed on a cycle ergometer. Volunteers (n = 8, 4 female) performed the 3-min tests during a familiarization visit and two experimental visits (thermoneutral vs. hot, randomized crossover design). Before experimental 3-min tests, the subjects were immersed in water (thermoneutral: 36°C for 30 min; hot: 40.5°C until Tc was ≥38.5°C). Mean Tc was significantly greater in the hot condition than in the thermoneutral condition (38.5 ± 0.0°C vs. 37.4 ± 0.2°C; means ± SD, P < 0.01). All 3-min tests were performed in an environmental chamber [thermoneutral: 18°C, 45% relative humidity (RH); hot: 38 °C, 40% RH]. EP was similar between thermoneutral (239 ± 57 W) and hot (234 ± 66 W; P = 0.55) conditions. WEP was similar between thermoneutral (10.9 ± 3.0 kJ) and hot conditions (9.3 ± 3.6; P = 0.19). These results suggest that elevated Tc has no significant impact on EP or WEP.NEW & NOTEWORTHY The parameters of the power-duration relationship (critical power and W') estimated by a 3-min all-out test were not altered by elevated body core temperature as compared with a thermoneutral condition.

The balance of muscle oxygen supply and demand reveals critical metabolic rate and predicts time to exhaustion.

We tested the hypothesis that during whole body exercise, the balance between muscle O2 supply and metabolic demand may elucidate intensity domains, reveal a critical metabolic rate, and predict time to exhaustion. Seventeen active, healthy volunteers (12 males, 5 females; 32 ± 2 yr) participated in two distinct protocols. Study 1 (n = 7) consisted of constant work rate cycling in the moderate, heavy, and severe exercise intensity domains with concurrent measures of pulmonary V̇o2 and local %SmO2 [via near-infrared spectroscopy (NIRS)] on quadriceps and forearm sites. Average %SmO2 at both sites displayed a domain-dependent response (P < 0.05). A negative %SmO2 slope was evident during severe-domain exercise but was positive during exercise below critical power (CP) at both muscle sites. In study 2 (n = 10), quadriceps and forearm site %SmO2 was measured during three continuous running trials to exhaustion and three intermittent intensity (ratio = 60 s severe: 30 s lower intensity) trials to exhaustion. Intensity-dependent negative %SmO2 slopes were observed for all trials (P < 0.05) and predicted zero slope at critical velocity. %SmO2 accurately predicted depletion and repletion of %D' balance on a second-by-second basis (R2 = 0.99, P < 0.05; both sites). Time to exhaustion predictions during continuous and intermittent exercise were either not different or better with %SmO2 [standard error of the estimate (SEE) < 20.52 s for quad, <44.03 s for forearm] versus running velocity (SEE < 65.76 s). Muscle O2 balance provides a dynamic physiological delineation between sustainable and unsustainable exercise (consistent with a "critical metabolic rate") and predicts real-time depletion and repletion of finite work capacity and time to exhaustion.NEW & NOTEWORTHY Dynamic muscle O2 saturation discriminates boundaries between exercise intensity domains, exposes a critical metabolic rate as the highest rate of steady state O2 supply and demand, describes time series depletion and repletion for work above critical power, and predicts time to exhaustion during severe domain whole body exercise. These results highlight the matching of O2 supply and demand as a primary determinant for sustainable exercise intensities from those that are unsustainable and lead to exhaustion.

Physiological demands of running at 2-hour marathon race pace.

The requirements of running a 2-h marathon have been extensively debated but the actual physiological demands of running at ∼21.1 km/h have never been reported. We therefore conducted laboratory-based physiological evaluations and measured running economy (O2 cost) while running outdoors at ∼21.1 km/h, in world-class distance runners as part of Nike's "Breaking 2" marathon project. On separate days, 16 world-class male distance runners (age, 29 ± 4 yr; height, 1.72 ± 0.04 m; mass, 58.9 ± 3.3 kg) completed an incremental treadmill test for the assessment of V̇O2peak, O2 cost of submaximal running, lactate threshold and lactate turn-point, and a track test during which they ran continuously at 21.1 km/h. The laboratory-determined V̇O2peak was 71.0 ± 5.7 mL/kg/min with lactate threshold and lactate turn-point occurring at 18.9 ± 0.4 and 20.2 ± 0.6 km/h, corresponding to 83 ± 5% and 92 ± 3% V̇O2peak, respectively. Seven athletes were able to attain a steady-state V̇O2 when running outdoors at 21.1 km/h. The mean O2 cost for these athletes was 191 ± 19 mL/kg/km such that running at 21.1 km/h required an absolute V̇O2 of ∼4.0 L/min and represented 94 ± 3% V̇O2peak. We report novel data on the O2 cost of running outdoors at 21.1 km/h, which enables better modeling of possible marathon performances by elite athletes. Using the value for O2 cost measured in this study, a sub 2-h marathon would require a 59 kg runner to sustain a V̇O2 of approximately 4.0 L/min or 67 mL/kg/min.NEW & NOTEWORTHY We report the physiological characteristics and O2 cost of running overground at ∼21.1 km/h in a cohort of the world's best male distance runners. We provide new information on the absolute and relative O2 uptake required to run at 2-h marathon pace.

Dynamics of the power-duration relationship during prolonged endurance exercise and influence of carbohydrate ingestion.

We tested the hypotheses that the parameters of the power-duration relationship, estimated as the end-test power (EP) and work done above EP (WEP) during a 3-min all-out exercise test (3MT), would be reduced progressively after 40 min, 80 min, and 2 h of heavy-intensity cycling and that carbohydrate (CHO) ingestion would attenuate the reduction in EP and WEP. Sixteen participants completed a 3MT without prior exercise (control), immediately after 40 min, 80 min, and 2 h of heavy-intensity exercise while consuming a placebo beverage, and also after 2 h of heavy-intensity exercise while consuming a CHO supplement (60 g/h CHO). There was no difference in EP measured without prior exercise (260 ± 37 W) compared with EP after 40 min (268 ± 39 W) or 80 min (260 ± 40 W) of heavy-intensity exercise; however, after 2 h EP was 9% lower compared with control (236 ± 47 W; P < 0.05). There was no difference in WEP measured without prior exercise (17.9 ± 3.3 kJ) compared with after 40 min of heavy-intensity exercise (16.1 ± 3.3 kJ), but WEP was lower (P < 0.05) than control after 80 min (14.7 ± 2.9 kJ) and 2 h (13.8 ± 2.7 kJ). Compared with placebo, CHO ingestion negated the reduction of EP following 2 h of heavy-intensity exercise (254 ± 49 W) but had no effect on WEP (13.5 ± 3.4 kJ). These results reveal a different time course for the deterioration of EP and WEP during prolonged endurance exercise and indicate that EP is sensitive to CHO availability.NEW & NOTEWORTHY The parameters of the power-duration relationship [critical power (CP) and the curvature constant (W')] have typically been considered to be static. Here we report the time course for reductions in CP and W', as estimated with the 3-min all-out cycle test, during 2 h of heavy-intensity exercise. We also show that carbohydrate ingestion during exercise preserves CP, but not W', without altering muscle glycogen depletion. These results provide new mechanistic and practical insight into the power-duration curve and its relationship to exercise-related fatigue development.

Changes in the power-duration relationship following prolonged exercise: estimation using conventional and all-out protocols and relationship with muscle glycogen.

It is not clear how the parameters of the power-duration relationship [critical power (CP) and W'] are influenced by the performance of prolonged endurance exercise. We used severe-intensity prediction trials (conventional protocol) and the 3-min all-out test (3MT) to measure CP and W' following 2 h of heavy-intensity cycling exercise and took muscle biopsies to investigate possible relationships to changes in muscle glycogen concentration ([glycogen]). Fourteen participants completed a rested 3MT to establish end-test power (Control-EP) and work done above EP (Control-WEP). Subsequently, on separate days, immediately following 2 h of heavy-intensity exercise, participants completed a 3MT to establish Fatigued-EP and Fatigued-WEP and three severe-intensity prediction trials to the limit of tolerance (Tlim) to establish Fatigued-CP and Fatigued-W'. A muscle biopsy was collected immediately before and after one of the 2-h exercise bouts. Fatigued-CP (256 ± 41 W) and Fatigued-EP (256 ± 52 W), and Fatigued-W' (15.3 ± 5.0 kJ) and Fatigued-WEP (14.6 ± 5.3 kJ), were not different (P > 0.05) but were ~11% and ~20% lower than Control-EP (287 ± 46 W) and Control-WEP (18.7 ± 4.7 kJ), respectively (P < 0.05). The change in muscle [glycogen] was not significantly correlated with the changes in either EP (r = 0.19) or WEP (r = 0.07). The power-duration relationship is adversely impacted by prolonged endurance exercise. The 3MT provides valid estimates of CP and W' following 2 h of heavy-intensity exercise, but the changes in these parameters are not primarily determined by changes in muscle [glycogen].

Critical Velocity during Intermittent Running with Changes of Direction.

PURPOSE: We tested the hypothesis that critical velocity (CV) during intermittent running with changes of direction is reliably and accurately identified from a simple shuttle field test. We also tested the hypothesis that CV during intermittent running with changes of direction running is not equivalent to continuous linear running. METHODS: Young adults performed a custom shuttle test of intermittent sprint running to reveal CV. Sprints were 18.3 m per direction, with rest between sprints of 15 s for 3 min, 10 s for 2 min, and no rest for 2 min (7 min total). To test reliability, the CV shuttle test (CVST) was performed twice. To test validity, blood lactate was assessed during two separate trials inclusive of 5% above or below CVST end velocity. To explore task specificity, CV during CVST was compared to CV obtained from three linear running time trials. RESULTS: Total distance and CSVT end test velocity were similar between visits (864 ± 21 m and 3.23 ± 0.13 m·s vs 900 ± 30 m and 3.21 ± 0.15 m·s, respectively). At 5% above CVST end velocity, all subjects failed to complete 20 min and had unstable blood lactate values. A steady state blood lactate profile was observed during trials 5% below end velocity and all subjects completed the trial. The CV from the CVST was lower than the CV from linear running (△ -17% ± 6%), highlighting the importance of test specificity for threshold determination. CONCLUSIONS: The CVST provides a reliable and accurate determination of CV and can be used by coaches, athletes, and trainers to better understand the physiological impact specific to practice or competitions involving intermittent change of direction running.

Effects of Two Hours of Heavy-Intensity Exercise on the Power-Duration Relationship.

INTRODUCTION: Changes in the parameters of the power-time relationship (critical power (CP) and W') during endurance exercise would have important implications for performance. We tested the hypotheses that CP and W', estimated using the end-test power (EP) and the work done above EP (WEP), respectively, during a the 3-min all-out test (3MT), can be reliably determined, and would be lower, after completing 2 h of heavy-intensity exercise. METHODS: In study 1, six cyclists completed a 3MT immediately after 2 h of heavy-intensity exercise on two occasions to establish the reliability of EP and WEP. In study 2, nine cyclists completed a control 3MT, and a fatigued 3MT and constant power output tests to 30 min or the limit of tolerance (Tlim) below and above F-EP after 2 h of heavy-intensity exercise. RESULTS: In study 1, EP (273 ± 52 vs 276 ± 58 W) and WEP (12.4 ± 4.3 vs 12.8 ± 4.3 kJ) after 2 h of heavy-intensity exercise were not different (P > 0.05) and were highly correlated (r = 0.99; P < 0.001). In study 2, both EP (F-EP: 282 ± 52 vs C-EP: 306 ± 56 W; P < 0.01) and WEP (F-WEP: 14.7 ± 4.9 vs C-WEP: 18.3 ± 4.1 kJ; P < 0.05) were lower after 2-h heavy-intensity exercise. However, maximum O2 uptake was not achieved during exercise >F-EP and Tlim was shorter than 30 min during exercise

Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans.

PURPOSE: Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA). METHODS: FBF (Doppler ultrasound) was assessed at rest and during 5 min of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: (1) oral SDF (n = 10), (2) intra-arterial L-NMMA (n = 20), (3) SDF and L-NMMA (n = 10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed. RESULTS: FBF increased with exercise (p < 0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17 ± 1 to 15 ± 1 mL/dL/min, p < 0.01). Although the hyperemic response to NTP was augmented by SDF (area under the curve: 41 ± 7 vs 61 ± 11 AU, p < 0.01), there was no effect of SDF on exercise hyperemia (p = 0.33). CONCLUSIONS: Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans.

Exercise is medicine in cystic fibrosis.

Exercise activates adrenergic and purinergic pathways that regulate activity of ion channels on airway epithelia cells and sweat glands. Therefore, we hypothesize that exercise is not only an important therapy for cystic fibrosis (CF) patients by facilitating systemic improvements but, more importantly, that exercise can improve the pathophysiological ion dysregulation at a cellular level, thereby enhancing quality of life in CF.

Nitric oxide-mediated vasodilation becomes independent of beta-adrenergic receptor activation with increased intensity of hypoxic exercise.

Hypoxic vasodilation in skeletal muscle at rest is known to include ß-adrenergic receptor-stimulated nitric oxide (NO) release. We previously reported that the augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes ß-adrenergic mechanisms. However, it is unclear whether a ß-adrenergic receptor-stimulated NO component exists during hypoxic exercise. We hypothesized that NO-mediated vasodilation becomes independent of ß-adrenergic receptor activation with increased exercise intensity during hypoxic exercise. Ten subjects (7 men, 3 women; 23 ± 1 yr) breathed hypoxic gas to titrate arterial O(2) saturation to 80% while remaining normocapnic. Subjects performed two consecutive bouts of incremental rhythmic forearm exercise (10% and 20% of maximum) with local administration (via a brachial artery catheter) of propranolol (ß-adrenergic receptor inhibition) alone and with the combination of propranolol and nitric oxide synthase inhibition [N(G)-monomethyl-l-arginine (l-NMMA)] under normoxic and hypoxic conditions. Forearm blood flow (FBF, ml/min; Doppler ultrasound) and blood pressure [mean arterial pressure (MAP), mmHg; brachial artery catheter] were assessed, and forearm vascular conductance (FVC, ml·min(-1)·100 mmHg(-1)) was calculated (FBF/MAP). During propranolol alone, the rise in FVC (Δ from normoxic baseline) due to hypoxic exercise was 217 ± 29 and 415 ± 41 ml·min(-1)·100 mmHg(-1) (10% and 20% of maximum, respectively). Combined propranolol-l-NMMA infusion during hypoxic exercise attenuated ΔFVC at 20% (352 ± 44 ml·min(-1)·100 mmHg(-1); P < 0.001) but not at 10% (202 ± 28 ml·min(-1)·100 mmHg(-1); P = 0.08) of maximum compared with propranolol alone. These data, when integrated with earlier findings, demonstrate that NO contributes to the compensatory vasodilation during mild and moderate hypoxic exercise; a ß-adrenergic receptor-stimulated NO component exists during low-intensity hypoxic exercise. However, the source of the NO becomes less dependent on ß-adrenergic mechanisms as exercise intensity increases.

Roles of nitric oxide synthase and cyclooxygenase in leg vasodilation and oxygen consumption during prolonged low-intensity exercise in untrained humans.

The vasodilator signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults leg muscle vasodilation during steady-state exercise would be reduced independently by sequential pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) with NG-nitro-L-arginine methyl ester (L-NAME) and ketorolac, respectively. We tested a second hypothesis that NOS and COX inhibition would increase leg oxygen consumption (VO2) based on the reported inhibition of mitochondrial respiration by nitric oxide. In 13 young adults, we measured heart rate (ECG), blood pressure (femoral venous and arterial catheters), blood gases, and venous oxygen saturation (indwelling femoral venous oximeter) during prolonged (25 min) steady-state dynamic knee extension exercise (60 kick/min, 19 W). Leg blood flow (LBF) was determined by Doppler ultrasound of the femoral artery. Whole body VO2 was measured, and leg VO2 was calculated from blood gases and LBF. Resting intra-arterial infusions of acetylcholine (ACh) and nitroprusside (NTP) tested inhibitor efficacy. Leg vascular conductance (LVC) to ACh was reduced up to 53±4% by L-NAME+ketorolac infusion, and the LVC responses to NTP were unaltered. Exercise increased LVC from 4±1 to 33.1±2 ml.min(-1).mmHg(-1) and tended to decrease after L-NAME infusion (31±2 ml.min(-1).mmHg(-1), P=0.09). With subsequent administration of ketorolac LVC decreased to 29.6±2 ml.min(-1).mmHg(-1) (P=0.02; n=9). While exercise continued, LVC returned to control values (33±2 ml.min(-1).mmHg(-1)) within 3 min, suggesting involvement of additional vasodilator mechanisms. In four additional subjects, LVC tended to decrease with L-NAME infusion alone (P=0.08) but did not demonstrate the transient recovery. Whole body and leg VO2 increased with exercise but were not altered by L-NAME or L-NAME+ketorolac. These data indicate a modest role for NOS- and COX-mediated vasodilation in the leg of exercising humans during prolonged steady-state exercise, which can be restored acutely. Furthermore, NOS and COX do not appear to influence muscle VO2 in untrained healthy young adults.

Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise.

We tested the hypotheses that (1) nitric oxide (NO) contributes to augmented skeletal muscle vasodilatation during hypoxic exercise and (2) the combined inhibition of NO production and adenosine receptor activation would attenuate the augmented vasodilatation during hypoxic exercise more than NO inhibition alone. In separate protocols subjects performed forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O(2) saturation). In protocol 1 (n = 12), subjects received intra-arterial administration of saline (control) and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). In protocol 2 (n = 10), subjects received intra-arterial saline (control) and combined L-NMMA-aminophylline (adenosine receptor antagonist) administration. Forearm vascular conductance (FVC; ml min(-1) (100 mmHg)(-1)) was calculated from forearm blood flow (ml min(-1)) and blood pressure (mmHg). In protocol 1, the change in FVC (Delta from normoxic baseline) due to hypoxia under resting conditions and during hypoxic exercise was substantially lower with L-NMMA administration compared to saline (control; P < 0.01). In protocol 2, administration of combined L-NMMA-aminophylline reduced the DeltaFVC due to hypoxic exercise compared to saline (control; P < 0.01). However, the relative reduction in DeltaFVC compared to the respective control (saline) conditions was similar between L-NMMA only (protocol 1) and combined L-NMMA-aminophylline (protocol 2) at 10% (-17.5 +/- 3.7 vs. -21.4 +/- 5.2%; P = 0.28) and 20% (-13.4 +/- 3.5 vs. -18.8 +/- 4.5%; P = 0.18) hypoxic exercise. These findings suggest that NO contributes to the augmented vasodilatation observed during hypoxic exercise independent of adenosine.

Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

Exercise intensity-dependent contribution of beta-adrenergic receptor-mediated vasodilatation in hypoxic humans.

We previously reported that hypoxia-mediated reductions in alpha-adrenoceptor sensitivity do not explain the augmented vasodilatation during hypoxic exercise, suggesting an enhanced vasodilator signal. We hypothesized that beta-adrenoceptor activation contributes to augmented hypoxic exercise vasodilatation. Fourteen subjects (age: 29 +/- 2 years) breathed hypoxic gas to titrate arterial O(2) saturation (pulse oximetry) to 80%, while remaining normocapnic via a rebreath system. Brachial artery and antecubital vein catheters were placed in the exercising arm. Under normoxic and hypoxic conditions, baseline and incremental forearm exercise (10% and 20% of maximum) was performed during control (saline), alpha-adrenoceptor inhibition (phentolamine), and combined alpha- and beta-adrenoceptor inhibition (phentolomine/propranolol). Forearm blood flow (FBF), heart rate, blood pressure, minute ventilation, and end-tidal CO(2) were determined. Hypoxia increased heart rate (P < 0.05) and minute ventilation (P < 0.05) at rest and exercise under all drug infusions, whereas mean arterial pressure was unchanged. Arterial adrenaline (P < 0.05) and venous noradrenaline (P < 0.05) were higher with hypoxia during all drug infusions. The change (Delta) in FBF during 10% hypoxic exercise was greater with phentolamine (Delta306 +/- 43 ml min(-1)) vs. saline (Delta169 +/- 30 ml min(-1)) or combined phentolamine/propranolol (Delta213 +/- 25 ml min(-1); P < 0.05 for both). During 20% hypoxic exercise, DeltaFBF was greater with phentalomine (Delta466 +/- 57 ml min(-1); P < 0.05) vs. saline (Delta346 +/- 40 ml min(-1)) but was similar to combined phentolamine/propranolol (Delta450 +/- 43 ml min(-1)). Thus, in the absence of overlying vasoconstriction, the contribution of beta-adrenergic mechanisms to the augmented hypoxic vasodilatation is dependent on exercise intensity.

Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome.

Patients with postural tachycardia syndrome (POTS) have excessive tachycardia without hypotension during orthostasis as well as exercise. We tested the hypothesis that excessive tachycardia during exercise in POTS is not related to abnormal baroreflex control of heart rate (HR). Patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter) and HR (ECG) were measured. Baroreflex sensitivity of HR was assessed by bolus intravenous infusion of phenylephrine at each workload. In both positions, HR was higher in the patients than the controls during exercise. Supine baroreflex sensitivity (HR/systolic pressure) in POTS patients was -1.3 +/- 0.1 beats.min(-1).mmHg(-1) at rest and decreased to -0.6 +/- 0.1 beats.min(-1).mmHg(-1) during 75-W exercise, neither significantly different from the controls (P > 0.6). In the upright position, baroreflex sensitivity in POTS patients at rest (-1.4 +/- 0.1 beats.min(-1).mmHg(-1)) was higher than the controls (-1.0 +/- 0.1 beats.min(-1).mmHg(-1)) (P < 0.05), and it decreased to -0.1 +/- 0.04 beats.min(-1).mmHg(-1) during 75-W exercise, lower than the controls (-0.3 +/- 0.09 beats.min(-1).mmHg(-1)) (P < 0.05). The reduced arterial baroreflex sensitivity of HR during upright exercise was accompanied by greater fluctuations in systolic and pulse pressure in the patients than in the controls with 56 and 90% higher coefficient of variations, respectively (P < 0.01). However, when baroreflex control of HR was corrected for differences in HR, it was similar between the patients and controls during upright exercise. These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR.