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In this article, we highlight the contributions of passive experiments that address important exercise-related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical "knockout" animal models among human research participants. Natural experiments are gleaned from data sets that allow population-based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879-4907, 2023., (Copyright © 2023 American Physiological Society. All rights reserved.)

New Findings: What is the central question of this study? Do humans with high-affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near-infrared spectroscopy-derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia., Abstract: Recently, researchers in our laboratory have shown that humans with genetic mutations resulting in high-affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal-affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near-infrared spectroscopy-derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal-affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects., (© 2022 The Authors. Experimental Physiology © 2022 The Physiological Society.)

Elite performing men continue to record faster record times in running events compared to women. These sex-based differences in running speed and endurance in humans are expected based on sexual dimorphisms that contribute to differences in the determinants of aerobic performance. Comparatively, the sexual dimorphisms contributing to sex-based differences in elite aerobic performance are not ubiquitous across other species that compete in running events. The purpose of this review is to offer a framework and model for ongoing discussions of the physiological determinants and ultimately limits of physical performance. The records for average running speed of champion athletes were delineated by sex for thoroughbred horses, greyhound dogs, and humans. Male and female performances within each of these species are being optimized by training, nutrition, and financial incentives, and are approaching a performance maximum. For horses and greyhounds breeding also plays a role. Analysis of athletic records shows that there is a sex-related difference of ~10% or more in elite athletic performance for humans; however, the upper limit of performance does not appear to be different between sexes for thoroughbred horses and greyhound dogs. In the context of the nil sex differences in running performance in thoroughbreds and greyhounds, we discuss the physiological role of sexual dimorphisms on sex-specific limits to running performance. We highlight that studies on both human and animal performance in athletic events stimulate critical physiological questions and drive novel research., (© 2021 Federation of American Societies for Experimental Biology.)

The oxygen transport cascade describes the physiological steps that bring atmospheric oxygen into the body where it is delivered and consumed by metabolically active tissue. As such, the oxygen cascade is fundamental to our understanding of exercise in health and disease. Our narrative review will highlight each step of the oxygen transport cascade from inspiration of atmospheric oxygen down to mitochondrial consumption in both healthy active males and females along with clinical conditions. We will focus on how different steps interact along with principles of homeostasis, physiological redundancies, and adaptation. In particular, we highlight some of the parallels between elite athletes and clinical conditions in terms of the oxygen cascade., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

This graphical review highlights a focused application of a key principle ('Krogh Principle') identified by Nobel-prize winning physiologist Professor August Krogh (1874-1949) that states "for many problems there is an animal on which it can be most conveniently studied". We apply the Krogh Principle to human physiology by proposing that "for many problems there is a unique group of humans on which it can be most conveniently studied". As such, we present 5 unique human case studies. Case 1 discusses whether signals from exercising muscles cause blood pressure to rise using a patient with a spinal cord lesion. Case 2 investigates the role of the sympathetic nervous system in the blood pressure response to exercise using patients who have undergone sympathectomy for hypertension. Case 3 asks whether increases in blood lactate are necessary for the non-linear increase in breathing with heavy exercise using patients with McArdle's disease. Case 4 applies fundamental scaling principles from comparative physiology to elite athletes to investigate the role of body size on maximal aerobic capacity. Finally, Case 5 describes our recent work that investigates whether a left shift in the oxygen hemoglobin dissociation curve can facilitate hypoxic exercise using patients with left-shifted hemoglobinopathies. In summary, we have expanded the inter-species message of the August Krogh Principle and highlighted the need to search for odd examples and experiments of nature. In this context, observations from unusual humans are a source of insights into physiology, which may be translated into therapeutic approaches for disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The past decade has witnessed growing scientific and commercial interest in the identification of bioactive oral compounds that mimic or potentiate the effects of exercise, so-called 'exercise pills' or 'exercise mimetics.' These compounds have, to date, typically targeted skeletal muscle in an attempt to stimulate some of the adaptations to exercise induced by endurance training. Accordingly, they fail to impart many of the broad health protecting effects of exercise that are seen in tissues and organs other than skeletal muscle. In the context that multiple integrative regulatory and often redundant pathways have evolved to detect and respond to human movement, here we consider the complex challenges of designing a pill that might mimic the extensive range of exercise benefits. In particular, we consider the limits of the current 'myocentric' paradigm given the wide-ranging array of impacts that exercise exerts on atherosclerosis and the cardiovascular system. We discuss the validity and limitations of the concept that low dose cardiovascular polypills, already in large scale trials, may represent one form of cardiovascular exercise mimetic. Finally, given that some calls for an exercise pill stem from a response to the perceived failure of expert advice, evidence-based guidelines and current public health approaches, we explore possible strategies that might address the global rise in inactivity. In the event that a broad spectrum exercise mimetic might ever be developed, we discuss some generic issues related to adoption and adherence of therapeutic interventions., (© 2019 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Although over 100 studies and reviews have examined the ergogenic effects of dietary nitrate (NO3) supplementation in young, healthy men and women, it is unclear if participant and environmental factors modulate the well-described ergogenic effects-particularly relevant factors include biological sex, aerobic fitness, and fraction of inspired oxygen (FiO2) during exercise. To address this limitation, the literature was systematically reviewed for randomized, crossover, placebo-controlled studies reporting exercise performance outcome metrics with NO3 supplementation in young, healthy adults. Of the 2033 articles identified, 80 were eligible for inclusion in the meta-analysis. Random-effects meta-analysis demonstrated that exercise performance improved with NO3 supplementation compared with placebo (d = 0.174; 95% confidence interval (CI), 0.120-0.229; P < 0.001). Subgroup analyses conducted on biological sex, aerobic fitness, and FiO2 demonstrated that the ergogenic effect of NO3 supplementation was as follows: 1) not observed in studies with only women (n = 6; d = 0.116; 95% CI, -0.126 to 0.358; P = 0.347), 2) not observed in well-trained endurance athletes (≥65 mL·kg·min; n = 26; d = 0.021; 95% CI, -0.103 to 0.144; P = 0.745), and 3) not modulated by FiO2 (hypoxia vs normoxia). Together, the meta-analyses demonstrated a clear ergogenic effect of NO3 supplementation in recreationally active, young, healthy men across different exercise paradigms and NO3 supplementation parameters; however, the effect size of NO3 supplementation was objectively small (d = 0.174). NO3 supplementation has more limited utility as an ergogenic aid in participants with excellent aerobic fitness that have optimized other training parameters. Mechanistic research and studies incorporating a wide variety of subjects (e.g., women) are needed to advance the study of NO3 supplementation; however, additional descriptive studies of young, healthy men may have limited utility.

Aging increases autonomic support of blood pressure; however, the impact of aerobic fitness on autonomic support of blood pressure has not been addressed in women. As such, we hypothesized that aerobic fitness would be related to the change in blood pressure during ganglionic blockade such that women with greater aerobic fitness would have a blunted fall in blood pressure during ganglionic blockade due to increased vagal tone. Thirteen young premenopausal and 13 older postmenopausal women completed a screening visit where aerobic fitness (maximal oxygen consumption, VO 2max ) was measured. On a separate study day, participants were instrumented for assessment of muscle sympathetic nerve activity, heart rate (electrocardiography), and beat by beat blood pressure (arterial catheter and pressure transducer) and underwent pharmacological blockade of the autonomic ganglia using trimethaphan camyslate. Heart rate, blood pressure, and muscle sympathetic nerve activity were analyzed before and during ganglionic blockade. In young women, there was a significant relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =0.761, P =0.003). In older women, there was no relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =-0.106, P =0.73). Measures of heart rate variability were related to fitness in young women, but not older women (root mean square of successive differences between normal heartbeats, r =0.713, P =0.006 versus r =-0.172, P =0.575). Our data suggest that in young women, autonomic support of blood pressure is attenuated in those that are highly fit; however, this relationship is not significant in older women.

Introduction: It remains unclear if naturally occurring respiratory muscle (RM) work influences leg diffusive O 2 transport during exercise in heart failure patients with reduced ejection fraction (HFrEF). In this retrospective study, we hypothesized that RM unloading during submaximal exercise will lead to increases in locomotor muscle O 2 diffusion capacity (D M O 2 ) contributing to the greater leg VO 2 ., Methods: Ten HFrEF patients and 10 healthy control matched participants performed two submaximal exercise bouts (i.e., with and without RM unloading). During exercise, leg blood flow was measured via constant infusion thermodilution. Intrathoracic pressure was measured via esophageal balloon. Radial arterial and femoral venous blood gases were measured and used to calculate leg arterial and venous content (CaO 2 and CvO 2 , respectively), VO 2 , O 2 delivery, and D M O 2 ., Results: From CTL to RM unloading, leg VO 2 , O 2 delivery, and D M O 2 were not different in healthy participants during submaximal exercise (all, p > .15). In HFrEF, leg VO 2 (CTL: 0.7 ± 0.3 vs. RM unloading: 1.0 ± 0.4 L/min, p < .01), leg O 2 delivery (CTL: 0.9 ± 0.4 vs. RM unloading: 1.4 ± 0.5 L/min, p < .01), and leg D M O 2 (CTL: 31.5 ± 11.4 vs. RM unloading: 49.7 ± 18.6 ml min -1  mmHg -1 ) increased from CTL to RM unloading during submaximal exercise (all, p < .01), whereas CaO 2 -CvO 2 was not different (p = .51). The degree of RM unloading (i.e., % decrease in esophageal pressure-time integral during inspiration) was related to the % increase in leg D M O 2 with RM unloading (r = -.76, p = .01)., Conclusion: Our data suggest RM unloading leads to increased leg VO 2 due to greater convective and diffusive O 2 transport during submaximal exercise in HFrEF patients., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O 2 partial pressure: 144 mmHg) and hypoxic ([Formula: see text]: 0.125; O 2 partial pressure: 82 mmHg) conditions before ( day 1 ) and after ( day 15 ) 14 days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (V̇o 2 ), and cardiac output (Q) were measured noninvasively, while arterial blood pressure (MAP) and blood gases ([Formula: see text], [Formula: see text], and [Formula: see text]) were measured invasively. The 14-day drug administration left shifted the oxygen-hemoglobin dissociation curve (ODC; p50 measured at standard pH and Pco 2 ; day 1 : 28.0 ± 2.1 mmHg vs. day 15 : 26.1 ± 1.8 mmHg, P < 0.05). RPE, dyspnea, V̇o 2 , Q, and MAP were not different between day 1 and day 15 . [Formula: see text] was similar during normoxia on day 1 and day 15 while stationary but higher during exercise ( day 1 : 95.2 ± 0.4% vs. day 15 : 96.6 ± 0.3%, P < 0.05). [Formula: see text] was higher during hypoxia on day 15 while stationary ( day 1 : 82.9 ± 3.4% vs. day 15 : 90.9 ± 1.8%, P < 0.05) and during exercise ( day 1 : 73.6 ± 2.5% vs. day 15 : 84.8 ± 2.7%, P < 0.01). [Formula: see text] and [Formula: see text]were systematically higher and lower, respectively, after drug ( P < 0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in [Formula: see text]. Oral administration of voxelotor left shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering V̇o 2 and central hemodynamics during rest and low-intensity exercise. This effect was more pronounced during submaximal hypoxic exercise, when arterial desaturation was more evident. Additional studies are needed to determine the effects of voxelotor during maximal exercise and under chronic forms of hypoxia. NEW & NOTEWORTHY In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.

New Findings: What is the central question of this study? How do locomotor muscle metabo- and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase-2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure., Abstract: Heart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo- and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase-2 (COX-2), purinergic 2X 3 (P2X 3 ), transient receptor potential vanilloid type 1 (TRP V 1), acid-sensing ion channel 3 (ASIC 3 ), Piezo 1 and Piezo 2 protein expression. TRP V 1 and COX-2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X 3 , ASIC 3 , and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX-2 protein expression was related to the percentage change in ventilation (r = -0.66) and mean arterial pressure (MAP) (r = -0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRP V 1 protein expression was related to the percentage change in systolic blood pressure (r = -0.77, P = 0.02) and MAP (r = -0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRP V 1 and COX-2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRP V 1 and COX-2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Key Points: Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange., Abstract: The longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P 50  = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P 50  = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end-exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects' oxyhaemoglobin saturation ( S a , O 2 ) was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake ( V ̇ O 2 max ) (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in V ̇ O 2 max between trials was related to the change in S a O 2 (r = -0.75, p < 0.0001). Compared to normoxia, the controls' alveolar-to-arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Maximum oxygen consumption ([Formula: see text]) is not only an indicator of endurance performance, but also a strong predictor of cardiovascular disease and mortality. This physiological parameter is known to decrease with aging. In turn, physical exercise might attenuate the rate of aging-related decline in [Formula: see text], which in light of the global population aging is of major clinical relevance, especially at advanced ages. In this narrative review, we summarize the evidence available from masters athletes about the role of lifelong endurance exercise on aging-related [Formula: see text] decline, with examples of the highest [Formula: see text] values reported in the scientific literature for athletes across different ages (e.g., 35 ml·kg -1 ·min -1 in a centenarian cyclist). These data suggest that a linear decrease in [Formula: see text] might be possible if physical exercise loads are kept consistently high through the entire life span, with [Formula: see text] values remaining higher than those of the general population across all ages. We also summarize the main physiological changes that occur with inactive aging at different system levels-pulmonary and cardiovascular function, blood O 2 carrying capacity, skeletal muscle capillary density and oxidative capacity-and negatively influence [Formula: see text], and review how lifelong exercise can attenuate or even prevent most-but apparently not all (e.g., maximum heart rate decline)-of them. In summary, although aging seems to be invariably associated with a progressive decline in [Formula: see text], maintaining high levels of physical exercise along the life span slows the multi-systemic deterioration that is commonly observed in inactive individuals, thereby attenuating age-related [Formula: see text] decline.

New Findings: What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high-dose intra-arterial infusion of either adenosine or ATP, on the rapid-onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism., Abstract: The hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid-onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high-dose intra-arterial infusion of either adenosine (ADO) or ATP. Twenty-four healthy young participants (28 ± 1 years) performed a single forearm contraction (20% maximal voluntary contraction) 75 min after commencement of a continuous infusion of ADO (n = 6), ATP (n = 8) or saline (control; n = 10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100 mmHg per decilitre of forearm volume) was significantly higher during ADO (33 ± 17) and ATP infusion (33 ± 17) compared with the control infusion (8 ± 3; P < 0.05). The peak FVCs post-contraction during ADO and ATP infusions were significantly greater than during the control infusion (P < 0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14 ± 1; ADO, 24 ± 2; and ATP, 23 ± 6; P = 0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333 ± 69 and 440 ± 125); however, total FVC during ATP infusion was significantly greater compared with the control value (150 ± 19; P < 0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Preeclampsia (PE) is a hypertensive disorder of pregnancy described as a condition of excessive sympathoexcitation. PE places a woman at increased risk for lifelong hypertension and cognitive impairment. Cerebral blood velocity is blunted in response to a vasoactive stimulus in women with a history of PE. This study investigated how a sympathoexcitatory stimulus affects cerebral blood velocity in women with a history of PE. Middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) were measured in postmenopausal women with a history of PE ( n = 21; age = 59 ± 5 yr) and a history of a normotensive pregnancy (NP; n = 27; age = 58 ± 4 yr), at baseline, during isometric handgrip to fatigue (IHG) followed by postexercise ischemia (PEI), and a recovery period (REC). Baseline MAP and MAP responses to IHG and PEI did not differ between groups. MCAv at baseline and throughout the stimulus was lower in PE women compared with NP women ( P < 0.05 for all). MCAv increased during IHG in both groups ( P < 0.05). This increase in MCAv was greater in PE compared with NP women during IHG and REC (IHG: PE 13 ± 2% vs. NP 9 ± 2%; REC: PE 3 ± 2% vs. NP -2 ± 2%; P < 0.05 for both). Thus, a history of PE is associated with low baseline cerebral blood velocity but an augmented response to a sympathoexcitatory stimulus. These changes in cerebral blood flow regulation may lead to an increased risk for cognitive impairment in women with a history of PE.

John O. Holloszy, as perhaps the world's preeminent exercise biochemist/physiologist, published >400 papers over his 50+ year career, and they have been cited >41,000 times. In 1965 Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in a very active era of skeletal muscle plasticity research. He subsequently went on to describe the consequences of and the mechanisms underlying these adaptations. Holloszy was first to show that muscle contractions increase muscle glucose transport independent of insulin, and he studied the mechanisms underlying this response throughout his career. He published important papers assessing the impact of training on glucose and insulin metabolism in healthy and diseased humans. Holloszy was at the forefront of rodent studies of caloric restriction and longevity in the 1980s, following these studies with important cross-sectional and longitudinal caloric restriction studies in humans. Holloszy was influential in the discipline of cardiovascular physiology, showing that older healthy and diseased populations could still elicit beneficial cardiovascular adaptations with exercise training. Holloszy and his group made important contributions to exercise physiology on the effects of training on numerous metabolic, hormonal, and cardiovascular adaptations. Holloszy's outstanding productivity was made possible by his mentoring of ~100 postdoctoral fellows and substantial NIH grant funding over his entire career. Many of these fellows have also played critical roles in the exercise physiology/biochemistry discipline. Thus it is clear that exercise biochemistry and physiology will be influenced by John Holloszy for numerous years to come.

This paper reports temporal changes in physiological measurements of exercise performance in a young man transitioning from alpine skiing until he became a world junior champion time trial cyclist after only 3 yr of bike-specific training. At the time he became World Champion he also achieved among the highest reported maximal oxygen uptake (V̇o 2max ) value, 96.7 ml·min -1 ·kg -1 , or 7,397 ml/min in absolute terms at 76.5 kg, which had increased by 29.6% from 74.6 ml·min -1 ·kg -1 pre-bike-specific training. After 15 mo with almost no structured exercise training, V̇o 2max returned to 77.0 mL·min -1 ·kg -1 and was similar to the value reported before specific bike training, albeit with absolute term (6,205 ml/min) still being 11.3% higher. Part of the explanation for his athletic achievements is likely also related to the up to 20.9% improvement in Power@4 mmol/l (W). Although genetic profiles of endurance athletes have not generated data suggesting a shared genetic signature associated with elite endurance performance, this case study highlights the importance of intrinsic biological factors in elite endurance performance. NEW & NOTEWORTHY This study shows that very high V̇o 2max values (>70 ml·min -1 ·kg -1 ) can be found in individuals not previously specializing in aerobic training and that values of >90 ml·min -1 ·kg -1 , as well as a cycling world junior champion title, can be achieved in such individuals with just 3 yr of dedicated exercise training.

The contribution of Adenosine (ADO) to exercise hyperemia remains controversial and it is unknown whether ADO can evoke the prolonged vasodilation seen during exercise bouts. Therefore, we tested hypotheses in the human forearm during 3 h of intra-arterial high dose ADO infusion: (1) skeletal muscle blood flow would wane over time; (2) exercise hyperemic responses during ADO administration would be unaffected compared to baseline. Using sodium nitroprusside (SNP), we tested parallel hypotheses regarding nitric oxide (NO) in a separate group of participants. Seventeen young healthy participants (ADO: n = 9; SNP: n = 8) performed multiple rhythmic handgrip exercise bouts (20% of maximum), two during saline and five during 3 h of continuous drug infusion. Five minutes of ADO infusion resulted in a ~5-fold increase in forearm vascular conductance (FVC; 4.8 ± 0.6 vs. 24.2 ± 3.2 mL/min/100 mmHg, P < 0.05). SNP caused a ~4-fold increase (4.4 ± 0.6 vs. 16.6 ± 2 mL/min/100 mmHg, P < 0.05). FVC did not wane over time with ADO (24.2 ± 3.2 and 22 ± 1.2 mL/min/100 mmHg [P > 0.05]) or SNP (16.6 ± 2 and 14.1 ± 2.4 mL/min / 100 mmHg [P > 0.05]) at 5 versus 150 min. Superimposed exercise during ADO or SNP infusions evoked marked and consistent additional dilation over the course of the infusions. Our findings demonstrate that in humans there is no reduction in endothelial or vascular smooth muscle responsiveness to the exogenous vasodilatory metabolites ADO and NO. Additionally, even in the presence of an exogenous vasodilator, superimposed exercise can cause significant hyperemia., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The increase in interstitial potassium (K + ) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K + in exercise hyperemia, we perfused skeletal muscle with K + before contractions, such that the effect of any endogenously-released K + would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF) (Doppler ultrasound) and forearm vascular conductance (FVC) (FBF/mean arterial pressure) during 4 min of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions, 2) infusion of KCl before the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly before the onset of exercise (control: 39 ± 6 vs. KCl: 81 ± 12 and SNP: 82 ± 13 ml·min -1 ·100 mmHg -1 ; both P < 0.05 vs. control). Infusion of KCl at rest diminished the hyperemic (ΔFBF) and vasodilatory (ΔFVC) response to subsequent exercise by 22 ± 5% and 30 ± 5%, respectively (both P < 0.05 vs. control), whereas SNP did not affect the change in FBF ( P = 0.74 vs. control) or FVC ( P = 0.61 vs. control) from rest to steady-state exercise. These findings implicate the K + ion as an essential vasodilator substance contributing to exercise hyperemia in humans. NEW & NOTEWORTHY Our findings support a significant and obligatory role for potassium signaling in the local vasodilatory and hyperemic response to exercise in humans.

The biological responses to acute and chronic exercise are marked by a high level of physiological redundancy that operates at various levels of integration, including the molecular, cellular, organ-system, and whole-body scale. During acute exercise, this redundancy protects whole-body homeostasis in the face of 10-fold or more increases in whole-body metabolic rate. In some cases, there are "trade-offs" between optimizing the performance of a given organ or system versus whole-body performance. Physiological redundancy also plays a key role in the adaptive responses to exercise training and high levels of habitual physical activity, including the positive effects of regular exercise on health. Appreciation of the general principles of physiological redundancy is critical to (1) gain an overall understanding of short- and long-term responses to exercise, and (2) place physiological responses occurring at various levels of integration in perspective., (Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.)

Nitric oxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase-5 (PDE-5). Whether PDE-5 limits exercise vasodilation onset kinetics is unknown. We hypothesized the time course of exercise vasodilation would be 1) accelerated during PDE-5 inhibition (sildenafil citrate, SDF) and 2) decelerated during NO synthase inhibition ( N G -monomethyl-l-arginine, l-NMMA), and 3) the effect of SDF on vasodilation onset kinetics would be attenuated with concurrent l-NMMA. Data from 29 healthy adults were analyzed. Individuals completed 5 min of moderate-intensity forearm exercise under control conditions and during 1) oral SDF ( n = 8), 2) intra-arterial l-NMMA ( n = 15), or 3) combined SDF + l-NMMA ( n = 6). Forearm blood flow (FBF; Doppler ultrasound of the brachial artery) and mean brachial artery blood pressure (MAP) were measured continuously. Forearm vascular conductance (FVC, FBF ÷ MAP) was curve-fit with a monoexponential model, and vasodilation onset kinetics were assessed by mean response time (MRT, time to achieve 63% of steady state). SDF had no effect on MRT ( P = 0.90). NOS inhibition increased MRT ( P = 0.01). MRT during SDF+l-NMMA was not different from control exercise ( P = 0.76). PDE-5 inhibition alone has no effect on rapid-onset vasodilation. Whereas NOS inhibition decelerates vasodilator kinetics, when combined with SDF, vasodilator kinetics do not differ from control. These data suggest NO-independent activation of cGMP occurs at exercise onset; thus PDE-5 inhibition may improve vasodilation in pathologies where NO bioavailability is impaired. NEW & NOTEWORTHY We show that when NO bioavailability is reduced, PDE-5 inhibition can restore vasodilation onset kinetics of exercise-mediated vasodilation via NO-independent cGMP pathways. These data suggest PDE-5 inhibition may improve exercise vasodilation onset kinetics in pathologies where NO bioavailability is impaired.

The carotid body chemoreceptors are activated during hypoglycemia and contribute to glucoregulation during prolonged exercise in dogs. Low-dose intravenous infusions of dopamine have been shown to blunt the activation of the carotid body chemoreceptors during hypoxia. Therefore, we tested the hypotheses that dopamine would blunt glucoregulatory responses and attenuate plasma glucose during prolonged aerobic exercise in healthy participants. Twelve healthy participants completed two randomized exercise sessions at 65% peak oxygen consumption for up to 120 min. Saline was infused during one exercise session, and dopamine (2 μg·kg -1 ·min -1 ) was infused during the other session. Arterial plasma glucose, growth hormone, glucagon, cortisol, norepinephrine, and epinephrine were measured every 10 min. Exercise duration during dopamine infusion was 107 ± 6 and 119 ± 0.8 min during saline infusion. Glucose area under the curve during exercise was lower during dopamine (9,821 ± 686 vs. 11,194 ± 395 arbitrary units; P = 0.016). The ratio of circulating growth hormone to glucose and the ratio of glucagon to glucose were greater during dopamine ( P = 0.045 and 0.037, respectively). These results indicate that the infusion of dopamine during aerobic exercise impairs glucoregulation. This suggests that the carotid body chemoreceptors contribute to glucoregulation during prolonged exercise in healthy exercise-trained humans.

Context: Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including the gonadotropic and corticotropic axes., Objective: To quantify the impact of acute exercise on coordinate luteinizing hormone (LH) and testosterone (T) and adrenocorticotropic hormone (ACTH) and cortisol secretion in healthy men in relation to age., Participants and Design: Prospectively randomized, within-subject crossover study in 23 men aged 19 to 77 years old. Subjects underwent rest and 30 minutes of mixed exercise at 65% of maximal aerobic capacity with 10-minute blood sampling between 7:00 am and 1:00 pm, 2 weeks apart., Main Outcome Measures: Incremental changes in LH, T, ACTH, and cortisol concentrations, the feedforward and feedback strength between exercise and rest, quantified by approximate entropy (ApEn), and bihormonal synchrony, quantitated by cross-ApEn., Results: Mean hourly exercise-minus-rest LH and ACTH increments increased from -0.055 ± 0.187 to 0.755 ± 0.245 IU/L (P = 0.003) and from 2.9 ± 2.2 to 71.2 ± 16.1 ng/L (P < 0.0001), respectively, during exercise. T and cortisol increments increased concurrently from -9.6 ± 16.7 to 47.6 ± 17.1 ng/dL (P < 0.0001) and 0.45 ± 0.76 to 7.27 ± 0.64 µg/dL (P < 0.0001), respectively. During exercise, feedforward and feedback LH-T and ACTH-cortisol cross-ApEn decreased markedly quantifying enhanced hormonal coupling., Conclusions: Acute moderate mixed exercise in healthy men rapidly enhances feedforward LH-T and ACTH-cortisol coordination and reciprocal feedback within the gonadotropic and corticotropic axes. In principle, enhancement of both LH-T and ACTH-cortisol secretory synchrony by exercise could reflect augmented coupling between brain-testicular and brain-adrenal neural outflow., (Copyright © 2017 Endocrine Society)

This brief review summarizes factors associated with elite endurance performance, trends in distance running training, and participation by men and more recently women. It is framed in the context of key ideas about the physiological determinants of endurance performance but also touches on some historical and sociological factors relevant to the overall topic. Historical trends that served to increase women's participation in elite endurance events are also discussed as is the role of increased volume and intensity of training. The rapid improvement in women's world record marathon times in the 1970s and 80s are emblematic of these trends and represent a combination of increased training volume and intensity and more competitive opportunities. This occurred as bans on participation by women in endurance events were lifted. For men these same trends evolved over a much longer time frame. The main physiological factor responsible for 10-12% slower times in women compared to men at the elite level are also considered and probably centre aroundV̇O2 max ., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

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-N G -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.

This perspective highlights some of the key contributions of Professor Bengt Saltin (1935-2014) to exercise physiology. The emergence of exercise physiology from work physiology as his career began is discussed as are his contributions in a number of areas. Saltin's open and question-based style of leadership is a model for the future of our field.

In humans, intra-arterial ATP infusion in limbs mimics many features of exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore, we addressed two questions during a continuous 3-h brachial artery infusion of ATP [20 μg·100 ml forearm volume (FAV)(-1)·min(-1)]: 1) would skeletal muscle blood flow remain robust or wane over time (tachyphylaxis); and 2) would the hyperemic response to moderate-intensity exercise performed during the ATP administration be blunted compared with that during control (saline) infusion. Nine participants (25 ± 1 yr) performed one trial consisting of seven bouts of rhythmic handgrip exercise (20 contractions/min at 20% of maximum), two bouts during saline (control), and five bouts during 180 min of continuous ATP infusion. Five minutes of ATP infusion resulted in a 710% increase in forearm vascular conductance (FVC) from control (4.8 ± 0.77 vs. 35.0 ± 5.7 ml·min(-1)·100 mmHg(-1)·dl FAV(-1), P < 0.05). Contrary to our expectations, FVC did not wane over time with values of 35.0 ± 5.7 and 36.0 ± 7.7 ml·min(-1)·100 mmHg(-1)·dl FAV(-1) (P > 0.05), seen prior to the exercise bouts at 5 vs. 150 min, respectively. During superimposed exercise, FVC increased from 35.0 ± 5.7 to 49.6 ± 5.4 ml·min(-1)·100 mmHg(-1)·dl FAV(-1) at 5 min and 36.0 ± 7.7 to 54.5 ± 5.0 at 150 min (P < 0.05). Our findings demonstrate ATP vasodilation is prolonged over time without tachyphylaxis; however, exercise hyperemia responses remain intact. Our results challenge the metabolic theory of exercise hyperemia, suggesting a disconnect between matching of blood flow and metabolic demand., (Copyright © 2016 the American Physiological Society.)

Although low- to moderate-intensity exercise has well-known cardiovascular benefits, it has been increasingly suggested that prolonged strenuous endurance exercise (SEE) could have potential deleterious cardiac effects. In effect, the term 'cardiac overuse injury' (or 'over-exercise') has been recently reported to group all the possible deleterious cardiac consequences of repeated exposure to SEE or 'over-exercise'. In this article, we provide a balanced overview of the current state of knowledge regarding the 'pros' and 'cons' of SEE from a cardiological point of view.

Background: Secondary pulmonary hypertension is common in heart failure (HF) patients. We hypothesized that inhibition of feedback from locomotor muscle group III/IV neurons contributes to reduced pulmonary vascular pressures independent of changes in cardiac function during exercise in HF., Methods: 9 HF patients (ages, 60 ± 2; EF, 26.7 ± 1.9%; New York Heart Association classes, I-III) and 9 age/gender matched controls (ages, 63 ± 2) completed five-minutes of constant-load cycling (65% Workloadpeak) with intrathecal fentanyl or placebo on randomized separate days. Mean arterial pressure (MAP), heart rate (HR), end-tidal partial pressure of CO2 (PETCO2), and oxygen consumption (VO2) were measured at rest and exercise. Non-invasive surrogates for cardiac power (circulatory power, CircP=VO2 × MAP), stroke volume (oxygen pulse, O2pulse=VO2/HR), and pulmonary arterial pressure (GXCAP=O2pulse × PETCO2) were calculated., Results: At rest and end-exercise, differences between fentanyl versus placebo were not significant for CircP in HF or controls. Differences between fentanyl versus placebo for GXCAP were not significant at rest in HF or controls. At end-exercise, GXCAP was significantly higher with fentanyl versus placebo in HF (691 ± 59 versus 549 ± 38 mL/beat × mmHg), but not controls (536 ± 59 versus 474 ± 43 mL/beat × mmHg). Slopes (rest to end-exercise) for GXCAP were significantly higher with fentanyl versus placebo in HF (95.1 ± 9.8 versus 71.6 ± 6.0 mL/beat × mmHg), but not controls (74.3 ± 9.5 versus 60.8 ± 6.5 mL/beat × mmHg). CircP slopes did not differ between fentanyl versus placebo in HF or controls (p>0.05)., Conclusion: We conclude that feedback from locomotor muscle group III/IV neurons may evoke increases in pulmonary vascular pressures independent of changes in cardiac function during exercise in HF., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Prolonged strenuous endurance exercise (SEE) such as marathon running has recently been associated with potential deleterious cardiac effects, particularly increased risk of atrial fibrillation (AF). This topic is medically important due to the increasing number of participants in SEE events lasting several hours, including older people. The aim of this narrative review is to provide a summary of the evidence available on SEE and related issues such as cardiovascular mortality, AF, potential cardiac remodeling, cardiovascular events during exertion, or the need for pre-participation screening (with a special focus on beginners). This type of information can help physicians giving advice to their patients and the general public regarding safe SEE practice., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Exercise evokes pulsatile GH release followed by autonegative feedback, whereas glucose suppresses GH release followed by rebound-like GH release (feedforward escape). Here we test the hypothesis that age, sex steroids, insulin, body composition and physical power jointly determine these dynamic GH responses., Methods: This was a prospectively randomized glucose-blinded study conducted in the Mayo Center for Advancing Translational Sciences in healthy men ages 19-77 years (N=23). Three conditions, fasting/rest/saline, fasting/exercise/saline and fasting/rest/iv glucose infusions, were used to drive GH dynamics during 10-min blood sampling for 6h. Linear correlation analysis was applied to relate peak/nadir GH dynamics to age, sex steroids, insulin, CT-estimated abdominal fat and physical power (work per unit time)., Results: Compared with the fasting/rest/saline (control) day, fasting/exercise/saline infusion evoked peak GH within 1h, followed by negative feedback 3-5h later. The dynamic GH excursion was strongly (R(2)=0.634) influenced by (i) insulin negatively (P=0.011), (ii) power positively (P=0.0008), and (iii) E2 positively (P=0.001). Dynamic glucose-modulated GH release was determined by insulin negatively (P=0.0039) and power positively (P=0.0034) (R(2)=0.454). Under rest/saline, power (P=0.031) and total abdominal fat (P=0.012) (R(2)=0.267) were the dominant correlates of GH excursions., Conclusion: In healthy men, dynamic GH perturbations induced by exercise and glucose are strongly related to physical power, insulin, estradiol, and body composition, thus suggesting a network of regulatory pathways., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans., (Copyright © 2015 the American Physiological Society.)

Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.

Hyperoxia can cause substantial reductions in peripheral and coronary blood flow at rest and during exercise, which may be caused by reactive oxygen species (ROS) generated during hyperoxia. The aim of this study was to investigate the role of ROS in hyperoxia-induced reductions in skeletal muscle blood flow during forearm exercise. We hypothesized that infusion of vitamin C would abolish the effects of hyperoxia on the forearm blood flow (FBF) responses to exercise. Twelve young healthy adults performed rhythmic forearm handgrip exercise (10% of maximum voluntary contraction for 5 min) during normoxia and hyperoxia. For each condition, two trials were conducted with intra-arterial administration of saline or vitamin C. FBF was measured using Doppler ultrasound. During hyperoxia with saline, FBF and forearm vascular conductance (FVC) were 86.3 ± 5.1 and 86.8 ± 5.2%, respectively, of the normoxic values (100%) (P < 0.05). During vitamin C, hyperoxic FBF and FVC responses were 90.9 ± 4.2 and 90.9 ± 4.1%, respectively, of the normoxic values (P = 0.57 and 0.59). Subjects were then divided into three subgroups based on their percent decrease in FBF (>20, 10-20, and <10%) during hyperoxia. In the subgroup that demonstrated the greatest hyperoxia-induced changes (>20%), FBF and FVC during hyperoxia were 67.1 ± 4.0 and 66.8 ± 3.6%, respectively, of the normoxic values. Vitamin C abolished these effects on FBF and FVC with values that were 102.0 ± 5.2 and 100.8 ± 6.1%, respectively. However, vitamin C had no effect in the other two subgroups. This analysis is consistent with the idea that ROS generation blunts the FBF responses to exercise in the subjects most affected by hyperoxia., (Copyright © 2014 the American Physiological Society.)

Exercise represents a major challenge to whole-body homeostasis provoking widespread perturbations in numerous cells, tissues, and organs that are caused by or are a response to the increased metabolic activity of contracting skeletal muscles. To meet this challenge, multiple integrated and often redundant responses operate to blunt the homeostatic threats generated by exercise-induced increases in muscle energy and oxygen demand. The application of molecular techniques to exercise biology has provided greater understanding of the multiplicity and complexity of cellular networks involved in exercise responses, and recent discoveries offer perspectives on the mechanisms by which muscle "communicates" with other organs and mediates the beneficial effects of exercise on health and performance.

In humans, β-adrenergic receptor activation causes a substantial portion of hypoxic vasodilation in skeletal muscle at rest and during forearm exercise. Recent evidence suggests that β-adrenergic receptors are either more sensitive or upregulated in young women vs. men. Therefore, we examined whether sex influences hypoxic vasodilation in 31 young subjects (15 women/16 men; 26 ± 1 yr). We also examined whether potential sex-related differences existed in a group of older adults (6 women/5 men; 61 ± 2 yr). All subjects performed forearm exercise at 10 and 20% of maximum under normoxic and hypoxic [80% arterial O2 saturation (So2)] conditions. Forearm vascular conductance (FVC; ml · min(-1) · 100 mmHg(-1)) was calculated from blood flow (ml/min) and blood pressure (mmHg). At rest, young women demonstrated a greater vasodilator response to hypoxia compared with men (39 ± 12 vs. 13 ± 6%, P < 0.05). The absolute compensatory vasodilator response (hypoxic FVC-normoxic FVC) during exercise was similar between sexes, but the relative change was greater in young women at 10% (28 ± 5 vs. 17 ± 3%, P < 0.05) and 20% exercise (29 ± 4% vs. 15 ± 3%, P < 0.01). Additionally, the absolute changes in vasodilation after normalizing the response to forearm volume or workload were greater in young women during exercise (P < 0.05). Interestingly, the compensatory vasodilator responses between older women and men were similar at 10 and 20% exercise, regardless of whether the response is expressed as absolute, relative, or absolute change normalized for forearm volume or workload (P = 0.054-0.97). Our data suggest that the compensatory vasodilator response to hypoxic exercise is greater in young women compared with men. However, sex-specific differences appear to be lost with aging.

Blood flow increases to exercising skeletal muscle, and this increase is driven primarily by vasodilation in the contracting muscles. When oxygen delivery to the contracting muscles is altered by changes in arterial oxygen content, the magnitude of the vasodilator response to exercise changes. It is augmented during hypoxia and blunted during hyperoxia. Because the magnitude of the increased vasodilation during hypoxic exercise tends to keep oxygen delivery to the contracting muscles constant, we have termed this phenomenon "compensatory vasodilation." In a series of studies, we have explored metabolic, endothelial, and neural mechanisms that might contribute to compensatory vasodilation. These include the contribution of vasodilating substances like nitric oxide (NO) and adenosine, along with altered interactions between sympathetic vasoconstriction and metabolic vasodilation. We have also compared the compensatory vasodilator responses to hypoxic exercise with those seen when oxygen delivery to contracting muscles is altered by acute reductions in perfusion pressure. A synthesis of our findings indicate that NO contributes to the compensatory dilator responses during both hypoxia and hypoperfusion, while adenosine appears to contribute only during hypoperfusion. During hypoxia, the NO-mediated component is linked to a β-adrenergic receptor mechanism during lower intensity exercise, while another source of NO is engaged at higher exercise intensities. There are also subtle interactions between α-adrenergic vasoconstriction and metabolic vasodilation that influence the responses to hypoxia, hyperoxia, and hypoperfusion. Together our findings emphasize both the tight linkage of oxygen demand and supply during exercise and the redundant nature of the vasomotor responses to contraction.

Background: Feedback from active locomotor muscles contributes to the exercise pressor response in healthy humans, and is thought to be more prominent in heart failure (HF). The purpose of this study was to examine the influence of metaboreflex stimulation on arterial pressure in HF., Methods: Eleven HF patients (51 ± 5 years, New York Heart Association Class I/II, left ventricular ejection fraction 32 ± 3%) and 11 controls (42 ± 3 years) were recruited. Participants completed two exercise sessions on separate days: (1) symptom limited graded exercise test; and (2) constant work rate cycling (60% peak oxygen consumption,V˙O2) for 4 minutes with 2 minutes passive recovery. Recovery was randomized to normal or locomotor muscle regional circulatory occlusion (RCO). Mean arterial pressure (MAP), systolic pressure (SBP), diastolic pressure, heart rate (HR) and V˙O2 were measured at rest, end-exercise and recovery. O2 pulse (V˙O2/HR) and the rate pressure product (RPP = HR × SBP) were calculated., Results: In response to RCO, mean arterial pressure and SBP increased in HF compared with CTLs (6.8 ± 5.8% vs -3.0 ± 7.8%, P < .01 and 3.4 ± 6.4% vs -12.7 ± 10.4%, P < .01, respectively), with no difference in diastolic pressure (P = .61). HF patients had a smaller reduction in HR and RPP, but also displayed a larger decrease in O2 pulse consequent to locomotor metaboreflex stimulation (P < .05, for all)., Conclusion: RCO resulted in a markedly increased pressor response in HF relative to controls, due primarily to an increase of SBP and attenuated cardiac recovery as noted by the persistent elevation in HR., (Copyright © 2014 Mosby, Inc. All rights reserved.)

New Findings: What is the central question of this study? Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients. What is the main finding and its importance? Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients. Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P(aCO(2)) and a decrease in oxygen (P(aO(2)); P < 0.05 for both) at rest. The control subjects demonstrated no change in P(aCO(2)), P(aO(2)), ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6 versus 44 ± 3 l min(-1), P < 0.05) due to a lower respiratory rate (30 ± 1 versus 26 ± 2 breaths min(-1), P < 0.05). The reduced ventilation resulted in lower P aO 2 (97.6 ± 2.5 versus 79.5 ± 3.0 mmHg, P < 0.05) and increased P(aCO(2)) (37.3 ± 0.9 versus 43.5 ± 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients.

Background: This study aimed to 1) describe physical activity (PA) in 15 post gastric bypass surgery (GB), 16 obese (Ob), and 14 lean (L) participants (mean ± se: age = 37.1 ± 1.6, 30.8 ± 1.9, 32.7 ± 2.3 yrs.; BMI = 29.7 ± 1.2, 38.2 ± 0.8, 22.9 ± 0.5 kg/m2, respectively); and 2) test associations between PA, body composition, and cardiorespiratory fitness (VO2max)., Methods: Participants completed a PA questionnaire after wearing accelerometers from 5-7 days. Body composition was determined with DEXA and CT scans, and VO2max with open circuit spirometry. ANOVA was used to detect differences between groups, and linear regressions to evaluate associations between PA (self-reported, accelerometer), body composition, and VO2max., Results: Self-reported moderate to vigorous PA (MVPA) in GB, Ob, and L participants was 497.7 ± 215.9, 988.6 ± 230.8, and 770.7 ± 249.3 min/week, respectively (P = .51); accelerometer MVPA was 185.9 ± 41.7, 132.3 ± 51.1, and 322.2 ± 51.1 min/week, respectively (P = .03); and steps/day were 6647 ± 141, 6603 ± 377, and 9591 ± 377, respectively (P = .03). Ob showed a marginally higher difference between self-report and accelerometer MVPA (P = .06). Accelerometer-MVPA and steps/day were inversely associated with percent fat (r = -0.53, -0.46), and abdominal fat (r = -0.36, -0.40), and directly associated with VO2max (r = .36)., Conclusions: PA was similar between GB and Ob participants, and both were less active than L. Higher MVPA was associated with higher VO2max and lower body fat.