Effet des précurseurs de monoxyde d'azote sur la fonction vasculaire et la performance à l'exercice

Primary and secondary prevention of cardiovascular diseases is a major public health concern. Cardiovascular prevention is mainly underpinned by the control of cardiovascular risks. Among them, arterial hypertension (30% of adults in France) and sedentarity (40% of french population) represents two main targets in cardiovascular prevention. Endothelial function as well as exercise tolerance and performance (fitness status) are used as powerful markers of cardiovascular morbidity-mortality.A normal vasomotor endothelial function allows to regulate vascular tone. By synthesising vasoactive substances, vascular endothelium continuously maintains an optimal balance between vasodilation and vasoconstriction to match oxygen and energetic substrate supply to the demand. Endothelial function is plastic, and is increased for instance by physical activity and decreased with age. Endothelial dysfunction is essentially characterized by the production of less vasodilation substances, inducing an increase in blood pressure, arterial stiffness and leading to blood-tissue exchanges alterations. Degrees of endothelial dysfunction is considered as a cardiovascular risk marker.One major vasoactive substance is nitric oxide (NO), which is produced by NO-synthase (NOS) in endothelium, and is a mediator of smooth muscle cells relaxation. This major endogen synthesis can be complemented by NO synthesis from simple reduction of nitrite to NO. Several mechanisms are provided to explain a decrease in NO endothelial synthesis, including decrease of enzymatic activity (NOS) and/or an inadequate substrate or cofactor bioavailability. This decrease in NO bioavailability can be offset, either by NOS activity optimization, or increase NO bioavailability at a vascular level. Although the effects of NO precursor supplementation on health and exercise performance have been extensively studied, results are somehow controversial, mainly due to methodological discrepancies. Thus, the real interest of these types of interventions stays unclear.Thought this thesis work, we were interested to physiological effect in healthy subjects of different interventions which may increase NO bioavailability at vascular level. Focusing on food supplement consumption, we differentiated two NO precursor, two supplementation modalities, and two populations.We have assessed effect of increasing NO bioavailability by acute or chronic supplementation of both NOS-dependent (L-arginine, L-citrulline) and/or NOS-independent (nitrate) pathways, with or without simultaneous training program, in young and older healthy subjects, on vascular function and exercise performances.In healthy young individuals, NO precursor intake increase endothelial function assessed by post-ischemic vasodilation, without effect neither on arterial pressure and fitness nor on exercise performances. However, nitrate and citrulline supplementation increase exercise training effect on maximal strength and strength endurance. In healthy older adults, chronic intake of nitrate and citrulline reduce arterial pressure and improve maximal aerobic power by decrease of submaximal VO2 and heart rate.Depuis de nombreuses années, la prévention primaire et secondaire des atteintes cardiovasculaires chez l’homme est devenue un véritable enjeu de santé publique. L’axe principal de cette prévention est l’identification et le contrôle des facteurs de risques cardiovasculaires. Parmis eux, l’hypertension artérielle (30% des adultes en France) et la sédentarité (40% de la population française) sont des acteurs majoritaiement dans la pathogénése des maladies cardiovasculaires. La fonction endothéliale ainsi que la tolérance et la performance à l’exercice, sont utilisées comme de puissants marqueurs de morbi-mortalité cardiovasculaires.Une fonction vasomotrice endothéliale normale permet de contrôler le tonus vasculaire, d’optimiser la circulation sanguine et participe au contrôle d’apports en oxygène et substrats énergétiques adaptés aux besoins tissulaires. Par la production de substances vasoactives, l’endothélium vasculaire assure en permanence un équilibre entre vasodilatation et vasoconstriction. La fonction endothéliale est plastique, s’améliorant par exemple avec l’activité physique et s’altérant avec l’âge. La dysfonction endothéliale de son côté, se caractérise essentiellement par une moindre sécrétion de substances vasodilatatrices participant à l’élévation de la pression artérielle, une augmentation de la rigidité artérielle et à une altération des échanges sang-tissus.L’une des substances vasodilatatrices majeures est le monoxyde d’azote (NO) synthétisé au niveau de l’endothélium, par la NO-synthase endothéliale (eNOS), et dont la diffusion vers les cellules musculaires lisses sous-jacentes, entraine leurs relâchements. Cette synthèse endogène majeure est complétée par une synthèse de NO à partir d’une simple réduction du nitrite circulant en NO. Les mécanismes proposés pour expliquer la baisse de la synthèse endothéliale de NO incluent une diminution de l’activité enzymatique (eNOS) et/ou une insuffisance en substrats et cofacteurs disponibles pour celle-ci. Cette diminution de la biodisponibilité en NO peut être compensée, soit par optimisation de l’activité de la NOS, soit par un apport de NO au niveau vasculaire. Bien que la littérature ait largement étudié l’effet de précurseur de NO sur la santé et la performance à l’exercice, les résultats restent très contrastés, notamment du fait de questions méthodologiques, et l’intérêt réel de ce type d’intervention reste à clarifier.Au cours de ce travail de thèse, nous nous sommes intéressés à l’effet de différentes interventions capables d’augmenter la biodisponibilité en NO au niveau vasculaire, chez le sujet sain. En se focalisant sur l’ingestion de compléments alimentaires, nous avons différencié deux types de précurseurs de NO et deux modalités de supplémentation (aiguë et chronique). Nous avons évalué l’effet de l’augmentation de la biodisponibilité en NO en supplémentant les voies NOS-dépendantes (L-arginine, L-citrulline) et/ou NOS-indépendantes (nitrate) de façon aigüe ou chronique, avec ou sans programme d’entraînement à l’effort simultané, chez des sujets sains jeunes ou âgés, sur la fonction vasculaire et les performances à l’effort.Chez le sujet jeune en bonne santé, il apparait que l’ingestion de précurseurs de NO améliore la fonction endothéliale évaluée par la vasodilatation post-ischémique, sans impacter ni la pression et la rigidité artérielle, ni la performance à l’exercice. En revanche, la supplémentation en nitrate et citrulline optimise les effets de l’entrainement sur la force maximale et l’endurance de force. Chez le sujet âgé, la prise chronique de nitrate et citrulline réduit la pression artérielle et améliore la puissance maximal aerobie en diminuant la VO2 et la fréquence cardiaque sous maximale

assessment of no precursors suppplement on exercise physiological response

Depuis de nombreuses années, la prévention primaire et secondaire des atteintes cardiovasculaires chez l’homme est devenue un véritable enjeu de santé publique. L’axe principal de cette prévention est l’identification et le contrôle des facteurs de risques cardiovasculaires. Parmis eux, l’hypertension artérielle (30% des adultes en France) et la sédentarité (40% de la population française) sont des acteurs majoritaiement dans la pathogénése des maladies cardiovasculaires. La fonction endothéliale ainsi que la tolérance et la performance à l’exercice, sont utilisées comme de puissants marqueurs de morbi-mortalité cardiovasculaires.Une fonction vasomotrice endothéliale normale permet de contrôler le tonus vasculaire, d’optimiser la circulation sanguine et participe au contrôle d’apports en oxygène et substrats énergétiques adaptés aux besoins tissulaires. Par la production de substances vasoactives, l’endothélium vasculaire assure en permanence un équilibre entre vasodilatation et vasoconstriction. La fonction endothéliale est plastique, s’améliorant par exemple avec l’activité physique et s’altérant avec l’âge. La dysfonction endothéliale de son côté, se caractérise essentiellement par une moindre sécrétion de substances vasodilatatrices participant à l’élévation de la pression artérielle, une augmentation de la rigidité artérielle et à une altération des échanges sang-tissus.L’une des substances vasodilatatrices majeures est le monoxyde d’azote (NO) synthétisé au niveau de l’endothélium, par la NO-synthase endothéliale (eNOS), et dont la diffusion vers les cellules musculaires lisses sous-jacentes, entraine leurs relâchements. Cette synthèse endogène majeure est complétée par une synthèse de NO à partir d’une simple réduction du nitrite circulant en NO. Les mécanismes proposés pour expliquer la baisse de la synthèse endothéliale de NO incluent une diminution de l’activité enzymatique (eNOS) et/ou une insuffisance en substrats et cofacteurs disponibles pour celle-ci. Cette diminution de la biodisponibilité en NO peut être compensée, soit par optimisation de l’activité de la NOS, soit par un apport de NO au niveau vasculaire. Bien que la littérature ait largement étudié l’effet de précurseur de NO sur la santé et la performance à l’exercice, les résultats restent très contrastés, notamment du fait de questions méthodologiques, et l’intérêt réel de ce type d’intervention reste à clarifier.Au cours de ce travail de thèse, nous nous sommes intéressés à l’effet de différentes interventions capables d’augmenter la biodisponibilité en NO au niveau vasculaire, chez le sujet sain. En se focalisant sur l’ingestion de compléments alimentaires, nous avons différencié deux types de précurseurs de NO et deux modalités de supplémentation (aiguë et chronique). Nous avons évalué l’effet de l’augmentation de la biodisponibilité en NO en supplémentant les voies NOS-dépendantes (L-arginine, L-citrulline) et/ou NOS-indépendantes (nitrate) de façon aigüe ou chronique, avec ou sans programme d’entraînement à l’effort simultané, chez des sujets sains jeunes ou âgés, sur la fonction vasculaire et les performances à l’effort.Chez le sujet jeune en bonne santé, il apparait que l’ingestion de précurseurs de NO améliore la fonction endothéliale évaluée par la vasodilatation post-ischémique, sans impacter ni la pression et la rigidité artérielle, ni la performance à l’exercice. En revanche, la supplémentation en nitrate et citrulline optimise les effets de l’entrainement sur la force maximale et l’endurance de force. Chez le sujet âgé, la prise chronique de nitrate et citrulline réduit la pression artérielle et améliore la puissance maximal aerobie en diminuant la VO2 et la fréquence cardiaque sous maximale.Primary and secondary prevention of cardiovascular diseases is a major public health concern. Cardiovascular prevention is mainly underpinned by the control of cardiovascular risks. Among them, arterial hypertension (30% of adults in France) and sedentarity (40% of french population) represents two main targets in cardiovascular prevention. Endothelial function as well as exercise tolerance and performance (fitness status) are used as powerful markers of cardiovascular morbidity-mortality.A normal vasomotor endothelial function allows to regulate vascular tone. By synthesising vasoactive substances, vascular endothelium continuously maintains an optimal balance between vasodilation and vasoconstriction to match oxygen and energetic substrate supply to the demand. Endothelial function is plastic, and is increased for instance by physical activity and decreased with age. Endothelial dysfunction is essentially characterized by the production of less vasodilation substances, inducing an increase in blood pressure, arterial stiffness and leading to blood-tissue exchanges alterations. Degrees of endothelial dysfunction is considered as a cardiovascular risk marker.One major vasoactive substance is nitric oxide (NO), which is produced by NO-synthase (NOS) in endothelium, and is a mediator of smooth muscle cells relaxation. This major endogen synthesis can be complemented by NO synthesis from simple reduction of nitrite to NO. Several mechanisms are provided to explain a decrease in NO endothelial synthesis, including decrease of enzymatic activity (NOS) and/or an inadequate substrate or cofactor bioavailability. This decrease in NO bioavailability can be offset, either by NOS activity optimization, or increase NO bioavailability at a vascular level. Although the effects of NO precursor supplementation on health and exercise performance have been extensively studied, results are somehow controversial, mainly due to methodological discrepancies. Thus, the real interest of these types of interventions stays unclear.Thought this thesis work, we were interested to physiological effect in healthy subjects of different interventions which may increase NO bioavailability at vascular level. Focusing on food supplement consumption, we differentiated two NO precursor, two supplementation modalities, and two populations.We have assessed effect of increasing NO bioavailability by acute or chronic supplementation of both NOS-dependent (L-arginine, L-citrulline) and/or NOS-independent (nitrate) pathways, with or without simultaneous training program, in young and older healthy subjects, on vascular function and exercise performances.In healthy young individuals, NO precursor intake increase endothelial function assessed by post-ischemic vasodilation, without effect neither on arterial pressure and fitness nor on exercise performances. However, nitrate and citrulline supplementation increase exercise training effect on maximal strength and strength endurance. In healthy older adults, chronic intake of nitrate and citrulline reduce arterial pressure and improve maximal aerobic power by decrease of submaximal VO2 and heart rate

Fatigue and Recovery after Single-Stage versus Multistage Ultramarathon Running

International audiencePurpose: Ultramarathon running includes two main types of events: single-stage race (SSR) and multistage races (MSR). Direct comparison of neuromuscular fatigue and recovery after SSR versus MSR race of comparable distance and elevation has never been performed. The aim of this study was to assess neuromuscular fatigue and recovery after two ultramarathons of equal distance performed either (i) in a single stage or (ii) in four successive days.Methods: Thirty-one runners participated in the study: 17 ran 169 km in a single-stage race and 14 performed around 40 km·d over 4 d. The two races were performed on the same course. Neuromuscular function was tested before (PRE), after (POST), and 2 (D + 2), 5 (D + 5) and 10 (D + 10) days after the races. Neuromuscular function was evaluated on both knee extensors (KE) and plantar flexors (PF) with voluntary and evoked contractions using electrical (femoral and tibial, respectively) nerve stimulation.Results: Reduction of voluntary activation measured in the KE was greater (i.e., central fatigue) for SSR than MSR directly after the race (-23% vs -7%), P < 0.01). Reductions in evoked mechanical KE and PF responses on relaxed muscle (i.e., peripheral fatigue) of both KE and PF took longer to recover in MSR than in SSR.Conclusions: Performing prolonged running exercise over several days, each separated by rest, elicits more prolonged impairments in contractile function compared with single-stage ultramarathon, whereas single-stage mountain ultramarathon ran on the same course is associated with greater central fatigue

Synergetic Effect of NO Precursor Supplementation and Exercise Training

International audienceIntroduction: Nitric oxide (NO) precursor supplementation has been shown to increase NO bioavailability and can potentially improve vascular function and exercise performance. It remains unclear whether the combination of NO precursor supplementation and exercise training has synergic effects on exercise performance. This study aims to assess the effect of chronic nitrate and citrulline intake on exercise training adaptations in healthy young individuals.Methods: In this randomized, double-bind trial, 24 healthy young (12 females) subjects performed vascular function assessment (blood pressure, pulse wave velocity, postischemia vasodilation, and cerebrovascular reactivity) and both local (submaximal isometric unilateral knee extension) and whole-body (incremental cycling) exercise tests to exhaustion before and after a 2-month exercise training program and daily intake of a placebo or a nitrate-rich salad and citrulline (N + C, 520 mg nitrate and 6 g citrulline) drink. Prefrontal cortex and quadriceps oxygenation was monitored continuously during exercise by near-infrared spectroscopy.Results: N + C supplementation had no effect on vascular function and muscle and cerebral oxygenation during both local and whole-body exercise. N + C supplementation induced a significantly larger increase in maximal knee extensor strength (+5.1 ± 3.5 vs +0.2 ± 5.5 kg, P = 0.008) as well as a trend toward a larger increase in knee extensor endurance (+35.2 ± 26.1 vs +24.0 ± 10.4 contractions, P = 0.092) than placebo, but no effect on exercise training-induced maximal aerobic performance improvement.Conclusion: These results suggest that chronic nitrate and citrulline supplementation enhances the effect of exercise training on quadriceps muscle function in healthy active young individuals, but this does not translate into improved maximal aerobic performances

Synergetic Effect of NO Precursor Supplementation and Exercise Training

International audienceIntroduction: Nitric oxide (NO) precursor supplementation has been shown to increase NO bioavailability and can potentially improve vascular function and exercise performance. It remains unclear whether the combination of NO precursor supplementation and exercise training has synergic effects on exercise performance. This study aims to assess the effect of chronic nitrate and citrulline intake on exercise training adaptations in healthy young individuals.Methods: In this randomized, double-bind trial, 24 healthy young (12 females) subjects performed vascular function assessment (blood pressure, pulse wave velocity, postischemia vasodilation, and cerebrovascular reactivity) and both local (submaximal isometric unilateral knee extension) and whole-body (incremental cycling) exercise tests to exhaustion before and after a 2-month exercise training program and daily intake of a placebo or a nitrate-rich salad and citrulline (N + C, 520 mg nitrate and 6 g citrulline) drink. Prefrontal cortex and quadriceps oxygenation was monitored continuously during exercise by near-infrared spectroscopy.Results: N + C supplementation had no effect on vascular function and muscle and cerebral oxygenation during both local and whole-body exercise. N + C supplementation induced a significantly larger increase in maximal knee extensor strength (+5.1 ± 3.5 vs +0.2 ± 5.5 kg, P = 0.008) as well as a trend toward a larger increase in knee extensor endurance (+35.2 ± 26.1 vs +24.0 ± 10.4 contractions, P = 0.092) than placebo, but no effect on exercise training-induced maximal aerobic performance improvement.Conclusion: These results suggest that chronic nitrate and citrulline supplementation enhances the effect of exercise training on quadriceps muscle function in healthy active young individuals, but this does not translate into improved maximal aerobic performances

Effect of chronic nitrate and citrulline supplementation on vascular function and exercise performance in older individuals

International audienceIncreased nitric oxide (NO) bioavailability may improve exercise performance and vascular function. It remains unclear whether older adults who experience a decreased NO bioavailability may benefit from chronic NO precursor supplementation. This randomised, double-blind, trial aims to assess the effect of chronic NO precursor intake on vascular function and exercise performance in older adults (60-70 years old). Twenty-four healthy older adults (12 females) performed vascular function assessment and both local (knee extensions) and whole-body (incremental cycling) exercise tests to exhaustion before and after one month of daily intake of a placebo (PLA) or a nitrate-rich salad and citrulline (N+C, 520mg nitrate and 6g citrulline) drink. Arterial blood pressure (BP) and stiffness, post-ischemic, hypercapnic and hypoxic vascular responses were evaluated. Prefrontal cortex and quadriceps oxygenation was monitored by near-infrared spectroscopy. N+C supplementation reduced mean BP (-3.3mmHg; p=0.047) without altering other parameters of vascular function and oxygenation kinetics. N+C supplementation reduced heart rate and oxygen consumption during submaximal cycling and increased maximal power output by 5.2% (p<0.05), but had no effect on knee extension exercise performance. These results suggest that chronic NO precursor supplementation in healthy older individuals can reduce resting BP and increase cycling performance by improving cardiorespiratory responses

Reduced voluntary activation and increased intracortical inhibition during leg extensions in severe obstructive sleep apnoea patients

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Neuromuscular Dysfunction and Cortical Impairment in Sleep Apnea Syndrome

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A randomized sham-controlled trial on the effect of continuous positive airway pressure treatment on gait control in severe obstructive sleep apnea patients

International audienceAbstract To determine the effect of continuous positive airway pressure (CPAP), the gold standard treatment for obstructive sleep apnea syndrome (OSAS), on gait control in severe OSAS patients. We conducted a randomized, double-blind, parallel-group, sham-controlled monocentric study in Grenoble Alpes University Hospital, France. Gait parameters were recorded under single and dual-task conditions using a visuo-verbal cognitive task (Stroop test), before and after the 8-week intervention period. Stride-time variability, a marker of gait control, was the primary study endpoint. Changes in the determinants of gait control were the main secondary outcomes. ClinicalTrials.gov Identifier: (NCT02345694). 24 patients [median (Q1; Q3)]: age: 59.5 (46.3; 66.8) years, 87.5% male, body mass index: 28.2 (24.7; 29.8) kg. m −2 , apnea–hypopnea index: 51.6 (35.0; 61.4) events/h were randomized to be treated by effective CPAP (n = 12) or by sham-CPAP (n = 12). A complete case analysis was performed, using a mixed linear regression model. CPAP elicited no significant improvement in stride-time variability compared to sham-CPAP. No difference was found regarding the determinants of gait control. This study is the first RCT to investigate the effects of CPAP on gait control. Eight weeks of CPAP treatment did not improve gait control in severe non-obese OSAS patients. These results substantiate the complex OSAS-neurocognitive function relationship

Management of pregnancy in a patient with highly unstable type 1 diabetes with DBL-hu closed-loop system.

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