Publications by authors named "Lasse Gliemann"

35 Publications

Histamine H and H receptors are essential transducers of the integrative exercise training response in humans.

Sci Adv 2021 Apr 14;7(16). Epub 2021 Apr 14.

Department of Movement and Sports Sciences, Ghent University, Ghent 9000, Belgium.

Exercise training is a powerful strategy to prevent and combat cardiovascular and metabolic diseases, although the integrative nature of the training-induced adaptations is not completely understood. We show that chronic blockade of histamine H/H receptors led to marked impairments of microvascular and mitochondrial adaptations to interval training in humans. Consequently, functional adaptations in exercise capacity, whole-body glycemic control, and vascular function were blunted. Furthermore, the sustained elevation of muscle perfusion after acute interval exercise was severely reduced when H/H receptors were pharmaceutically blocked. Our work suggests that histamine H/H receptors are important transducers of the integrative exercise training response in humans, potentially related to regulation of optimal post-exercise muscle perfusion. These findings add to our understanding of how skeletal muscle and the cardiovascular system adapt to exercise training, knowledge that will help us further unravel and develop the exercise-is-medicine concept.
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http://dx.doi.org/10.1126/sciadv.abf2856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046361PMC
April 2021

A High Activity Level Is Required for Augmented Muscle Capillarization in Older Women.

Med Sci Sports Exerc 2021 May;53(5):894-903

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, DENMARK.

Purpose: This study aimed to evaluate the influence of lifelong regular physical activity on skeletal muscle capillarization in women.

Methods: Postmenopausal women, 61±4 yr old, were divided according to self-reported physical activity level over the past 20 yrs: sedentary (SED; n = 14), moderately active (MOD; n = 12), and very active (VERY; n = 15). Leg blood flow (LBF) was determined by ultrasound Doppler, and blood samples were drawn from the femoral artery and vein for calculation of leg oxygen uptake (LVO2) at rest and during one-legged knee extensor exercise. A skeletal muscle biopsy was obtained from the vastus lateralis and analyzed for capillarization and vascular endothelial growth factor (VEGF) and mitochondrial OXPHOS proteins. Platelets were isolated from venous blood and analyzed for VEGF content and effect on endothelial cell proliferation.

Results: The exercise-induced rise in LBF and LVO2 was faster (P = 0.008) in VERY compared with SED and MOD. Steady-state LBF and LVO2 were lower (P < 0.04) in MOD and VERY compared with SED. Capillary-fiber ratio and capillary density were greater (P < 0.03) in VERY (1.65 ± 0.48 and 409.3 ± 57.5) compared with MOD (1.30 ± 0.19 and 365.0 ± 40.2) and SED (1.30 ± 0.30 and 356.2 ± 66.3). Skeletal muscle VEGF and OXPHOS complexes I, II, and V were ~1.6-fold and ~1.25-fold (P < 0.01) higher, respectively, in VERY compared with SED. Platelets from all groups induced an approximately nine-fold (P < 0.001) increase in endothelial cell proliferation.

Conclusion: A very active lifestyle is associated with superior skeletal muscle exercise hemodynamics and greater potential for oxygen extraction concurrent with a higher skeletal muscle capillarization and mitochondrial capacity.
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http://dx.doi.org/10.1249/MSS.0000000000002566DOI Listing
May 2021

The Impact of Lower Limb Immobilization and Rehabilitation on Angiogenic Proteins and Capillarization in Skeletal Muscle.

Med Sci Sports Exerc 2021 Mar 25. Epub 2021 Mar 25.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark Technical University of Munich, Germany. Sylvia Lawry Centre for Multiple Sclerosis Research, Munich, Germany.

Purpose: Skeletal muscle vascularization is important for tissue regeneration after injury and immobilization. We examined whether complete immobilization influences capillarization and oxygen delivery to the muscle and assessed the efficacy of rehabilitation by aerobic exercise training.

Methods: Young healthy males had one leg immobilized for 14 days and subsequently completed four weeks of intense aerobic exercise training. Biopsies were obtained from m.vastus lateralis and a-v blood sampling for assessment of oxygen extraction and leg blood flow during exercise was done before and after immobilization and training. Muscle capillarization, muscle and platelet content of vascular endothelial growth factor (VEGF) and muscle thrombospondin-1 were determined.

Results: Immobilization did not have a significant impact on capillary per fiber ratio or capillary density. The content of VEGF protein in muscle samples was reduced by 36% (P=0.024) and VEGF to thrombospondin-1 ratio was 94 % lower (P=0.046). The subsequent four-week training period increased the muscle VEGF content and normalized the muscle VEGF to thrombospondin-1 ratio but did not influence capillarization. Platelet VEGF content followed the trend of muscle VEGF. At the functional level, oxygen extraction, blood flow and oxygen delivery at rest and during submaximal exercise were not affected by immobilization or training.

Conclusion: The results demonstrate that just two weeks of leg immobilization leads to a strongly reduced angiogenic potential as evidenced by reduced muscle and platelet VEGF content and a reduced muscle VEGF to thrombospondin-1 ratio. Moreover, a subsequent period of intensive aerobic exercise training fails to increase capillarization in the previously immobilized leg, possibly due to the angiostatic condition caused by immobilization.
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http://dx.doi.org/10.1249/MSS.0000000000002665DOI Listing
March 2021

Does Exercise Influence the Susceptibility to Arterial Thrombosis? An Integrative Perspective.

Front Physiol 2021 23;12:636027. Epub 2021 Feb 23.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Arterial thrombosis is the primary cause of death worldwide, with the most important risk factors being smoking, unhealthy diet, and physical inactivity. However, although there are clear indications in the literature of beneficial effects of physical activity in lowering the risk of cardiovascular events, exercise can be considered a double-edged sword in that physical exertion can induce an immediate pro-thrombotic environment. Epidemiological studies show an increased risk of cardiovascular events after acute exercise, a risk, which appear to be particularly apparent in individuals with lifestyle-related disease. Factors that cause the increased susceptibility to arterial thrombosis with exercise are both chemical and mechanical in nature and include circulating catecholamines and vascular shear stress. Exercise intensity plays a marked role on such parameters, and evidence in the literature accordingly points at a greater susceptibility to thrombus formation at high compared to light and moderate intensity exercise. Of importance is, however, that the susceptibility to arterial thrombosis appears to be lower in exercise-conditioned individuals compared to sedentary individuals. There is currently limited data on the role of acute and chronic exercise on the susceptibility to arterial thrombosis, and many studies include incomplete assessments of thrombogenic clotting profile. Thus, further studies on the role of exercise, involving valid biomarkers, are clearly warranted.
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http://dx.doi.org/10.3389/fphys.2021.636027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940832PMC
February 2021

Hypertension is associated with blunted NO-mediated leg vasodilator responsiveness that is reversed by high-intensity training in postmenopausal women.

Am J Physiol Regul Integr Comp Physiol 2020 12 14;319(6):R712-R723. Epub 2020 Oct 14.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

The menopausal transition is associated with increased prevalence of hypertension, and in time, postmenopausal women (PMW) will exhibit a cardiovascular disease risk score similar to male counterparts. Hypertension is associated with vascular dysfunction, but whether hypertensive (HYP) PMW have blunted nitric oxide (NO)-mediated leg vasodilator responsiveness and whether this is reversible by high-intensity training (HIT) is unknown. To address these questions, we examined the leg vascular conductance (LVC) in response to femoral infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) and skeletal muscle markers of oxidative stress and NO bioavailability before and after HIT in PMW [12.9 ± 6.0 (means ± SD) years since last menstrual cycle]. We hypothesized that ACh- and SNP-induced LVC responsiveness was reduced in hypertensive compared with normotensive (NORM) PMW and that 10 wk of HIT would reverse the blunted LVC response and decrease blood pressure (BP). Nine hypertensive (HYP (clinical systolic/diastolic BP, 149 ± 11/91 ± 83 mmHg) and eight normotensive (NORM (122 ± 13/75 ± 8 mmHg) PMW completed 10 wk of biweekly small-sided floorball training (4-5 × 3-5 min interspersed by 1-3-min rest periods). Before training, the SNP-induced change in LVC was lower ( < 0.05) in HYP compared with in NORM. With training, the ACh- and SNP-induced change in LVC at maximal infusion rates, i.e., 100 and 6 µg·min·kg leg mass, respectively, improved ( < 0.05) in HYP only. Furthermore, training decreased ( < 0.05) clinical systolic/diastolic BP (-15 ± 11/-9 ± 7 mmHg) in HYP and systolic BP (-10 ± 9 mmHg) in NORM. Thus, the SNP-mediated LVC responsiveness was blunted in HYP PMW and reversed by a period of HIT that was associated with a marked decrease in clinical BP.
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http://dx.doi.org/10.1152/ajpregu.00170.2020DOI Listing
December 2020

Ischemic Preconditioning Improves Microvascular Endothelial Function in Remote Vasculature by Enhanced Prostacyclin Production.

J Am Heart Assoc 2020 08 29;9(15):e016017. Epub 2020 Jul 29.

Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark.

BACKGROUND The mechanisms underlying the effect of preconditioning on remote microvasculature remains undisclosed. The primary objective was to document the remote effect of ischemic preconditioning on microvascular function in humans. The secondary objective was to test if exercise also induces remote microvascular effects. METHODS AND RESULTS A total of 12 healthy young men and women participated in 2 experimental days in a random counterbalanced order. On one day the participants underwent 4×5 minutes of forearm ischemic preconditioning, and on the other day they completed 4×5 minutes of hand-grip exercise. On both days, catheters were placed in the brachial and femoral artery and vein for infusion of acetylcholine, sodium nitroprusside, and epoprostenol. Vascular conductance was calculated from blood flow measurements with ultrasound Doppler and arterial and venous blood pressures. Ischemic preconditioning enhanced (<0.05) the remote vasodilator response to intra-arterial acetylcholine in the leg at 5 and 90 minutes after application. The enhanced response was associated with a 6-fold increase (<0.05) in femoral venous plasma prostacyclin levels and with a transient increase (<0.05) in arterial plasma levels of brain-derived neurotrophic factor and vascular endothelial growth factor. In contrast, hand-grip exercise did not influence remote microvascular function. CONCLUSIONS These findings demonstrate that ischemic preconditioning of the forearm improves remote microvascular endothelial function and suggest that one of the underlying mechanisms is a humoral-mediated potentiation of prostacyclin formation.
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http://dx.doi.org/10.1161/JAHA.120.016017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792245PMC
August 2020

Dodging physical activity and healthy diet: can resveratrol take the edge off the consequences of your lifestyle?

Authors:
Lasse Gliemann

Am J Clin Nutr 2020 10;112(4):905-906

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1093/ajcn/nqaa199DOI Listing
October 2020

Muscle Metabolism and Fatigue during Simulated Ice Hockey Match-Play in Elite Players.

Med Sci Sports Exerc 2020 10;52(10):2162-2171

Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, DENMARK.

Purpose: The present study investigated muscle metabolism and fatigue during simulated elite male ice hockey match-play.

Methods: Thirty U20 male national team players completed an experimental game comprising three periods of 8 × 1-min shifts separated by 2-min recovery intervals. Two vastus lateralis biopsies were obtained either during the game (n = 7) or pregame and postgame (n = 6). Venous blood samples were drawn pregame and at the end of the first and last periods (n = 14). Activity pattern and physiological responses were continuously monitored using local positioning system and heart rate recordings. Further, repeated-sprint ability was tested pregame and after each period.

Results: Total distance covered was 5980 ± 199 m with almost half the distance covered at high skating speeds (>17 km·h). Average and peak on-ice heart rate was 84% ± 2% and 97% ± 2% of maximum heart rate, respectively. Muscle lactate increased (P ≤ 0.05) more than fivefold and threefold, whereas muscle pH decreased (P ≤ 0.05) from 7.31 ± 0.04 pregame to 6.99 ± 0.07 and 7.13 ± 0.11 during the first and last periods, respectively. Muscle glycogen decreased by 53% postgame (P ≤ 0.05) with ~65% of fast- and slow-twitch fibers depleted of glycogen. Blood lactate increased sixfold (P ≤ 0.05), whereas plasma free fatty acid levels increased 1.5-fold and threefold (P ≤ 0.05) after the first and last periods. Repeated-sprint ability was impaired (~3%; P ≤ 0.05) postgame concomitant with a ~10% decrease in the number of accelerations and decelerations during the second and last periods (P ≤ 0.05).

Conclusions: Our findings demonstrate that a simulated ice hockey match-play scenario encompasses a high on-ice heart rate response and glycolytic loading resulting in a marked degradation of muscle glycogen, particularly in specific sub-groups of fibers. This may be of importance both for fatigue in the final stages of a game and for subsequent recovery.
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http://dx.doi.org/10.1249/MSS.0000000000002370DOI Listing
October 2020

Microvascular Function Is Impaired after Short-Term Immobilization in Healthy Men.

Med Sci Sports Exerc 2020 10;52(10):2107-2116

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, DENMARK.

Purpose: We examined whether 2 wk of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function.

Methods: Study participants were healthy young men (n = 12; 20-24 yr of age). Leg microvascular function was determined before the intervention, after the immobilization period, and after a 4-wk exercise training period. Microvascular function was assessed as the vasodilator response to intra-arterial infusion of acetylcholine and sodium nitroprusside and as the vasoconstrictor response to endogenous noradrenaline release induced by tyramine infusion. Vasodilator enzymes as well as prooxidant and antioxidant enzymes were assessed by protein analysis in skeletal muscle samples: endothelial nitric oxide synthase, NADPH oxidase (NOX p67 and NOX gp91), and superoxide dismutase 2 (SOD2).

Results: The acetylcholine-induced change in vascular conductance was reduced after the 2 wk of immobilization (P = 0.003), tended to increase (P = 0.061), and was back to baseline levels after the subsequent 4 wk of exercise training. Plasma prostacyclin levels in response to acetylcholine infusion were lower after immobilization than before (P = 0.041). The changes in vascular conductance with sodium nitroprusside and tyramine were similar during all conditions. Skeletal muscle protein levels of endothelial nitric oxide synthase in the experimental leg were unchanged with immobilization and subsequent training but increased 47% in the control leg with training (P = 0.002). NOX p67, NOX gp91, and SOD2 in the experimental leg remained unaltered with immobilization, and SOD2 was higher than preimmobilization after 4 wk of training (P < 0.001).

Conclusions: The study shows that 2 wk of immobilization impairs leg microvascular endothelial function and prostacyclin formation but that 4 wk of intense aerobic exercise training restores the function. The underlying mechanism may reside in the prostacyclin system.
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http://dx.doi.org/10.1249/MSS.0000000000002369DOI Listing
October 2020

Increased prostacyclin formation after high-intensity interval training in late postmenopausal women.

Eur J Appl Physiol 2020 Jul 30;120(7):1711-1720. Epub 2020 May 30.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen Ø, Denmark.

Purpose: Aging impairs vascular function in women, with the largest detrimental effects occurring during the menopausal transition. Deficiency in the nitric oxide system has been suggested to be responsible for impairment in vascular function with aging, but recent observations suggest that the prostacyclin system, acting in redundancy with the nitric oxide system, may be of importance too. Improvement in vascular function is a hallmark of exercise training and we hypothesize that leg vascular function is improved by exercise training in late postmenopausal women, and that the underlying mechanism is increased endothelial formation of prostacyclin and responsiveness to prostacyclin by the vascular smooth muscle cells.

Method: Femoral-arterial infusion of acetylcholine and epoprostenol was used to assess vascular function and prostacyclin release in ten late postmenopausal women (62 ± 7 years) before and after 10 weeks of high-intensity interval training (floorball conducted as small-sided games).

Result: The training intervention increased fitness level (V̇O) by 7 ± 7% and reduced systolic and diastolic blood pressure by 10 ± 10 and 5 ± 6 mmHg, respectively. Leg vascular responsiveness to during acetylcholine and epoprostenol infusion was unchanged with training, whereas the release of prostacyclin during acetylcholine infusion increased by 125%.

Conclusions: In late postmenopausal women, vascular function assessed by femoral-arterial infusion of acetylcholine was not improved after 10 weeks of floorball training, but acetylcholine-induced prostacyclin formation and blood pressure were substantially improved. It is possible that a longer training period could lead to improvements in vascular function and that the observed increase in prostacyclin formation is one of the initial underlying changes.
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http://dx.doi.org/10.1007/s00421-020-04405-6DOI Listing
July 2020

Hyperthermia: The hotter the body, the hungrier the brain?

J Physiol 2020 06 11;598(11):2053-2054. Epub 2020 Apr 11.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1113/JP279745DOI Listing
June 2020

Insulin-induced membrane permeability to glucose in human muscles at rest and following exercise.

J Physiol 2020 01 9;598(2):303-315. Epub 2020 Jan 9.

Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

Key Points: Increased insulin action is an important component of the health benefits of exercise, but its regulation is complex and not fully elucidated. Previous studies of insulin-stimulated GLUT4 translocation to the skeletal muscle membrane found insufficient increases to explain the increases in glucose uptake. By determination of leg glucose uptake and interstitial muscle glucose concentration, insulin-induced muscle membrane permeability to glucose was calculated 4 h after one-legged knee-extensor exercise during a submaximal euglycaemic-hyperinsulinaemic clamp. It was found that during submaximal insulin stimulation, muscle membrane permeability to glucose in humans increases twice as much in previously exercised vs. rested muscle and outstrips the supply of glucose, which then becomes limiting for glucose uptake. This methodology can now be employed to determine muscle membrane permeability to glucose in people with diabetes, who have reduced insulin action, and in principle can also be used to determine membrane permeability to other substrates or metabolites.

Abstract: Increased insulin action is an important component of the health benefits of exercise, but the regulation of insulin action in vivo is complex and not fully elucidated. Previously determined increases in skeletal muscle insulin-stimulated GLUT4 translocation are inconsistent and mostly cannot explain the increases in insulin action in humans. Here we used leg glucose uptake (LGU) and interstitial muscle glucose concentration to calculate insulin-induced muscle membrane permeability to glucose, a variable not previously possible to quantify in humans. Muscle membrane permeability to glucose, measured 4 h after one-legged knee-extensor exercise, increased ∼17-fold during a submaximal euglycaemic-hyperinsulinaemic clamp in rested muscle (R) and ∼36-fold in exercised muscle (EX). Femoral arterial infusion of N -monomethyl l-arginine acetate or ATP decreased and increased, respectively, leg blood flow (LBF) in both legs but did not affect membrane glucose permeability. Decreasing LBF reduced interstitial glucose concentrations to ∼2 mM in the exercised but only to ∼3.5 mM in non-exercised muscle and abrogated the augmented effect of insulin on LGU in the EX leg. Increasing LBF by ATP infusion increased LGU in both legs with uptake higher in the EX leg. We conclude that it is possible to measure functional muscle membrane permeability to glucose in humans and it increases twice as much in exercised vs. rested muscle during submaximal insulin stimulation. We also show that muscle perfusion is an important regulator of muscle glucose uptake when membrane permeability to glucose is high and we show that the capillary wall can be a significant barrier for glucose transport.
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http://dx.doi.org/10.1113/JP278600DOI Listing
January 2020

Lifelong Physical Activity Determines Vascular Function in Late Postmenopausal Women.

Med Sci Sports Exerc 2020 03;52(3):627-636

Department of Nutrition Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Introduction: The study evaluated the role of lifelong physical activity for leg vascular function in postmenopausal women (61 ± 1 yr).

Method: The study design was cross-sectional with three different groups based on self-reported physical activity level with regard to intensity and volume over the past decade: inactive (n = 14), moderately active (n = 12), and very active (n = 15). Endothelial-dependent and smooth muscle-dependent leg vascular function were assessed by ultrasound Doppler measurements of the femoral artery during infusion of acetylcholine (Ach), the nitric oxide (NO) donor sodium nitroprusside and the prostacyclin analog epoprostenol. Thigh muscle biopsies, arterial and venous plasma samples were obtained for assessment of vasodilator systems.

Results: The very active group was found to have 76% greater responsiveness to Ach compared with the sedentary group accompanied by 200% higher prostacyclin synthesis during Ach infusion. Smooth muscle cell responsiveness to sodium nitroprusside and epoprostenol was not different between groups. The protein amount of endothelial NO synthase and endogenous antioxidant enzymes in muscle tissue was higher in the very active than the inactive group. The moderately active group had a similar endothelial and smooth muscle cell responsiveness as the inactive group. A secondary comparison with a smaller group (n = 5) of habitually active young (24 ± 2 yr) women indicated that smooth muscle cell responsiveness and endothelial responsiveness are affected by age per se.

Conclusions: This study shows that leg vascular function and the potential to form prostacyclin and NO in late postmenopausal women, is influenced by the extent of lifelong physical activity.
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http://dx.doi.org/10.1249/MSS.0000000000002180DOI Listing
March 2020

Copenhagen Consensus statement 2019: physical activity and ageing.

Br J Sports Med 2019 Jul 21;53(14):856-858. Epub 2019 Feb 21.

Department of Physiology, Universitat de Valencia, Valencia, Spain.

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term 'older adults' represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults' fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual's physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements.
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http://dx.doi.org/10.1136/bjsports-2018-100451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613739PMC
July 2019

The Endothelial Mechanotransduction Protein Platelet Endothelial Cell Adhesion Molecule-1 Is Influenced by Aging and Exercise Training in Human Skeletal Muscle.

Front Physiol 2018 18;9:1807. Epub 2018 Dec 18.

Department of Nutrition, Exercise and Sports, Section for Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.

The aim was to determine the role of aging and exercise training on endothelial mechanosensor proteins and the hyperemic response to shear stress by passive leg movement. We examined the expression of mechanosensor proteins and vascular function in young ( = 14, 25 ± 3 years) and old ( = 14, 72 ± 5 years) healthy male subjects with eight weeks of aerobic exercise training. Before and after training, the hyperaemic response to passive leg movement was determined and a thigh muscle biopsy was obtained before and after passive leg movement to assess the acute effect of increased shear stress. Biopsies were analyzed for protein amount and phosphorylation of mechanosensor proteins; Platelet endothelial cell adhesion molecule-1 (PECAM-1), Vascular endothelial cadherin, Vascular endothelial growth factor receptor-2 and endothelial nitric oxide synthase (eNOS). Before training, the old group presented a lower hyperaemic response to passive leg movement and a 35% lower ( < 0.05) relative basal phosphorylation level of PECAM-1 whereas there was no difference for the other mechanosensor proteins. After training, the eNOS protein amount, the amount of PECAM-1 protein and the passive leg movement-induced phosphorylation of PECAM-1 were higher in both groups. The hyperaemic response to passive leg movement was higher after training in the young group only. Aged individuals have a lower hyperaemic response to passive leg movement and a lower relative basal phosphorylation of PECAM-1 than young. The higher PECAM-1 phosphorylation despite a similar hyperemic level in the aged observed after training, suggests that training improved shear stress responsiveness of this mechanotransduction protein.
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http://dx.doi.org/10.3389/fphys.2018.01807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305393PMC
December 2018

Methods for the determination of skeletal muscle blood flow: development, strengths and limitations.

Eur J Appl Physiol 2018 Jun 14;118(6):1081-1094. Epub 2018 May 14.

Department of Nutrition Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Since the first measurements of limb blood flow at rest and during nerve stimulation were conducted in the late 1800s, a number of methods have been developed for the determination of limb and skeletal muscle blood flow in humans. The methods, which have been applied in the study of aspects such as blood flow regulation, oxygen uptake and metabolism, differ in terms of strengths and degree of limitations but most have advantages for specific settings. The purpose of this review is to describe the origin and the basic principles of the methods, important aspects and requirements of the procedures. One of the earliest methods, venous occlusion plethysmography, is a noninvasive method which still is extensively used and which provides similar values as other more direct blood flow methods such as ultrasound Doppler. The constant infusion thermodilution method remains the most appropriate for the determination of blood flow during maximal exercise. For resting blood flow and light-to-moderate exercise, the non-invasive ultrasound Doppler methodology, if handled by a skilled operator, is recommendable. Positron emission tomography with radiolabeled water is an advanced method which requires highly sophisticated equipment and allows for the determination of muscle-specific blood flow, regional blood flows and estimate of blood flow heterogeneity within a muscle. Finally, the contrast-enhanced ultrasound method holds promise for assessment of muscle-specific blood flow, but the interpretation of the data obtained remains uncertain. Currently lacking is high-resolution methods for continuous visualization and monitoring of the skeletal muscle microcirculation in humans.
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http://dx.doi.org/10.1007/s00421-018-3880-5DOI Listing
June 2018

Effects of aging and exercise training on leg hemodynamics and oxidative metabolism in the transition from rest to steady-state exercise: role of cGMP signaling.

Am J Physiol Regul Integr Comp Physiol 2018 08 18;315(2):R274-R283. Epub 2018 Apr 18.

Department of Nutrition, Exercise and Sports, University of Copenhagen , Copenhagen , Denmark.

Aging is associated with slower skeletal muscle O uptake (V̇o) kinetics; however, the mechanisms underlying this effect of age are unclear. Also, the effects of exercise training in elderly on the initial vascular and metabolic response to exercise remain to be elucidated. We measured leg hemodynamics and oxidative metabolism in the transition from rest to steady-state exercise engaging the knee-extensor muscles in young ( n = 15, 25 ± 1 yr) and older ( n = 15, 72 ± 1 yr) subjects before and after a period of aerobic high-intensity exercise training. To enhance cGMP signaling, pharmacological inhibition of phosphodiesterase 5 (PDE5) was performed. Before training, the older group had a slower ( P <0.05) increase in femoral arterial blood flow and leg vascular conductance in the transition from rest to steady-state exercise at low- and moderate-intensity compared with the young group. The rate of increase in leg V̇o was, however, similar in the two groups as a result of higher ( P < 0.05) arteriovenous O difference in the older group. Potentiation of cGMP signaling did not affect the rate of increase in blood flow or V̇o in either group. Exercise training augmented ( P < 0.05) the increase in leg vascular conductance and blood flow during the onset of moderate-intensity exercise in both groups without altering V̇o. These findings suggest that an age-related reduction in the initial vascular response to low- and moderate-intensity knee-extensor exercise is not limiting for V̇o in older individuals. A lower blood flow response in aging does not appear to be a result of reduced cGMP signaling.
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http://dx.doi.org/10.1152/ajpregu.00446.2017DOI Listing
August 2018

What are the chances that resveratrol will be the drug of tomorrow?

Authors:
Lasse Gliemann

Pharmacol Res 2018 03 6;129:139-140. Epub 2018 Feb 6.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, DK-2100, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.phrs.2018.02.004DOI Listing
March 2018

Sympatholysis: the more we learn, the less we know.

J Physiol 2018 03 12;596(6):963-964. Epub 2018 Feb 12.

Department of Nutrition, Exercise and Sports, Section for Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1113/JP275513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851886PMC
March 2018

Probenecid Inhibits α-Adrenergic Receptor-Mediated Vasoconstriction in the Human Leg Vasculature.

Hypertension 2018 01 30;71(1):151-159. Epub 2017 Oct 30.

From the Department of Nutrition, Exercise and Sports (M.N., P.P., O.T.K., C.M., T.S.J., J.E., L.G., Y.H.) and Department of Biomedical Sciences, Faculty of Health and Medical Sciences (M.S.N.), University of Copenhagen, Denmark; Department of Orthopedics, Herlev and Gentofte Hospital, Hellerup, Denmark (T.S.J.); and Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville (B.E.I.).

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (<0.05) leg vascular conductance at baseline by ≈15% and attenuated (<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876717PMC
January 2018

Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling.

J Appl Physiol (1985) 2018 01 5;124(1):109-117. Epub 2017 Oct 5.

Department of Nutrition, Exercise and Sports, University of Copenhagen , Copenhagen , Denmark.

Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training-induced adaptations in the regulation of skeletal muscle blood flow and oxidative metabolism during exercise in aging humans. We measured leg hemodynamics and oxidative metabolism during exercise engaging the knee extensor muscles in young [ n = 15, 25 ± 1 (SE) yr] and older ( n = 15, 72 ± 1 yr) subjects before and after a period of aerobic high-intensity exercise training. To determine the role of cGMP signaling, pharmacological inhibition of phosphodiesterase 5 (PDE5) was performed. Before training, inhibition of PDE5 increased ( P < 0.05) skeletal muscle blood flow and O uptake during moderate-intensity exercise in the older group; however, these effects of PDE5 inhibition were not detected after training. These findings suggest a role for enhanced cGMP signaling in the training-induced improvement of regulation of blood flow in contracting skeletal muscle of older men. NEW & NOTEWORTHY The present study provides evidence for enhanced cyclic GMP signaling playing an essential role in the improved regulation of blood flow in contracting skeletal muscle of older men with aerobic exercise training.
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http://dx.doi.org/10.1152/japplphysiol.00634.2017DOI Listing
January 2018

Endothelial mechanotransduction proteins and vascular function are altered by dietary sucrose supplementation in healthy young male subjects.

J Physiol 2017 08;595(16):5557-5571

Section for Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.

Key Points: Mechanotransduction in endothelial cells is a central mechanism in the regulation of vascular tone and vascular remodelling Mechanotransduction and vascular function may be affected by high sugar levels in plasma because of a resulting increase in oxidative stress and increased levels of advanced glycation end-products (AGE). In healthy young subjects, 2 weeks of daily supplementation with 3 × 75 g of sucrose was found to reduce blood flow in response to passive lower leg movement and in response to 12 W of knee extensor exercise. This vascular impairment was paralleled by up-regulation of platelet endothelial cell adhesion molecule (PECAM)-1, endothelial nitric oxide synthase, NADPH oxidase and Rho family GTPase Rac1 protein expression, an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. There were no measurable changes in AGE levels. The findings of the present study demonstrate that daily high sucrose intake markedly affects mechanotransduction proteins and has a detrimental effect on vascular function.

Abstract: Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular function in humans, 12 young healthy male subjects supplemented their diet with 3 × 75 g sucrose day for 14 days in a randomized cross-over design. Before and after the intervention period, the hyperaemic response to passive lower leg movement and active knee extensor exercise was determined by ultrasound doppler. A muscle biopsy was obtained from the thigh muscle before and after acute passive leg movement to allow assessment of protein amounts and the phosphorylation status of mechanosensory proteins and NADPH oxidase. The sucrose intervention led to a reduced flow response to passive movement (by 17 ± 2%) and to 12 W of active exercise (by 9 ± 1%), indicating impaired vascular function. A reduced flow response to passive and active exercise was paralleled by a significant up-regulation of platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho family GTPase Rac1 protein expression in the muscle tissue, as well as an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. The phosphorylation status was not acutely altered with passive leg movement. These findings indicate that a regular intake of high levels of sucrose can impair vascular mechanotransduction and increase the oxidative stress potential, and suggest that dietary excessive sugar intake may contribute to the development of vascular disease.
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http://dx.doi.org/10.1113/JP274623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556152PMC
August 2017

Training for skeletal muscle capillarization: a Janus-faced role of exercise intensity?

Authors:
Lasse Gliemann

Eur J Appl Physiol 2016 Aug 24;116(8):1443-4. Epub 2016 Jun 24.

Section for Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen Ø, Denmark.

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http://dx.doi.org/10.1007/s00421-016-3419-6DOI Listing
August 2016

Effects of exercise training and resveratrol on vascular health in aging.

Free Radic Biol Med 2016 09 13;98:165-176. Epub 2016 Apr 13.

Department of Nutrition, Exercise and Sports, Section for Integrative Physiology, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen Ø, Denmark. Electronic address:

Cardiovascular disease is a leading cause of death in the western world with aging being one of the strongest predictors of cardiovascular events. Aging is associated with impaired vascular function due to endothelial dysfunction and altered redox balance, partly caused by an increased formation of reactive oxygen species combined with a reduction in the endogenous antioxidant capacity. The consequence of these alterations is a reduced bioavailability of nitric oxide (NO) with implications for aspects such as control of vascular tone and low grade inflammation. However, it is not only aging per se but also the accumulative influence of physical inactivity and other life-style factors, which negatively affect the vascular system. Regular physical activity improves NO bioavailability, the redox balance and the plasma lipid profile and, at a functional level, reduces or even reverses a majority of the observed detrimental effects of aging on vascular function. The effects of aging and physical activity on vascular function are, in part, related to alterations in cellular signaling through sirtuin-1, AMPK and the estrogen receptor. The polyphenol resveratrol can activate these same pathways and has, in animals and in vitro models, been shown to act as a partial mimetic of physical activity. However, support for beneficial effects of resveratrol in human is weak and studies even show that resveratrol supplementation, similarly to supplementation with other antioxidants, can counteract the positive effects of physical activity. Regular physical activity remains the most effective way of maintaining and improving vascular health status and caution should be taken regarding potential interference of supplements on training adaptations.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.03.037DOI Listing
September 2016

What turns off the angiogenic switch in skeletal muscle?

Exp Physiol 2015 Jul;100(7):772-3

Department of Nutrition, Exercise and Sports, Section for Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1113/EP085164DOI Listing
July 2015

Effects of Exercise Training on Regulation of Skeletal Muscle Glucose Metabolism in Elderly Men.

J Gerontol A Biol Sci Med Sci 2015 Jul 19;70(7):866-72. Epub 2015 May 19.

Centre of Inflammation and Metabolism, The August Krogh Centre, Department of Biology, and

Background: The aim was to investigate the molecular mechanisms behind exercise training-induced improvements in glucose regulation in aged subjects.

Methods: Twelve elderly male subjects completed 8 weeks of exercise training. Before and after the training period, the subjects completed an oral glucose tolerance test (OGTT) and a muscle biopsy was obtained from the vastus lateralis before and 45 minutes into the OGTT. Blood samples were collected before and up to 120 minutes after glucose intake.

Results: Exercise training increased Hexokinase II, GLUT4, Akt2, glycogen synthase (GS), pyruvate dehydrogenase (PDH)-E1α, PDK2 protein, and glycogen content in skeletal muscle. Furthermore, in response to glucose, GS activity was increased and the dephosphorylation of GS site 2 + 2a and 3a was enhanced after the training intervention. The glucose-mediated insulin stimulation of TBC1D4 Thr(642) phosphorylation was increased after exercise training. In the trained state, the PDHa activity was reduced following glucose intake and without changes in phosphorylation level of PDH-E1α.

Conclusions: The present results suggest that exercise training improves glucose regulation in elderly subjects by enhancing the capacity and acute regulation of glucose uptake and by enhancing intracellular glucose removal to glycogen synthesis rather than glucose oxidation.
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http://dx.doi.org/10.1093/gerona/glv012DOI Listing
July 2015

10-20-30 training increases performance and lowers blood pressure and VEGF in runners.

Scand J Med Sci Sports 2015 Oct 1;25(5):e479-89. Epub 2014 Dec 1.

Section of Integrated Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

The present study examined the effect of training by the 10-20-30 concept on performance, blood pressure (BP), and skeletal muscle angiogenesis as well as the feasibility of completing high-intensity interval training in local running communities. One hundred sixty recreational runners were divided into either a control group (CON; n = 28), or a 10-20-30 training group (10-20-30; n = 132) replacing two of three weekly training sessions with 10-20-30 training for 8 weeks and performance of a 5-km run (5-K) and BP was measured. VO2max was measured and resting muscle biopsies were taken in a subgroup of runners (n = 18). 10-20-30 improved 5-K time (38 s) and lowered systolic BP (2 ± 1 mmHg). For hypertensive subjects in 10-20-30 (n = 30), systolic and diastolic BP was lowered by 5 ± 4 and 3 ± 2 mmHg, respectively, which was a greater reduction than in the non-hypertensive subjects (n = 102). 10-20-30 increased VO2max but did not influence muscle fiber area, distribution or capillarization, whereas the expression of the pro-angiogenic vascular endothelial growth factor (VEGF) was lowered by 22%. No changes were observed in CON. These results suggest that 10-20-30 training is an effective and easily implemented training intervention improving endurance performance, VO2max and lowering BP in recreational runners, but does not affect muscle morphology and reduces muscle VEGF.
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http://dx.doi.org/10.1111/sms.12356DOI Listing
October 2015

Resveratrol modulates the angiogenic response to exercise training in skeletal muscles of aged men.

Am J Physiol Heart Circ Physiol 2014 Oct 15;307(8):H1111-9. Epub 2014 Aug 15.

Integrative Physiology Group, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark; and.

In animal studies, the polyphenol resveratrol has been shown to influence several pathways of importance for angiogenesis in skeletal muscle. The aim of the present study was to examine the angiogenic effect of resveratrol supplementation with parallel exercise training in aged men. Forty-three healthy physically inactive aged men (65 ± 1 yr) were divided into 1) a training group that conducted 8 wk of intense exercise training where half of the subjects received a daily intake of either 250 mg trans-resveratrol (n = 14) and the other half received placebo (n = 13) and 2) a nontraining group that received either 250 mg trans-resveratrol (n = 9) or placebo (n = 7). The group that trained with placebo showed a ~20% increase in the capillary-to-fiber ratio, an increase in muscle protein expression of VEGF, VEGF receptor-2, and tissue inhibitor of matrix metalloproteinase (TIMP-1) but unaltered thrombospodin-1 levels. Muscle interstitial VEGF and thrombospodin-1 protein levels were unchanged after the training period. The group that trained with resveratrol supplementation did not show an increase in the capillary-to-fiber ratio or an increase in muscle VEGF protein. Muscle TIMP-1 protein levels were lower in the training and resveratrol group than in the training and placebo group. Both training groups showed an increase in forkhead box O1 protein. In nontraining groups, TIMP-1 protein was lower in the resveratrol-treated group than the placebo-treated group after 8 wk. In conclusion, these data show that exercise training has a strong angiogenic effect, whereas resveratrol supplementation may limit basal and training-induced angiogenesis.
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http://dx.doi.org/10.1152/ajpheart.00168.2014DOI Listing
October 2014

Exercise training modulates functional sympatholysis and α-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals.

J Physiol 2014 Jul 23;592(14):3063-73. Epub 2014 May 23.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics were measured before and after 8 weeks of aerobic training (3-4 times per week) in eight hypertensive (47 ± 2 years) and eight normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise hyperaemia and leg vascular conductance (LVC) were lower in the hypertensive individuals (P < 0.05) and tyramine lowered exercise hyperaemia and LVC in both groups (P < 0.05). Training lowered blood pressure in the hypertensive individuals (P < 0.05) and exercise hyperaemia was similar to the normotensive individuals in the trained state. After training, tyramine did not reduce exercise hyperaemia or LVC in either group. When tyramine was infused at rest, the reduction in blood flow and LVC was similar between groups, but exercise training lowered the magnitude of the reduction in blood flow and LVC (P < 0.05). There was no difference in the vasodilatory response to infused ATP or in muscle P2Y2 receptor content between the groups before and after training. However, training lowered the vasodilatory response to ATP and increased skeletal muscle P2Y2 receptor content in both groups (P < 0.05). These results demonstrate that exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo- and hypertensive individuals. The ability for functional sympatholysis and the vasodilator and sympatholytic effect of intravascular ATP appear not to be altered in essential hypertension.
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http://dx.doi.org/10.1113/jphysiol.2014.273722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214660PMC
July 2014