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The effect of nitric oxide synthase inhibition with and without inhibition of prostaglandins on blood flow in different human skeletal muscles

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Purpose: Animal studies suggest that the inhibition of nitric oxide synthase (NOS) affects blood flow differently in different skeletal muscles according to their muscle fibre type composition (oxidative vs glycolytic). Quadriceps femoris (QF) muscle consists of four different muscle parts: vastus intermedius (VI), rectus femoris (RF), vastus medialis (VM), and vastus lateralis (VL) of which VI is located deep within the muscle group and is generally regarded to consist mostly of oxidative muscle fibres. Methods: We studied the effect of NOS inhibition on blood flow in these four different muscles by positron emission tomography in eight young healthy men at rest and during one-leg dynamic exercise, with and without combined blockade with prostaglandins. Results: At rest blood flow in the VI (2.6 ± 1.1 ml/100 g/min) was significantly higher than in VL (1.9 ± 0.6 ml/100 g/min, p = 0.015) and RF (1.7 ± 0.6 ml/100 g/min, p = 0.0015), but comparable to VM (2.4 ± 1.1 ml/100 g/min). NOS inhibition alone or with prostaglandins reduced blood flow by almost 50% (p < 0.001), but decrements were similar in all four muscles (drug × muscle interaction, p = 0.43). During exercise blood flow was also the highest in VI (45.4 ± 5.5 ml/100 g/min) and higher compared to VL (35.0 ± 5.5 ml/100 g/min), RF (38.4 ± 7.4 ml/100 g/min), and VM (36.2 ± 6.8 ml/100 g/min). NOS inhibition alone did not reduce exercise hyperemia (p = 0.51), but combined NOS and prostaglandin inhibition reduced blood flow during exercise (p = 0.002), similarly in all muscles (drug × muscle interaction, p = 0.99). Conclusion: NOS inhibition, with or without prostaglandins inhibition, affects blood flow similarly in different human QF muscles both at rest and during low-to-moderate intensity exercise.
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Eur J Appl Physiol (2017) 117:1175–1180
DOI 10.1007/s00421-017-3604-2
The effect ofnitric oxide synthase inhibition withandwithout
inhibition ofprostaglandins onblood flow indifferent human
skeletal muscles
IlkkaHeinonen1,2,3 · BengtSaltin5· YlvaHellsten4· KariK.Kalliokoski1
Received: 22 November 2016 / Accepted: 22 March 2017 / Published online: 21 April 2017
© Springer-Verlag Berlin Heidelberg 2017
in VL (1.9 ± 0.6 ml/100 g/min, p = 0.015) and RF
(1.7±0.6ml/100g/min, p=0.0015), but comparable to
VM (2.4 ± 1.1 ml/100 g/min). NOS inhibition alone or
with prostaglandins reduced blood flow by almost 50%
(p<0.001), but decrements were similar in all four mus-
cles (drug×muscle interaction, p=0.43). During exercise
blood flow was also the highest in VI (45.4±5.5ml/100g/
min) and higher compared to VL (35.0 ± 5.5 ml/100 g/
min), RF (38.4 ± 7.4 ml/100 g/min), and VM
(36.2 ± 6.8 ml/100 g/min). NOS inhibition alone did not
reduce exercise hyperemia (p=0.51), but combined NOS
and prostaglandin inhibition reduced blood flow during
exercise (p=0.002), similarly in all muscles (drug×mus-
cle interaction, p=0.99).
Conclusion NOS inhibition, with or without prostaglan-
dins inhibition, affects blood flow similarly in different
human QF muscles both at rest and during low-to-moderate
intensity exercise.
Keywords Muscle fibres· Blood flow· Nitric oxide·
Prostanoids· Exercise· Humans
NOS Nitric oxide synthase
VI Vastus intermedius
RF Rectus femoris
VM Vastus medialis
VL Vastus lateralis
The continuous supply of oxygen via blood is of para-
mount importance for proper function of the muscle,
especially during exercise (Heinonen etal. 2014, 2015;
Purpose Animal studies suggest that the inhibition of
nitric oxide synthase (NOS) affects blood flow differently
in different skeletal muscles according to their muscle fibre
type composition (oxidative vs glycolytic). Quadriceps
femoris (QF) muscle consists of four different muscle parts:
vastus intermedius (VI), rectus femoris (RF), vastus media-
lis (VM), and vastus lateralis (VL) of which VI is located
deep within the muscle group and is generally regarded to
consist mostly of oxidative muscle fibres.
Methods We studied the effect of NOS inhibition on
blood flow in these four different muscles by positron emis-
sion tomography in eight young healthy men at rest and
during one-leg dynamic exercise, with and without com-
bined blockade with prostaglandins.
Results At rest blood flow in the VI
(2.6 ± 1.1 ml/100 g/min) was significantly higher than
Communicated by: Keith Phillip George
Bengt Saltin: Deceased.
* Ilkka Heinonen
1 Turku PET Centre, University ofTurku, PO Box52,
20521Turku, Finland
2 Department ofClinical Physiology andNuclear Medicine,
University ofTurku, Turku, Finland
3 Division ofExperimental Cardiology, Thoraxcenter, Erasmus
MC, University Medical Center Rotterdam, Rotterdam,
4 Exercise andSport Sciences, Section ofHuman Physiology,
University ofCopenhagen, Copenhagen, Denmark
5 Copenhagen Muscle Research Center, University
ofCopenhagen, Copenhagen, Denmark
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... nNOS enzyme expression was elevated in the hindlimb (predominantly in fast-twitch lateral gastrocnemius muscle) of exercise trained rats, suggesting a causal link between NOS enzyme expression and NO mediated vascular function (Jendzjowsky et al., 2014a). However, studies by Heinonen et al. (2011);Heinonen et al. (2017) indicate that nonselective NOS inhibition does not alter blood flow to active and inactive muscle during mild-intensity, single-leg kneeextension exercise. In contrast, several studies in rodents indicate that NO contributes to the distribution of muscle blood flow during exercise, and is particularly important to the distribution of flow during intense exercise (Hirai et al., 1994;Musch et al., 2001;Copp et al., 2010;Copp et al., 2013). ...
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The process of matching skeletal muscle blood flow to metabolism is complex and multi-factorial. In response to exercise, increases in cardiac output, perfusion pressure and local vasodilation facilitate an intensity-dependent increase in muscle blood flow. Concomitantly, sympathetic nerve activity directed to both exercising and non-active muscles increases as a function of exercise intensity. Several studies have reported the presence of tonic sympathetic vasoconstriction in the vasculature of exercising muscle at the onset of exercise that persists through prolonged exercise bouts, though it is blunted in an exercise-intensity dependent manner (functional sympatholysis). The collective evidence has resulted in the current dogma that vasoactive molecules released from skeletal muscle, the vascular endothelium, and possibly red blood cells produce local vasodilation, while sympathetic vasoconstriction restrains vasodilation to direct blood flow to the most metabolically active muscles/fibers. Vascular smooth muscle is assumed to integrate a host of vasoactive signals resulting in a precise matching of muscle blood flow to metabolism. Unfortunately, a critical review of the available literature reveals that published studies have largely focused on bulk blood flow and existing experimental approaches with limited ability to reveal the matching of perfusion with metabolism, particularly between and within muscles. This paper will review our current understanding of the regulation of sympathetic vasoconstriction in contracting skeletal muscle and highlight areas where further investigation is necessary.
... The most important functions of nNOS include modulation of synapse plasticity in the central nervous system, central regulation of blood pressure, maintenance of smooth muscle tone of internal organs, in particular by generating NO in nitrergic nerve endings, control of blood supply to skeletal muscle fibers [35,38,44,49,51]. ...
The sources of the nitric oxide (NO) formation in the uterus and the dynamics of changes in its content in different periods of organ functioning in human and animals are analyzed. The biochemical mechanisms of NO action on the myometrium contractile activity, the significance of NO in the physiological processes during pregnancy and labor, the importance of mitochondria as a reliable NO source in the smooth muscle and the possible ways of NO influence on Ca2+ transport and bioenergetic processes in mitochondria are considered. The authors’ data concerning ionic and membrane mechanisms of NO action on Ca2+-homeostasis of uterine myocytes, identification of nitric oxide in uterine smooth muscle mitochondria, biochemical characteristics of the NO-synthase reaction and the possible role of NO in the regulation of Ca2+ transport in these subcellular structures and in the electron transport chain functioning are presented and discussed.
... While the role of NOS in maintaining resting blood flow is established in the peripheral circulation (Gardiner et al. 1990;Imig et al. 1993, Lefroy et al. 1993Huang et al. 1995;Shesely et al. 1996;Duffy et al. 1999;Heinonen et al. 2011;Heinonen et al. 2017;Heinonen et al. 2018), studies of the cerebral circulation report contradictory findings. For example, inhibition of NOS using N G -monomethyl-L-arginine (L-NMMA) decreased CBF through a single internal carotid artery by 16% (White et al. 1998) and reduced global CBF by 20% (White et al. 1999). ...
Key points: Cerebral blood flow (CBF) is vital for brain health, but the signals key to regulating CBF remain unclear. Nitric oxide (NO) is produced in the brain, but its importance in regulating CBF remains controversial since prior studies have not studied all regions of the brain simultaneously. Using modern MRI approaches, a drug that inhibits enzymes that make NO (L-NMMA) reduced CBF up to 11% in different brain regions. NO helps maintain proper CBF in healthy adults. These data will help us understand if reductions in CBF which occur during aging or cardiovascular disease are related to shifts in NO signaling. Abstract: The importance of nitric oxide (NO) in regulating cerebral blood flow (CBF) remains unresolved, due in part to methodological approaches, which lack comprehensive assessment of both global and regional effects. Importantly, NO synthase (NOS) expression and activity appear greater in some anterior brain regions, suggesting region-specific NOS influence on CBF. We hypothesized that NO contributes to basal CBF in healthy adults, in a regionally distinct pattern that predominates in the anterior circulation. 14 healthy adults (7 females; 24±5 years) underwent two magnetic resonance imaging (MRI) study visits with saline (placebo) or the NOS inhibitor, L-NMMA, administered in a randomized, single-blind approach. 4D Flow MRI quantified total and regional macrovascular CBF, whereas arterial spin labeling (ASL) MRI quantified total and regional microvascular perfusion. L-NMMA (or volume-matched saline) was infused intravenously for 5 minutes prior to imaging. L-NMMA reduced CBF (L-NMMA: 722±100 vs. placebo: 771±121 mL/min, p = 0.01) with similar relative reductions (5-7%) in anterior and posterior cerebral circulations, due in part to reduced cross sectional area of 9 of 11 large cerebral arteries. Global microvascular perfusion (ASL) was reduced by L-NMMA (L-NMMA: 42±7 vs. placebo: 47±8 mL/100g/min, p = 0.02), with 7-11% reductions in both hemispheres of frontal, parietal, and temporal lobes, and in the left occipital lobe. We conclude NO contributes to macrovascular and microvascular regulation including larger artery resting diameter. Contrary to our hypothesis, the influence of NO on cerebral perfusion appears regionally uniform in healthy young adults. Abstract figure legends EC, endothelial cell; L-arg, L-arginine; L-NMMA, NG -monomethyl-L-arginine; NO, nitric oxide; NOS, nitric oxide synthase. NO contributes to the maintenance of resting brain blood flow in humans. Inhibition of nitric oxide synthase by L-NMMA in endothelial cells leads to reduced bulk flow and regional perfusion. This article is protected by copyright. All rights reserved.
... However, this view was also challenged in numerous studies in which NO accounted only for a minor part (if any) of the dilation in active hyperemia [4]. In humans, NOS inhibition attenuated blood flow during exercise only in combination with blockade of prostaglandin synthesis indicating a substantial redundancy between these two systems [14], whereas EDH cannot compensate their impairment [28]. ...
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Functional hyperemia is fundamental to provide enhanced oxygen delivery during exercise in skeletal muscle. Different mechanisms are suggested to contribute, mediators from skeletal muscle, transmitter spillover from the neuromuscular synapse as well as endothelium-related dilators. We hypothesized that redundant mechanisms that invoke adenosine, endothelial autacoids, and KATP channels mediate the dilation of intramuscular arterioles in mice. Arterioles (maximal diameter: 20–42 µm, n = 65) were studied in the cremaster by intravital microscopy during electrical stimulation of the motor nerve to induce twitch or tetanic skeletal muscle contractions (10 or 100 Hz). Stimulation for 1–60 s dilated arterioles rapidly up to 65% of dilator capacity. Blockade of nicotinergic receptors blocked muscle contraction and arteriolar dilation. Exclusive blockade of adenosine receptors (1,3-dipropyl-8-(p-sulfophenyl)xanthine) or of NO and prostaglandins (nitro-L-arginine and indomethacin, LN + Indo) exerted only a minor attenuation. Combination of these blockers, however, reduced the dilation by roughly one-third during longer stimulation periods (> 1 s at 100 Hz). Blockade of KATP channels (glibenclamide) which strongly reduced adenosine-induced dilation reduced responses upon electrical stimulation only moderately. The attenuation was strongly enhanced if glibenclamide was combined with LN + Indo and even observed during brief stimulation. LN was more efficient than indomethacin to abrogate dilations if combined with glibenclamide. Arteriolar dilations induced by electrical stimulation of motor nerves require muscular contractions and are not elicited by acetylcholine spillover from neuromuscular synapses. The dilations are mediated by redundant mechanisms, mainly activation of KATP channels and release of NO. The contribution of K+ channels and hyperpolarization sets the stage for ascending dilations that are crucial for a coordinated response in the network.
... Alternatively, endothelial nitric oxide synthase (eNOS) has been suggested as an important regulator of muscle blood flow as its concentration increases with exercise (Roberts et al. 1999). Known to work in concert with adrenergic responses, its inhibition during exercise also demonstrated a decrease in muscle blood flow, further supporting its implication as a strong vasodilator (Johnson et al. 2014;Heinonen et al. 2017). Recent reviews have offered insights into the role eNOS on vasoconstriction and have pointed out that its role reaches beyond a simple decrease in synthesis and could further stem from the role of its different isoforms (Johnson and Kellog 2010;Johnson et al 2014). ...
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PurposeThis study investigated whether muscle cooling and its associated effects on skeletal muscle oxidative responses, blood gases, and hormonal concentrations influenced energy metabolism during cycling.Methods Twelve healthy participants (Males: seven; Females: five) performed two steady-state exercise sessions at 70% of ventilatory threshold on a cycle ergometer. Participants completed one session with pre-exercise leg cooling until muscle temperature (Tm) decreased by 6 °C (LCO), and a separate session without cooling (CON). They exercised until Tm returned to baseline and for an additional 30 min. Cardiovascular, respiratory, metabolic, hemodynamic variables, and skeletal muscle tissue oxidative responses were assessed continuously. Venous blood samples were collected to assess blood gases, and hormones.ResultsHeart rate, stroke volume, and cardiac output all increased across time but were not different between conditions. V̇O2 was greater in LCO when muscle temperature was restored until the end of exercise (p < 0.05). Cycling in the LCO condition induced lower oxygen availability, tissue oxygenation, blood pH, sO2%, and pO2 (p < 0.05). Insulin concentrations were also higher in LCO vs. CON (p < 0.05). Importantly, stoichiometric equations from respiratory gases indicated no differences in fat and CHO oxidation between conditions.Conclusion The present study demonstrated that despite muscle cooling and the associated oxidative and biochemical changes, energy metabolism remained unaltered during cycling. Whether lower local and systemic oxygen availability is counteracted via a cold-induced activation of lipid metabolism pathways needs to be further investigated.
... Humans also show an increase in salivary NO concentration at one and three hours after both a maximal aerobic test and a high-intensity interval training test on a mechanical ergometer, but not after resistance exercise of swats, leg curls, and stiff exercises [35]. NO is produced during events of oxidative stress and its increase following exercise can be predicted due to its role (together with PGE2) in facilitating increases in local blood flow to the exercising skeletal muscles [36,37] and reviewed in [38]. There are variations in NO production depending on exercise intensity [35]; it is possible that the lack of effect observed in the current study resulted from the relatively low intensity of the exercise bout. ...
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There is little information available to describe the inflammatory consequences of and recovery from moderate-intensity exercise bouts in hunting dogs. The purpose of the current study is to generate pilot data on the appearance and disappearance of biomarkers of inflammation and inflammation resolution following a typical one-hour exercise bout in basset hounds. Four hounds were set out to find a scent and freely adopted running or walking over wooded terrain for approximately one hour. Venous blood samples were obtained before the exercise and at 1, 2, 4, 6, and 10 hours following cessation of exercise and were analyzed for biomarkers of inflammation (prostaglandin E2 (PGE2), nitric oxide (NO), interleukin 1β (IL-1β)) tumour necrosis factor-α (TNF-α)), and inflammation resolution (resolvin D1 (RvD1)). There was an increase in inflammation one hour after the exercise, shown by a significant increase in PGE2. Following this peak, PGE2 steadily declined at the same time as RvD1 increased, with RvD1 peaking at six hours. This pilot study provides evidence that dogs that undergo an hour of hunt exercise experience transient inflammation that peaks one hour after the end of exercise; inflammation resolution peaks six hours after the end of exercise. Future studies should seek to further understand the distinct and combined roles of PGE2 and RvD1 in dog adaptation to exercise stress.
... 115 Prostanoids (e.g., prostaglandin E2 (PGE 2 ), prostaglandin F2 alpha (PGF 2a )) may exert proinflammatory effects and function as acute signaling molecules for muscle adaptation and regulation of blood flow. 107,117,118 The largest number of oxylipins following heavy exertion come from the n-6 PUFA substrate ARA, and these eicosanoids include at least 15 varieties of hydroxy-eicosatetraenoic acids and dihydroxy-eicosatrienoic acids (DiHETrEs) from lipoxygenase and CYP enzymes. 103,107,110 The hydroxy-eicosatetraenoic acids and DiHETrEs may have multiple potential roles during exercise recovery, including the regulation of leukocyte migration and chemotaxis, macrophage efferocytosis and tissue repair, inflammation, peroxisome proliferator-activated receptor activation, vascular tone, and platelet regulation. ...
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Several decades of research in the area of exercise immunology have shown that the immune system is highly responsive to acute and chronic exercise training. Moderate exercise bouts enhance immunosurveillance and when repeated over time mediate multiple health benefits. Most of the studies prior to 2010 relied on a few targeted outcomes related to immune function. During the past decade, technologic advances have created opportunities for a multi-omics and systems biology approach to exercise immunology. This article provides an overview of metabolomics, lipidomics, and proteomics as they pertain to exercise immunology, with a focus on immunometabolism. This review also summarizes how the composition and diversity of the gut microbiota can be influenced by exercise, with applications to human health and immunity. Exercise-induced improvements in immune function may play a critical role in countering immunosenescence and the development of chronic diseases, and emerging omics technologies will more clearly define the underlying mechanisms. This review summarizes what is currently known regarding a multi-omics approach to exercise immunology and provides future directions for investigators.
... The HETEs, DiHETEs, and DiHETrEs have multiple roles including the regulation of leukocyte migration and chemotaxis, PPAR activation, vascular tone, and platelet regulation (Caligiuri et al. 2017, Powell & Rokach 2015. Exercise-induced increases in prostanoids such as PGE 2 , PGF 2α , and 6-keto-PGF 1α (a product of prostacyclin or PG1 2 ) exert proinflammatory effects, may function as acute signaling molecules for postexercise muscle adaptation, and help regulate blood flow (Boushel et al. 2002;Heinonen et al. 2017;Markworth et al. 2014Markworth et al. , 2016a. However, chronic ingestion of COXinhibiting drugs such as ibuprofen does not interfere with muscle adaptations to exercise training; to the contrary, it may promote muscle mass and strength gains by upregulating the PGF 2α receptor (Trappe & Liu 2013. ...
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Immunometabolism is an evolving field of scientific endeavor that merges immunology and metabolism and has provided valuable context when evaluating the influence of dietary interventions on exercise-induced immune dysfunction. Metabolomics, lipidomics, and proteomics provide a system-wide view of the metabolic response to exercise by simultaneously measuring and identifying a large number of small molecule metabolites, lipids, and proteins. Many of these are involved with immune function and regulation and are sensitive to dietary influences, especially acute carbohydrate ingestion from either sugar beverages or fruits such as bananas. Emerging evidence using large multi-omics data sets supports the combined intake of fruit sugars and phytochemicals by athletes during heavy exertion as an effective strategy to improve metabolic recovery, augment viral defense, and counter postexercise inflammation and immune dysfunction at the cell level. Multi-omics methodologies have given investigators new outcome targets to assess the efficacy of various dietary interventions for physiologically stressed athletes. Expected final online publication date for the Annual Review of Food Science and Technology Volume 10 is March 25, 2019. Please see for revised estimates.
... A major advantage of the PET methodology is that it can provide quantitation of blood flow in specific regions of the muscle (Fig. 6), allowing for determination of regional differences of flow in the muscles (Laaksonen et al. 2013;Heinonen et al. 2017). The method also allows for determination of blood flow heterogeneity (Kalliokoski et al. 2000(Kalliokoski et al. , 2001a which is a useful complementary parameter to understand changes in muscle perfusion with aging, training, etc. ...
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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.
... The most important functions of nNOS include modulation of the synapse plasticity in CNS, central regulation of blood pressure, the tone of smooth muscles of the internal organs, in particular by generating NO in the nitrergic nerve endings, control of the blood supply to skeletal muscle fibers [4,30,39,43,53]. ...
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Modern data on biochemical patterns of nitric oxide biosynthesis in mammal cells from L-arginine in normoxic conditions is described. The attention of the authors is given to the results of the recent years on the structure and regulation features isoforms of NO-synthase. The emphasis is put on the latest conception of the compartmentalization of certain isoforms of these enzymes in cells and on the possibility of the directed transport of nitric oxide in the vascular wall. The central place in the review is devoted to issues on the endogenous formation of NO in mitochondria and its potential physiological significance. Our own results on the identification of NO in mitochondria of the uterine smooth muscle, biochemical characteristics of this process and NO possible role in Са2+ transport regulation by organelles are presented and discussed.
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The ergogenic effects of dietary nitrate supplementation may be related to specific physiological effects on type II muscle fibers.
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Virtually all tissues in the human body rely on aerobic metabolism for energy production and are therefore critically dependent on continuous supply of oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ perfusion are also closely associated with alterations in tissue metabolism. In response to acute exercise, blood flow is markedly increased in contracting skeletal muscles and myocardium, but perfusion in other organs (brain and bone) is only slightly enhanced or is even reduced (visceral organs). Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits. However, the physiological adaptations and driving-force mechanisms in organs such as brain, liver, pancreas, gut, bone, and adipose tissue, remain largely obscure in humans. Along these lines, this review integrates current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the state-of-the-art, noninvasive human imaging studies, and directions for future novel research are proposed throughout the review.
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Background The role of nitric oxide in controlling substrate metabolism in humans is incompletely understood. Methods The present study examined the effect of nitric oxide blockade on glucose uptake, and free fatty acid and lactate exchange in skeletal muscle of eight healthy young males. Exchange was determined by measurements of muscle perfusion by positron emission tomography and analysis of arterial and femoral venous plasma concentrations of glucose, fatty acids and lactate. The measurements were performed at rest and during exercise without (control) and with blockade of nitric oxide synthase (NOS) with NG-monomethyl-l-arginine (L-NMMA). Results Glucose uptake at rest was 0.40 ± 0.21 μmol/100 g/min and increased to 3.71 ± 2.53 μmol/100 g/min by acute one leg low intensity exercise (p < 0.01). Prior inhibition of NOS by L-NMMA did not affect glucose uptake, at rest or during exercise (0.40 ± 0.26 and 4.74 ± 2.69 μmol/100 g/min, respectively). In the control trial, there was a small release of free fatty acids from the limb at rest (−0.05 ± 0.09 μmol/100 g/min), whereas during inhibition of NOS, there was a small uptake of fatty acids (0.04 ± 0.05 μmol/100 g/min, p < 0.05). During exercise fatty acid uptake was increased to (0.89 ± 1.07 μmol/100 g/min), and there was a non-significant trend (p = 0.10) for an increased FFA uptake with NOS inhibition 1.23 ± 1.48 μmol/100 g/min) compared to the control condition. Arterial concentrations of all substrates and exchange of lactate over the limb at rest and during exercise remained unaltered during the two conditions. Conclusion In conclusion, inhibition of nitric oxide synthesis does not alter muscle glucose uptake during low intensity exercise, but affects free fatty acid exchange especially at rest, and may thus be involved in the modulation of energy metabolism in the human skeletal muscle.
The systematic increase in O2 uptake and O2 extraction with increasing work rates conceals a substantial heterogeneity of O2 delivery (Q˙O2)-to-V˙O2 matching across and within muscles and other organs. We hypothesize that whether increased/decreased Q˙O2/V˙O2 heterogeneity can be judged as "good" or "bad", for example after exercise training or in aged individuals or with disease (heart failure, diabetes), depends on the resultant effects on O2 transport and contractile performance.Summary statementMuscle Q˙O2/V˙O2 heterogeneity may be key to subserving different regional exercise O2 demands in health but derangements in disease may be detrimental to blood-myocyte O2 flux and contractile performance in disease states.
Resolving the bases for different physiological functioning or exercise performance within a population is dependent upon our understanding of control mechanisms. For example, when most young healthy individuals run or cycle at moderate intensities oxygen uptake (V˙O2) kinetics are rapid and the amplitude of the V˙O2 response is not constrained by O2 delivery. For this to occur muscle O2 delivery (i.e., blood flow x arterial O2 concentration) must be coordinated superbly with muscle O2 requirements (V˙O2); the efficacy of which may differ among muscles and distinct fiber types. When the O2 transport system succumbs to the predations of aging or disease (emphysema, heart failure, Type II diabetes) muscle O2 delivery and O2 delivery-V˙O2 matching, and therefore muscle contractile function, become impaired. This forces greater influence of the upstream O2 transport pathway on muscle aerobic energy production, and the O2 delivery-V˙O2 relationship(s) assumes increased importance. This review is the first of its kind to bring a broad range of available techniques, most state-of-the art, including computer modeling, radiolabelled microspheres, positron emission tomography (PET), magnetic resonance imaging (MRI), near infrared spectroscopy (NIRS), and phosphorescence quenching to resolve the O2 delivery-V˙O2 relationships and inherent heterogeneities at the whole body, inter-organ, muscle(s), intramuscular and microvascular/myocyte levels. Emphasis is placed upon: 1. Intact humans and animals as these provide the platform essential for framing and interpreting subsequent investigations. 2. Contemporary findings using novel technological approaches to elucidate O2 delivery-V˙O2 heterogeneities in humans. 3. Future directions for investigating how normal physiological responses can be explained by O2 delivery-V˙O2 heterogeneities and the impact of aging/disease on these processes.
Samples of skeletal muscle were taken from 50 sites in each of 6 previously normal male autopsy subjects aged between 17 and 30 years. The respective percentages of Type I and Type II fibres were calculated and showed that there was a wide variation in fibre type proportions between the 6 samples in almost all the muscles studied. Examination of the mean fibre type proportions of each muscle revealed that predominantly tonic muscles had a high percentage of Type I fibres and predominantly phasic muscles had a high percentage of Type II fibres. Most of the muscles studied were known to fulfil both tonic and phasic functions, however, and showed no striking preponderance of either fibre type.The spatial distribution of the fibre types was examined in order to determine whether this was random or not. The number of “enclosed” fibres observed in the actual samples was compared statistically with the number expected to occur in a hexagonal lattice model, assuming a random distribution. In the great majority of muscles, the distribution of the fibre types was in fact random, though isolated instances of grouping of fibres of uniform type were noted in some distal muscles and more regularly in extensor digitorum brevis.The methods used in the quantitative assessment of the proportions and spatial distribution of the respective fibre types in normal muscle have obvious applications in the study of neuromuscular disease.
Blood flow (BF) increases with increasing exercise intensity in skeletal, respiratory, and cardiac muscle. In humans during maximal exercise intensities, 85% to 90% of total cardiac output is distributed to skeletal and cardiac muscle. During exercise BF increases modestly and heterogeneously to brain and decreases in gastrointestinal, reproductive, and renal tissues and shows little to no change in skin. If the duration of exercise is sufficient to increase body/core temperature, skin BF is also increased in humans. Because blood pressure changes little during exercise, changes in distribution of BF with incremental exercise result from changes in vascular conductance. These changes in distribution of BF throughout the body contribute to decreases in mixed venous oxygen content, serve to supply adequate oxygen to the active skeletal muscles, and support metabolism of other tissues while maintaining homeostasis. This review discusses the response of the peripheral circulation of humans to acute and chronic dynamic exercise and mechanisms responsible for these responses. This is accomplished in the context of leading the reader on a tour through the peripheral circulation during dynamic exercise. During this tour, we consider what is known about how each vascular bed controls BF during exercise and how these control mechanisms are modified by chronic physical activity/exercise training. The tour ends by comparing responses of the systemic circulation to those of the pulmonary circulation relative to the effects of exercise on the regional distribution of BF and mechanisms responsible for control of resistance/conductance in the systemic and pulmonary circulations. © 2012 American Physiological Society. Compr Physiol 2:321-447, 2012.