ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine

2009 ◽  
Vol 296 (4) ◽  
pp. R1140-R1148 ◽  
Author(s):  
Stefan P. Mortensen ◽  
José González-Alonso ◽  
Laurids T. Bune ◽  
Bengt Saltin ◽  
Henriette Pilegaard ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Purinergic Receptors ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Pcr Analysis ◽  
Receptor Subtypes ◽  
Vastus Lateralis Muscle

Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P2 receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5–7 min of femoral intra-arterial infusion of ATP [0.45–2.45 μmol/min] in 19 healthy male subjects with and without coinfusion of NG-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 ± 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 ± 12 μg/min), and/or theophylline (adenosine receptor blocker; 400 ± 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 ± 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 ± 6, 15 ± 9, and 39 ± 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O2 extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P2Y2 receptors of the 10 investigated P2 receptor subtypes. Immunohistochemistry showed that P2Y2 receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P2X1 receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P2Y2 and P2X1 receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle.

Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

2006 ◽  
Vol 291 (3) ◽  
pp. R803-R809 ◽  
Author(s):  
Kari K. Kalliokoski ◽  
Henning Langberg ◽  
Ann Kathrine Ryberg ◽  
Celena Scheede-Bergdahl ◽  
Simon Doessing ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Vastus Lateralis Muscle ◽  
Substrate Uptake ◽  
Skeletal Muscle Blood Flow ◽  
Lateralis Muscle

Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-d-[18F]glucose without and with local blockade of NO and PG at rest and during one-legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-l-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1 and 4 cm away from the infusion of blockers. Local blockade during exercise at 25 and 40 watts significantly decreased blood flow in the infusion region and in the region 1 cm away from the site of infusion but not in the region 4 cm away. During exercise, muscle glucose uptake did not show any regional differences in response to blockade. These results show that NO and PG synergistically contribute to the local regulation of blood flow in skeletal muscle independently of muscle glucose uptake in healthy young men. Thus these vasodilators can play a role in regulating microvascular blood flow in localized regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.

Muscle blood flow during exercise in sedentary and trained hypothyroid rats

1995 ◽  
Vol 269 (6) ◽  
pp. H1949-H1954 ◽  
Author(s):  
R. M. McAllister ◽  
M. D. Delp ◽  
K. A. Thayer ◽  
M. H. Laughlin
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Citrate Synthase ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Treadmill Running ◽  
Exercise Intolerance ◽  
Vastus Lateralis Muscle ◽  
Blood Flows ◽  
Vastus Intermedius

Hypothyroidism is characterized by exercise intolerance. We hypothesized that active muscle blood flow during in vivo exercise is inadequate in the hypothyroid state. Additionally, we hypothesized that endurance exercise training would restore normal blood flow during acute exercise. To test these hypotheses, rats were made hypothyroid (Hypo) over 3-4 mo with propylthiouracil. A subset of Hypo rats was trained (THypo) on a treadmill at 30 m/min (15% grade) for 60 min/day 5 days/wk over 10-15 wk. Hypothyroidism was evidenced by approximately 80% reductions in plasma triiodothyronine levels in Hypo and THypo and by 40-50% reductions in citrate synthase activities in high oxidative muscles in Hypo compared with euthyroid (Eut) rats. Training efficacy was indicated by increased (25-100%) citrate synthase activities in muscles of THypo vs. Hypo. Regional blood flows were determined by the radiolabeled microsphere method before exercise and at 1-2 min of treadmill running at 15 m/min (0% grade). Preexercise muscle blood flows were generally similar among groups. During exercise, however, flows were lower in Hypo than in Eut for high oxidative muscles such as the red section of vastus lateralis [277 +/- 24 and 153 +/- 13 (SE) ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01] and vastus intermedius (317 +/- 32 and 187 +/- 20 ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01) muscles. Training (THypo) did not normalize these flows (168 +/- 24 and 181 +/- 24 ml.min-1.100 g-1 for red section of vastus lateralis and vastus intermedius muscles, respectively). Blood flows to low oxidative muscle, such as the white section of vastus lateralis muscle, were similar among groups (21 +/- 5, 25 +/- 4, and 34 +/- 7 ml.min-1.100 g-1 for Eut, Hypo, and THypo, respectively; P = NS). These findings indicate that hypothyroidism is associated with reduced blood flow to skeletal muscle during exercise, suggesting that impaired delivery of nutrients to and/or removal of metabolites from skeletal muscle contributes to the poor exercise tolerance characteristic of hypothyroidism.

scholarly journals Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

2002 ◽  
Vol 543 (2) ◽  
pp. 691-698 ◽  
Author(s):  
Robert Boushel ◽  
Henning Langberg ◽  
Carsten Gemmer ◽  
Jens Olesen ◽  
Regina Crameri ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Muscle Blood Flow ◽  
Skeletal Muscle Blood Flow

Role of nitric oxide in skeletal muscle blood flow at rest and during dynamic exercise in humans

1997 ◽  
Vol 273 (1) ◽  
pp. H405-H410 ◽  
Author(s):  
R. C. Hickner ◽  
J. S. Fisher ◽  
A. A. Ehsani ◽  
W. M. Kohrt
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Dynamic Exercise ◽  
Skeletal Muscle Blood Flow ◽  
Blood Flows ◽  
And Control

The role of nitric oxide at rest and in the active hyperemic response within skeletal muscle was investigated in eight physically active men. Three microdialysis probes were inserted into the vastus lateralis of the quadriceps femoris muscle group in each subject. Microdialysis probes were perfused with a Ringer solution containing 5.0 mM ethanol, 2.5 mM glucose, and either 10 mg/ml of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) monoacetate salt, 30 mg/ml of the nitric oxide precursor L-arginine, or no additional substance (control probe). Subjects performed one-legged cycling exercise at work rates ranging from 25 to 100 W. Dialysate and perfusate ethanol concentrations were presented as the ratio of [ethanol]dialysate to [ethanol]perfusate (ethanol outflow-to-inflow ratio), an indicator that is inversely related to blood flow. The ethanol outflow-to-inflow ratios at rest were 0.614 +/- 0.032, 0.523 +/- 0.023, and 0.578 +/- 0.039 in the L-NMMA, L-arginine, and control probes, respectively. Calculated resting blood flows were therefore 8.7 +/- 4.1, 20.5 +/- 4.6, and 14.0 +/- 4.7 ml.min-1.100 g-1 around the L-NMMA, L-arginine, and control probes, respectively. The ethanol outflow-to-inflow ratios were significantly higher at all exercise intensities in the L-NMMA probe than in the control and L-arginine probes, resulting in calculated blood flows of 195 +/- 55, 407 +/- 47, and 352 +/- 60 ml.min-1.100 g-1 at 25 W and 268 +/- 65, 602 +/- 129, and 519 +/- 113 ml.min-1.100 g-1 at 100 W around the L-NMMA, L-arginine, and control probes, respectively. Skeletal muscle blood flow was therefore reduced both at rest and during continuous, dynamic exercise by the action of L-NMMA, whereas blood flow was increased only at rest by L-arginine.

scholarly journals The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle

2007 ◽  
Vol 103 (3) ◽  
pp. 1012-1020 ◽  
Author(s):  
T. Gustafsson ◽  
H. Rundqvist ◽  
J. Norrbom ◽  
E. Rullman ◽  
E. Jansson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Vastus Lateralis ◽  
Exercise Bout ◽  
Voluntary Exercise ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Ki 67

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 min with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 min after the first and last exercise bouts. Basal Ang-2 and Tie-1 mRNA levels increased in both legs with training. The Ang-2-to-Ang-1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang-1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxia/ischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle.

Skeletal muscle blood flow and flow heterogeneity during dynamic and isometric exercise in humans

2003 ◽  
Vol 284 (3) ◽  
pp. H979-H986 ◽  
Author(s):  
Marko S. Laaksonen ◽  
Kari K. Kalliokoski ◽  
Heikki Kyröläinen ◽  
Jukka Kemppainen ◽  
Mika Teräs ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Isometric Exercise ◽  
Dynamic Exercise ◽  
Emg Activity ◽  
Vastus Lateralis Muscle ◽  
Skeletal Muscle Blood Flow ◽  
Flow Heterogeneity

The effects of dynamic and intermittent isometric knee extension exercises on skeletal muscle blood flow and flow heterogeneity were studied in seven healthy endurance-trained men. Regional muscle blood flow was measured using positron emission tomography (PET) and an [15O]H2O tracer, and electromyographic (EMG) activity was recorded in the quadriceps femoris (QF) muscle during submaximal intermittent isometric and dynamic exercises. QF blood flow was 61% ( P = 0.002) higher during dynamic exercise. Interestingly, flow heterogeneity was 13% ( P = 0.024) lower during dynamic compared with intermittent isometric exercise. EMG activity was significantly higher ( P < 0.001) during dynamic exercise, and the change in EMG activity from isometric to dynamic exercise was tightly related to the change in blood flow in the vastus lateralis muscle ( r = 0.98, P < 0.001) but not in the rectus femoris muscle ( r = −0.09, P = 0.942). In conclusion, dynamic exercise causes higher and less heterogeneous blood flow than intermittent isometric exercise at the same exercise intensity. These responses are, at least partly, related to the increased EMG activity.

scholarly journals Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1

2017 ◽  
Vol 122 (1) ◽  
pp. 38-47 ◽  
Author(s):  
Leryn J. Reynolds ◽  
Daniel P. Credeur ◽  
Camila Manrique ◽  
Jaume Padilla ◽  
Paul J. Fadel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Vastus Lateralis ◽  
Glucose Disposal ◽  
Endothelin 1 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)−1·min−1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM−1·min−1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D ( P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion ( P < 0.05) but did not increase with insulin in either group ( P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 ( P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients. NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways

2004 ◽  
Vol 97 (3) ◽  
pp. 1130-1137 ◽  
Author(s):  
Csongor Csekő ◽  
Zsolt Bagi ◽  
Akos Koller
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Hydrogen Peroxide ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Muscle Blood Flow ◽  
Skeletal Muscle Blood Flow ◽  
Local Regulation ◽  
Prostaglandin H ◽  
Arteriolar Tone

We hypothesized that hydrogen peroxide (H2O2) has a role in the local regulation of skeletal muscle blood flow, thus significantly affecting the myogenic tone of arterioles. In our study, we investigated the effects of exogenous H2O2 on the diameter of isolated, pressurized (at 80 mmHg) rat gracilis skeletal muscle arterioles (diameter of ∼150 μm). Lower concentrations of H2O2 (10−6–3 × 10−5 M) elicited constrictions, whereas higher concentrations of H2O2 (6 × 10−5–3 × 10−4 M), after initial constrictions, caused dilations of arterioles (at 10−4 M H2O2, −19 ± 1% constriction and 66 ± 4% dilation). Endothelium removal reduced both constrictions (to −10 ± 1%) and dilations (to 33 ± 3%) due to H2O2. Constrictions due to H2O2 were completely abolished by indomethacin and the prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist SQ-29548. Dilations due to H2O2 were significantly reduced by inhibition of nitric oxide synthase (to 38 ± 7%) but were unaffected by clotrimazole or sulfaphenazole (inhibitors of cytochrome P-450 enzymes), indomethacin, or SQ-29548. In endothelium-denuded arterioles, clotrimazole had no effect, whereas H2O2-induced dilations were significantly reduced by charybdotoxin plus apamin, inhibitors of Ca2+-activated K+ channels (to 24 ± 3%), the selective blocker of ATP-sensitive K+ channels glybenclamide (to 14 ± 2%), and the nonselective K+-channel inhibitor tetrabutylammonium (to −1 ± 1%). Thus exogenous administration of H2O2 elicits 1) release of PGH2/TxA2 from both endothelium and smooth muscle, 2) release of nitric oxide from the endothelium, and 3) activation of K+ channels, such as Ca2+-activated and ATP-sensitive K+ channels in the smooth muscle resulting in biphasic changes of arteriolar diameter. Because H2O2 at low micromolar concentrations activates several intrinsic mechanisms, we suggest that H2O2 contributes to the local regulation of skeletal muscle blood flow in various physiological and pathophysiological conditions.

Phosphorylase a in human skeletal muscle during exercise and electrical stimulation

1978 ◽  
Vol 45 (6) ◽  
pp. 852-857 ◽  
Author(s):  
P. D. Gollnick ◽  
J. Karlsson ◽  
K. Piehl ◽  
B. Saltin
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Muscular Activity ◽  
Voluntary Exercise ◽  
Vastus Lateralis Muscle ◽  
Minor Importance ◽  
Muscle Lactate ◽  
Needle Technique

Experiments were conducted to examine the conversions of phosphorylase b to phosphorylase a in human skeletal muscle during bicycle exercise or isometric contractions. Muscle biopsies were obtained from the vastus lateralis with the needle technique at rest and either during or immediately after activity and frozen in liquid nitrogen within 2--4 s. Total phosphorylase and phosphorylase a activities were differentiated by measurement in the presence and absence of AMP, respectively. At rest 8.5% of the total phosphorylase activity existed in the a form. Little or no change in the percent of phosphorylase in the a form occurred during voluntary dynamic or static muscular activity that produced muscle lactate concentrations in excess of 18 mmol.kg-1 wet muscle. Electrical stimulation of the vastus lateralis muscle also failed to produce an increase in the percentage of phosphorylase a. These data suggest that during exercise the conversion of phosphorylase to the a form is of minor importance. An increased activity of phosphorylase b due to changes in muscle concentrations of ATP, AMP, and inorganic phosphate may regulate glycogenolysis during voluntary exercise in man.

scholarly journals Contractile activity-specific transcriptome response to acute endurance exercise and training in human skeletal muscle

2019 ◽  
Vol 316 (4) ◽  
pp. E605-E614 ◽  
Author(s):  
Daniil V. Popov ◽  
Pavel A. Makhnovskii ◽  
Elena I. Shagimardanova ◽  
Guzel R. Gazizova ◽  
Evgeny A. Lysenko ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Contractile Activity ◽  
Vastus Lateralis ◽  
Aerobic Exercise Training ◽  
Vastus Lateralis Muscle ◽  
Transcriptome Response ◽  
The One

Reduction in daily activity leads to dramatic metabolic disorders, while regular aerobic exercise training is effective for preventing this problem. The purpose of this study was to identify genes that are directly related to contractile activity in human skeletal muscle, regardless of the level of fitness. Transcriptome changes after the one-legged knee extension exercise in exercised and contralateral nonexercised vastus lateralis muscle of seven men were evaluated by RNA-seq. Transcriptome change at baseline after 2 mo of aerobic training (5/wk, 1 h/day) was evaluated as well. Postexercise changes in the transcriptome of exercised muscle were associated with different factors, including circadian oscillations. To reveal transcriptome response specific for endurance-like contractile activity, differentially expressed genes between exercised and nonexercised muscle were evaluated at 1 and 4 h after the one-legged exercise. The contractile activity-specific transcriptome responses were associated only with an increase in gene expression and were regulated mainly by CREB/ATF/AP1-, MYC/MAX-, and E2F-related transcription factors. Endurance training-induced changes (an increase or decrease) in the transcriptome at baseline were more pronounced than transcriptome responses specific for acute contractile activity. Changes after training were associated with widely different biological processes than those after acute exercise and were regulated by different transcription factors (IRF- and STAT-related factors). In conclusion, adaptation to regular exercise is associated not only with a transient (over several hours) increase in expression of many contractile activity-specific genes, but also with a pronounced change (an increase or decrease) in expression of a large number of genes under baseline conditions.

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