Skeletal muscle blood flow and vascular conductance are enhanced in humans with high‐affinity hemoglobin during handgrip exercise in severe hypoxia

We tested the hypothesis that tonic adrenergic and nonadrenergic receptor-mediated sympathetic vasoconstriction would increase at rest and during exercise with advancing age. Young ( n = 6; 22 ± 1 mo; means ± SE) and old ( n = 6; 118 ± 9 mo) beagles were studied. Selective antagonists for alpha-1, alpha-2, neuropeptide Y (NPY), and purinergic (P2x) receptors were infused at rest and during treadmill running at 2.5 mph and 4 mph with 2.5% grade. Prazosin produced similar increases in vascular conductance in young and old beagles at rest (Young: 158 ± 34%; Old: 98 ± 19%) and during exercise at 2.5 mph (Young: 80 ± 10%; Old: 58 ± 12%) and 4 mph and 2.5% grade (Young: 57 ± 5%; Old: 26 ± 4%). Rauwolscine caused similar ( P > 0.05) increases in vascular conductance in old compared with young dogs at rest (Young: 119 ± 25%; Old: 64 ± 22%) and at 2.5 mph (Young: 86 ± 13%; Old: 60 ± 7%) and 4 mph with 2.5% grade (Young: 61 ± 5%; Old: 43 ± 7%). N2-(diphenylacetyl)-N-[4-hydroxyphenyl)methyl]-d-arginine amide (BIBP) caused a smaller increase ( P < 0.05) in vascular conductance in old compared with young dogs at rest (Young: 179 ± 44%; Old: 91 ± 22%), whereas similar increases ( P > 0.05) of experimental limb vascular conductance in young and old dogs occurred following BIBP during exercise at 2.5 mph (Young: 56 ± 16%; Old: 50 ± 12%) and 4 mph and 2.5% grade (Young: 45 ± 10%; Old: 25 ± 7%). Pyridoxal-phosphate-6-azophenyl-2′-4′-disulfonic acid infusion produced a larger increase in vascular conductance in old compared with young beagles at rest (Young: 88 ± 14%; Old: 191 ± 58%), whereas similar increases were observed at 2.5 mph (Young: 47 ± 18%; Old: 31 ± 11%) and 4 mph with 2.5% grade (Young: 26 ± 13%; Old: −18 ± 8%). At rest, NPY receptor-mediated restraint of skeletal muscle blood flow was reduced with advancing age, whereas P2x receptor-mediated restraint of skeletal muscle blood flow was increased. During exercise, the magnitude of adrenergic and nonadrenergic sympathetic vasoconstriction was not different between young and old dogs. Overall, these data demonstrate that adrenergic receptor-mediated vasoconstriction was not elevated at rest, but nonadrenergic sympathetic vasoconstriction was altered under basal conditions in aged beagles.

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Folic acid ingestion improves skeletal muscle blood flow during graded handgrip and plantar flexion exercise in aged humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00234.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. H658-H666 ◽

Cited By ~ 8

Author(s):

Steven A. Romero ◽

Daniel Gagnon ◽

Amy N. Adams ◽

Gilbert Moralez ◽

Ken Kouda ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Folic Acid ◽

Muscle Blood Flow ◽

Plantar Flexion ◽

Serum Folate ◽

Whole Body ◽

Vascular Conductance ◽

Skeletal Muscle Blood Flow ◽

Plantar Flexion Exercise

Skeletal muscle blood flow is attenuated in aged humans performing dynamic exercise, which is due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole body heating through nitric oxide-dependent mechanisms. However, it is unclear whether folic acid improves vasodilation in other vascular beds during conditions of increased metabolism (i.e., exercise). The purpose of this study was to test the hypothesis that folic acid ingestion improves skeletal muscle blood flow in aged adults performing graded handgrip and plantar flexion exercise via increased vascular conductance. Nine healthy, aged adults (two men and seven women; age: 68 ± 5 yr) performed graded handgrip and plantar flexion exercise before (control), 2 h after (acute, 5 mg), and after 6 wk (chronic, 5 mg/day) folic acid ingestion. Forearm (brachial artery) and leg (superficial femoral artery) blood velocity and diameter were measured via Duplex ultrasonography and used to calculate blood flow. Acute and chronic folic acid ingestion increased serum folate (both P < 0.05 vs. control). During handgrip exercise, acute and chronic folic acid ingestion increased forearm blood flow (both conditions P < 0.05 vs. control) and vascular conductance (both P < 0.05 vs. control). During plantar flexion exercise, acute and chronic folic acid ingestion increased leg blood flow (both P < 0.05 vs. control), but only acute folic acid ingestion increased vascular conductance ( P < 0.05 vs. control). Taken together, folic acid ingestion increases blood flow to active skeletal muscle primarily via improved local vasodilation in aged adults. NEW & NOTEWORTHY Our findings demonstrate that folic acid ingestion improves blood flow via enhanced vascular conductance in the exercising skeletal muscle of aged humans. These findings provide evidence for the therapeutic use of folic acid to improve skeletal muscle blood flow, and perhaps exercise and functional capacity, in human primary aging. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/folic-acid-and-exercise-hyperemia-in-aging/ .

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00106.2004 ◽

2004 ◽

Vol 97 (3) ◽

pp. 1130-1137 ◽

Cited By ~ 49

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.

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Modeling of Oxygen Transport to Skeletal Muscle: Blood Flow Distribution, Shunt, and Diffusion

Advances in Experimental Medicine and Biology - Oxygen Transport to Tissue XIII ◽

10.1007/978-1-4615-3404-4_1 ◽

1992 ◽

pp. 3-10 ◽

Cited By ~ 5

Author(s):

Johannes Piiper

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Oxygen Transport ◽

Muscle Blood Flow ◽

Flow Distribution ◽

Blood Flow Distribution ◽

Skeletal Muscle Blood Flow ◽

And Diffusion

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Is Sympathetic Restraint of Skeletal Muscle Blood Flow Present During Exercise?

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.1136.2 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Zachary Barrett‐O'Keefe ◽

Stephen J. Ives ◽

Joel D. Trinity ◽

Melissa A.H. Witman ◽

Matthew J. Rossman ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Muscle Blood Flow ◽

Skeletal Muscle Blood Flow

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PL - 031 Skeletal muscle blood flow determination using gold standard invasive arterial input function and non-invasive image-based input function by positron emission tomography (PET)

Exercise Biochemistry Review ◽

10.14428/ebr.v1i1.8493 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Ilkka Heinonen ◽

Kari Kalliokoski ◽

Vesa Oikonen ◽

Christopher Mawhinney ◽

Warren Gregson ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Data Analysis ◽

Arterial Input Function ◽

Muscle Blood Flow ◽

Input Function ◽

Invasive Approach ◽

Skeletal Muscle Blood Flow ◽

Non Invasive ◽

Arterial Blood

Objective Skeletal muscle is unique among organs in that its blood flow, thus oxygen supply that is critical for muscular function, can change over a remarkably large range. Compared to the rest, muscle blood flow can increase over 20-fold during intense exercise. Positron emission tomography (PET) and [15O]-H2O tracer provide a unique tool for the direct measurement of muscle blood flow in specific muscle regions. Quantification of PET blood flow requires knowledge of the arterial input function, which is usually provided by arterial blood sampling. However, arterial sampling is an invasive approach requiring arterial cannulation. In the current study, we aimed to explore the analysis and error estimation based on non-invasive, PET image-based input function for skeletal muscle blood flow in PET [15O]-labeled radiowater study. Methods Thirty healthy untrained men volunteered to participate in this study. [15O]-labeled radio water PET perfusion scans were performed at rest and right after cycling exercise. GE Discovery PET-CT scanner was used for image acquisition. The 15O isotope was produced with a Cyclone 3 cyclotron (IBA Molecular, Belgium). After 455 MBq of 15O-H2O was injected intravenously and after 20 seconds, dynamic scanning images were performed in following frames: 6x5 seconds, 12x10 seconds, 7x30 seconds and 12x10 seconds. Arterial blood was sampled continuously from radial artery during imaging for radioactivity with a detector during PET scanning. All the data analysis was performed using all in-house developed programs. Arterial input function was preprocessed with delay correction. Image-based input function was defined based on sum image of dynamic images. Blood flow was calculated using the 1-tissue compartment model, k1 is considered as blood flow without any further correction. All data analysis was performed by Carimas software (http://www.turkupetcentre.fi/carimas). Data analysis was performed in five parts: 1) Modelling data using input function from artery. 2) By defining femoral artery Volume Of Interest (VOI) on PET images. 3) Modelling data using image-based input function. 4) Calculating the correlation for blood flow between artery (blood) input function and image-based input function. 5) Predicted true blood flow was calculated based on correlation based on the initial linear relationship between blood and image-based input functions. Results Skeletal muscle blood flow had a good linear relationship calculated by femoral artery VOI and by arterial (blood) input function (y = 2,9587x - 0,096, R² = 0,8852, p<0.0001). Further, by using the prediction equation obtained by the linear relationship between VOI-determined (femoral) artery blood flow and direct gold standard (radial) artery input function determined blood flow, image-based input function determined blood flow was well predicted using this non-invasive approach (y = 1,1812x + 0,1219, R² = 0,9259, p<0.0001). Conclusions It is concluded that there is a strong linear correlation between gold standard invasive approach and non-invasive image-based approach to measure skeletal muscle blood flow by PET, but if no further corrections are made, image-based approach overestimates correct blood flow. However, this can be corrected by linear prediction equation, suggesting that invasive arterial input function may not always be needed in the future when measuring skeletal muscle blood flow by PET. This will be of benefit particularly for exercise studies.

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Impact of Changes in Tissue Optical Properties on Near-Infrared Diffuse Correlation Spectroscopy Measures of Skeletal Muscle Blood Flow

Journal of Applied Physiology ◽

10.1152/japplphysiol.00857.2020 ◽

2021 ◽

Author(s):

Miles F. Bartlett ◽

Scott M. Jordan ◽

Dennis M. Hueber ◽

Michael D. Nelson

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Optical Properties ◽

Near Infrared ◽

Muscle Blood Flow ◽

Reactive Hyperemia ◽

Correlation Spectroscopy ◽

Skeletal Muscle Blood Flow ◽

Diffuse Correlation Spectroscopy ◽

Tissue Optical Properties

Near-infrared diffuse correlation spectroscopy (DCS) is increasingly utilized to study relative changes in skeletal muscle blood flow. However, most diffuse correlation spectrometers assume that tissue optical properties- such as absorption (μa) and reduced scattering (μ's) coefficients- remain constant during physiological provocations, which is untrue for skeletal muscle. Here, we interrogate how changes in tissue μa and μ's affect DCS calculations of blood flow index (BFI). We recalculated BFI using raw autocorrelation curves and μa/μ's values recorded during a reactive hyperemia protocol in 16 healthy young individuals. First, we show that incorrectly assuming baseline μa and μ's substantially affects peak BFI and BFI slope when expressed in absolute terms (cm2/s, p<0.01) but these differences are abolished when expressed in relative terms (% baseline). Next, to evaluate the impact of physiologic changes in μa and μ's, we compared peak BFI and BFI slope when μa and μ's were held constant throughout the reactive hyperemia protocol versus integrated from a 3s-rolling average. Regardless of approach, group means for peak BFI and BFI slope did not differ. Group means for peak BFI and BFI slope were also similar following ad absurdum analyses, where we simulated supraphysiologic changes in μa/μ's. In both cases, however, we identified individual cases where peak BFI and BFI slope were indeed affected, with this result being driven by relative changes in μa over μ's. Overall, these results provide support for past reports in which μa/μ's were held constant but also advocate for real-time incorporation of μa and μ's moving forward.

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