Cytochrome P450 2C9 plays an important role in the regulation of exercise‐induced skeletal muscle blood flow and oxygen uptake in humans

Hyperaemia occurs early in the renal and retinal microcirculation of patients with type I (insulin-dependent) diabetes mellitus, and may be critical in the development of nephropathy and retinopathy. We therefore sought to determine whether resting and exercise-induced hyperaemia was also apparent in the skeletal muscle circulation of young subjects with type I diabetes. Blood flow was assessed by venous occlusion plethysmography in 18 diabetic (DM) subjects and 20 matched controls. Exercise entailed 2 min of isotonic exercise against no load. Endothelium-dependent and -independent vasodilator function was assessed following intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. Forearm blood flow (FBF) was higher in DM subjects than in controls (3.3±0.3 and 2.2±0.2 ml·min-1·100 ml-1 forearm respectively; P < 0.005). This was not due to differences in forearm or body size, blood pressure, heart rate, lipid status or glycaemic control. Peripheral insulin levels were higher in DM subjects than in controls (48.5±8 and 15.5±1.5 μ-units/ml respectively; P < 0.005). Resting FBF was closely correlated with insulin levels (r2 = 0.4; P < 0.005). Parameters of exercise-induced hyperaemia [including peak flow (16.4±1.4 and 12.0±0.7 ml·min-1·100 ml-1 forearm in DM and control subjects respectively; P < 0.01) and the volume repaid to the forearm at 5 min post-exercise (32.1±3.1 and 23.1±1.4 ml·100 ml-1 forearm respectively; P < 0.05)] were also significantly greater in DM subjects, even when differences in resting FBF were taken into account. Peak hyperaemic blood flow and the volume repaid at 5 min were also related to insulin levels (r2 = 0.16; P < 0.05 and r2 = 0.27; P < 0.005 respectively). The vasodilator response to acetylcholine was reduced in DM subjects (P < 0.05; analysis of variance), and the slope of this dose–flow relationship was inversely related to insulin levels (r2 = 0.2; P < 0.05). These data show that both resting and exercise-induced skeletal muscle blood flow are augmented in young patients with type I diabetes, possibly due to the vasodilatory effect of increased insulin levels. Diminished vasodilator responses to acetylcholine may also, in part, be a consequence of insulin-augmented resting muscle blood flow.

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Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00996.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. H1510-H1517 ◽

Cited By ~ 69

Author(s):

Heinonen Ilkka ◽

Saltin Bengt ◽

Kemppainen Jukka ◽

Hannu T. Sipilä ◽

Oikonen Vesa ◽

...

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Blood Flow ◽

Oxygen Uptake ◽

Muscle Blood Flow ◽

Arterial Infusion ◽

Skeletal Muscle Blood Flow ◽

Muscle Oxygen ◽

Resting Muscle ◽

Muscle Oxygen Uptake

The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H2O15 and 15O2 during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of NG-monomethyl-l-arginine (l-NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of l-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced ( P < 0.05) muscle blood flow. NOS inhibition increased ( P < 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ∼20% increase ( P < 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased ( P < 0.05). NOS and COX inhibition reduced ( P < 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake.

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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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