Increase In Muscle Perfusion Research Articles

The ergogenic effect of acute carnosine and anserine supplementation: dosing, timing, and underlying mechanism.

ABSTRACTBackgroundRecent studies suggest that acute-combined carnosine and anserine supplementation has the potential to improve the performance of certain cycling protocols. Yet, data on optimal dose, timing of ingestion, effective exercise range, and mode of action are lacking. Three studies were conducted to establish dosing and timing guidelines concerning carnosine and anserine intake and to unravel the mechanism underlying the ergogenic effects.MethodsFirst, a dose response study A was conducted in which 11 men randomly received placebo, 10, 20, or 30 mg.kg−1 of both carnosine and anserine. They performed 3x maximal voluntary isometric contractions (MVC), followed by a 5 x 6 s repeated cycling sprint ability test (RSA), once before the supplement and 30 and 60 minutes after. In a second study, 15 men performed 3x MVCs with femoral nerve electrical stimulation, followed by an RSA test, once before 30 mg.kg−1 carnosine and anserine and 60 minutes after. Finally, in study C, eight men performed a high intensity cycling training after randomly ingesting 30 mg.kg−1 of carnosine and anserine, a placebo or antihistamines (reduce post-exercise blood flow) to investigate effects on muscle perfusion.ResultsStudy A showed a 3% peak power (p = 0.0005; 95% CI = 0.07 to 0.27; ES = 0.91) and 4.5% peak torque (p = 0.0006; 95% CI = 0.12 to 0.50; ES = 0.87) improvement on RSA and MVC, with 30 mg.kg−1 carnosine + anserine ingestion 60 minutes before the performance yielding the best results. Study B found no performance improvement on group level; however, a negative correlation (r = −0.54; p = 0.0053; 95% CI = −0.77 to −0.19) was found between carnosinase enzyme activity (responsible for carnosine and anserine breakdown) and performance improvement. No effect of the supplement on neuromuscular function nor on muscle perfusion was found.ConclusionsThese studies reveal that acute ingestion of 30 mg.kg−1 of both carnosine and anserine, 60 minutes before a high intensity exercise, can potentially improve performance, such as short cycling sprints or maximal muscle contractions. Subjects with lower carnosinase activity, and thus a slower breakdown of circulating dipeptides, appear to benefit more from this ergogenic effect. Finally, neither the involvement of a direct effect on neuromuscular function, nor an indirect effect on recovery through increased muscle perfusion could be confirmed as potential mechanism of action. The ergogenic mechanism therefore remains elusive.

Hyperpolarized 13C MR Spectroscopy Depicts in Vivo Effect of Exercise on Pyruvate Metabolism in Human Skeletal Muscle.

Background Pyruvate dehydrogenase (PDH) and lactate dehydrogenase are essential for adenosine triphosphate production in skeletal muscle. At the onset of exercise, oxidation of glucose and glycogen is quickly enabled by dephosphorylation of PDH. However, direct measurement of PDH flux in exercising human muscle is daunting, and the net effect of covalent modification and other control mechanisms on PDH flux has not been assessed. Purpose To demonstrate the feasibility of assessing PDH activation and changes in pyruvate metabolism in human skeletal muscle after the onset of exercise using carbon 13 (13C) MRI with hyperpolarized (HP) [1-13C]-pyruvate. Materials and Methods For this prospective study, sedentary adults in good general health (mean age, 42 years ± 18 [standard deviation]; six men) were recruited from August 2019 to September 2020. Subgroups of the participants were injected with HP [1-13C]-pyruvate at resting, during plantar flexion exercise, or 5 minutes after exercise during recovery. In parallel, hydrogen 1 arterial spin labeling MRI was performed to estimate muscle tissue perfusion. An unpaired t test was used for comparing 13C data among the states. Results At rest, HP [1-13C]-lactate and [1-13C]-alanine were detected in calf muscle, but [13C]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP 13C signals (tC) increased 2.8-fold because of increased muscle perfusion (P = .005), and HP [1-13C]-lactate-to-tC ratio increased 1.7-fold (P = .04). HP [13C]-bicarbonate-to-tC ratio increased 8.4-fold (P = .002) and returned to the resting level 5 minutes after exercise, whereas the lactate-to-tC ratio continued to increase to 2.3-fold as compared with resting (P = .008). Conclusion Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 {13C}]-pyruvate in skeletal muscle rapidly reflected the onset and the termination of exercise. These results demonstrate the feasibility of imaging skeletal muscle metabolism using HP [1-13C]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. © RSNA, 2021 Online supplemental material is available for this article.

Stroke effort and relative lung volume influence heart rate in diving sea lions.

The dive response, bradycardia (decreased heart rate) and peripheral vasoconstriction, is the key mechanism allowing breath-hold divers to perform long-duration dives while actively swimming and hunting prey. This response is variable and modulated by factors such as dive duration, depth, exercise and cognitive control. This study assessed the potential role of exercise and relative lung volume in the regulation of heart rate (fH) during dives of adult female California sea lions instrumented with electrocardiogram (ECG), depth and tri-axial acceleration data loggers. A positive relationship between activity (minimum specific acceleration) and fH throughout dives suggested increased muscle perfusion associated with exercise. However, apart from late ascent, fH during dives was still less than or equal to resting fH (on land). In addition, the activity-fH relationship was weaker in long, deep dives consistent with prioritization of blood oxygen conservation over blood oxygen delivery to muscle in those dives. Pulmonary stretch receptor reflexes may also contribute to fH regulation as fH profiles generally paralleled changes in relative lung volume, especially in shallower dives and during early descent and late ascent of deeper dives. Overall, these findings support the concept that both exercise and pulmonary stretch receptor reflexes may influence the dive response in sea lions.

The Role of Muscle Perfusion in the Age-Associated Decline of Mitochondrial Function in Healthy Individuals.

Maximum oxidative capacity of skeletal muscle measured by in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) declines with age, and negatively affects whole-body aerobic capacity. However, it remains unclear whether the loss of oxidative capacity is caused by reduced volume and function of mitochondria or limited substrate availability secondary to impaired muscle perfusion. Therefore, we sought to elucidate the role of muscle perfusion on the age-related decline of muscle oxidative capacity and ultimately whole-body aerobic capacity. Muscle oxidative capacity was assessed by 31P-MRS post-exercise phosphocreatine recovery time (τPCr), with higher τPCr reflecting lower oxidative capacity, in 75 healthy participants (48 men, 22–89 years) of the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing study. Muscle perfusion was characterized as an index of blood volume at rest using a customized diffusion-weighted MRI technique and analysis method developed in our laboratory. Aerobic capacity (peak-VO2) was also measured during a graded treadmill exercise test in the same visit. Muscle oxidative capacity, peak-VO2, and resting muscle perfusion were significantly lower at older ages independent of sex, race, and body mass index (BMI). τPCr was significantly associated with resting muscle perfusion independent of age, sex, race, and BMI (p-value = 0.004, β = −0.34). τPCr was also a significant independent predictor of peak-VO2 and, in a mediation analysis, significantly attenuated the association between muscle perfusion and peak-VO2 (34% reduction for β in perfusion). These findings suggest that the age-associated decline in muscle oxidative capacity is partly due to impaired muscle perfusion and not mitochondrial dysfunction alone. Furthermore, our findings show that part of the decline in whole-body aerobic capacity observed with aging is also due to reduced microvascular blood volume at rest, representing a basal capacity of the microvascular system, which is mediated by muscle oxidative capacity. This finding suggests potential benefit of interventions that target an overall increase in muscle perfusion for the restoration of energetic capacity and mitochondrial function with aging.

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.

Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for 10 minutes after intravenous injection of 2×108 lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signaling pathways were assessed by studying interventions that (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or KATP channels; or (3) inhibited downstream signaling pathways involving endothelial nitric oxide synthase or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease. Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with sickle cell disease. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced an ≈40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of endothelial nitric oxide synthase abolished the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins. Therapeutic ultrasound using microbubble cavitation to increase muscle perfusion relies on shear-dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. These events can reverse hindlimb ischemia in mice for >24 hours and increase muscle blood flow in patients with sickle cell disease. URL: http://clinicaltrials.gov. Unique identifier: NCT01566890.

Perfusion has no effect on the in vivo CEST effect from Cr (CrCEST) in skeletal muscle.

Creatine, a key component of muscle energy metabolism, exhibits a chemical exchange saturation transfer (CEST) effect between its amine group and bulk water, which has been exploited to spatially and temporally map creatine changes in skeletal muscle before and after exercise. In addition, exercise leads to an increase in muscle perfusion. In this work, we determined the effects of perfused blood on the CEST effects from creatine in skeletal muscle. Experiments were performed on healthy human subjects (n=5) on a whole-body Siemens 7T magnetic resonance imaging (MRI) scanner with a 28-channel radiofrequency (RF) coil. Reactive hyperemia, induced by inflation and subsequent deflation of a pressure cuff secured around the thigh, was used to increase tissue perfusion whilst maintaining the levels of creatine kinase metabolites. CEST, arterial spin labeling (ASL) and 31 P MRS data were acquired at baseline and for 6min after cuff deflation. Reactive hyperemia resulted in substantial increases in perfusion in human skeletal muscle of the lower leg as measured by the ASL mean percentage difference. However, no significant changes in CrCEST asymmetry (CrCESTasym ) or 31 P MRS-derived PCr levels of skeletal muscle were observed following cuff deflation. This work demonstrates that perfusion changes do not have a major confounding effect on CrCEST measurements.

Energy production in patients with chronic obstructive pulmonary disease: Evidence of mitochondrial and not O2 supply limitation

It is well documented that chronic obstructive pulmonary disease (COPD) is associated with both muscular and vascular dysfunctions. Interestingly, although both peripheral oxygen (O2) transport and muscle O2 utilization capacity appear to be impaired in patients with COPD, it is still unclear which peripheral component of the O2 cascade actually limits overall muscle aerobic capacity. Therefore, purpose of the present study was to determine whether mitochondrial function in vivo is limited by convective O2 delivery or the intrinsic capacity of mitochondria to synthesize ATP in patients with COPD. To this aim, we combined phosphorus magnetic resonance spectroscopy (31P‐MRS), near‐infrared spectroscopy (NIRS), and Doppler ultrasound, to examine the effect of superimposing reactive hyperaemia (RH), induced by a period of brief ischemia during the last min of exercise, on O2 delivery and mitochondrial function in the calf muscle of 16 patients with moderate to severe COPD in comparison to free‐flow conditions (FF). Limb blood flow [area under the curve (AUC), FF: 2.5 ± 1.2 L; RH: 3.3 ± 1.0 L, P<0.05] and convective O2 delivery (AUC, FF: 0.46 ± 0.23 L; RH: 0.61 ± 0.21 L, P=0.08) were increased in RH in comparison to FF. RH was also associated with significantly higher capillary blood flow (AUC, FF: 26 ± 14 L; RH: 37 ± 25 L, P<0.05). However, despite an increased muscle perfusion and O2 delivery, the peak rate of mitochondrial ATP synthesis did not differ significantly between conditions (FF: 28 ± 14 mM.min−1; RH: 27 ± 9 mM.min−1, P=0.83). Taken together, these results indicate that an increase in convective O2 delivery does not improve mitochondrial function in the plantar flexor muscles of the patients with COPD, thereby revealing that the peak rate of mitochondrial ATP synthesis of these patients appears to be limited by the intrinsic mitochondrial capacity and not O2 availability.Support or Funding InformationThis work was funded in part by grants from the Flight Attendant Medical Research Institute (FAMRI), NIH National Heart, Lung, and Blood Institute (K99HL125756, PO1 HL 091830) and VA Merit grant E6910R.

A pilot study of regional perfusion and oxygenation in calf muscles of individuals with diabetes with a noninvasive measure

To assess alterations in the regional perfusion and oxygenation of the calf muscles in individuals with diabetes. Age-matched individuals with (n = 5) and without diabetes (n = 6) were investigated. Skeletal muscle perfusion, oxygen extraction fraction, and oxygen consumption rate were measured by newly developed noncontrast magnetic resonance imaging (MRI) techniques. The subjects lay supine on the MRI table with their foot firmly strapped to a custom-built isometric exercise device. The measurements were performed at rest and during an isometric plantar flexion muscle contraction. Individuals without diabetes had up to a 10-fold increase in muscle perfusion, 25% elevation in muscle oxygen extraction fraction, and a 12-fold increase in oxygen consumption rate in the calf during the plantar flexion isometric contraction. In patients with diabetes, the increases in these parameters were only up to sixfold, 2%, and sixfold, respectively. Exercise oxygen consumption rate was inversely associated with blood HbA1c levels (r(2) = .91). This is the first study to quantify regional skeletal muscle oxygenation in patients with diabetes using noncontrast MRI and warrants additional study. Attenuation of perfusion and oxygenation during exercise may have implications for understanding diabetic complications in the lower extremities.

Comparison of Muscle and Skin Perfusion Over the Ischial Tuberosities in Response to Wheelchair Tilt-in-Space and Recline Angles in People With Spinal Cord Injury

ObjectiveTo compare the efficacy of wheelchair tilt-in-space and recline on enhancing muscle and skin perfusion over the ischial tuberosities in people with spinal cord injury (SCI). DesignRepeated-measures and before-after trial design. SettingUniversity research laboratory. ParticipantsPower wheelchair users with SCI (N=20). InterventionsSix combinations of wheelchair tilt-in-space and recline angles were presented to participants in a random order. The testing protocol consisted of a baseline 5 minutes sitting with no tilt/recline and 5 minutes positioned in a tilted and reclined position at each of 6 conditions, including: (1) 15° tilt-in-space and 100° recline, (2) 25° tilt-in-space and 100° recline, (3) 35° tilt-in-space and 100° recline, (4) 15° tilt-in-space and 120° recline, (5) 25° tilt-in-space and 120° recline, and (6) 35° tilt-in-space and 120° recline. Main Outcome MeasuresMuscle and skin perfusion were assessed by near-infrared spectroscopy and laser Doppler flowmetry, respectively. ResultsMuscle perfusion was significantly increased at 25° and 35° tilt-in-space when combined with 120° recline, and skin perfusion was significantly increased at 3 tilt-in-space angles (15°, 25°, 35°) when combined with 120° recline and at 35° tilt-in-space when combined with 100° recline (P<.05). Even in the positions of increased muscle perfusion and skin perfusion (25° and 35° of tilt-in-space combined with 120° of recline), the amount of muscle perfusion change was significantly lower than the amount of skin perfusion change (P<.05). ConclusionsOur results indicate that a larger angle of tilt-in-space and recline is needed to improve muscle perfusion compared with skin perfusion. A position of 25° tilt-in-space combined with 120° recline is effective in enhancing muscle and skin perfusion of weight-bearing soft tissues at the ischial tuberosities.

Effect of vibration on muscle perfusion: a systematic review

Vibration has become of increasing interest to health professionals, primarily owing to reports that vibration can increase tissue blood flow. The aim of this review was to investigate the available scientific evidence on the effects of exogenous vibration on skeletal muscle perfusion. The databases searched from inception to December 2010 included Ovid MEDLINE, EMBASE, CINAHL via EbscoHost and CENTRAL. Experimental and observational studies, where exogenous vibration was an intervention, were included in this review. The main outcomes of interest were muscle blood volume, blood flow, blood flow velocity, arterial diameter and muscle temperature. One reviewer selected studies for inclusion, extracted data and assessed the quality of the eligible studies. Percentage change in muscle perfusion outcome was the measure of treatment effect, and regression analysis was used to investigate associations between vibratory load and muscle perfusion. Twenty-two studies with a total of 302 participants were included in this review. Muscle blood volume increased with vibration in five of nine studies and decreased in two studies; muscle blood flow velocity increased with vibration in five of six studies; muscle blood flow increased with vibration in two of three studies; vibration had a positive effect on arterial diameter in three of three studies; vibration had no effect on muscle temperature in two of two studies. The magnitude of increase in muscle perfusion was positively associated with vibratory load (P<0·001). We conclude that vibration increases muscle perfusion with the magnitude of increase positively related to the vibratory load applied.

The need for speed: Central command commanding vasodilation in human skeletal muscle?

muscular contractions lead to a large ([2][1]) and rapid ([14][2]) increase in muscle perfusion, providing a challenging field of research for over a century. A particular challenge has been deciphering the mechanism(s) that regulate the increase in vascular conductance that, in turn, enables the

Time kinetics of acute changes in muscle architecture in response to resistance exercise

Objectives: The study aimed to assess acute changes in muscle architecture and its recovery after exhaustive exercise. We hypothesised that repetitive leg press exercise would decrease vastus lateralis fascicle length, while increasing both muscle thickness and pennation angles. By investigating the time kinetics of recovery of these parameters, we wished to gain insight into the mechanisms responsible for muscle architectural changes during exercise. Design: Muscle architecture was assessed in 41 male volunteers (25.2 ± 3.7 yrs; 1.78 ± 0.06 m; 76.4 ± 11.7 kg) before and directly after, as well as 5, 10, 15, and 30 min after induction of fatigue by leg press exercise. Method: Vastus lateralis muscle thickness, pennation angles and fascicle lengths were measured at rest by ultrasonography. Muscular fatigue was induced by an exhaustive series of maximum power, single leg press repetitions. Results: Following leg press exercise vastus lateralis muscle thickness and pennation angles were increased by approximately 7 and 10%, whereas fascicle lengths decreased by 2%. Different recovery times (muscle thickness: 30 min; pennation angles: 15 min; fascicle lengths: 5 min) were observed. Conclusions: The differential time courses of recovery suggest that changes in muscle thickness, pennation angles, and fascicle lengths are driven by different exercise-related stimuli. Increased muscle perfusion and tendon creep are likely candidates accounting for short-term changes in muscle architecture.

Mononuclear inflammatory cells and angiogenesis

Wragg et al., in this issue, report on a novel model of angiogenesis [1]. The authors sampled rat bone marrow and cultured bone marrow-derived cells under conditions designed to produce so-called multipotent adult progenitor cells (MAPC). They termed their cells, MAPC-derived progenitor cells (MDPC). MDPC expressed appropriate surface markers, such as MHC class I, CD44, CD90, but not MHC class II, CD45 or CD73. The cells expressed vascular endothelial growth factor receptor (VEGFR) 1 and the chemokine receptor CXCR4. The authors measured in vitro cytokine levels produced in culture over 24 h and found MDCP produced monocyte chemoattractant protein (MCP)-1, growth-related oncogene (Gro/KC), stromalderived factor (SDF)-1, and macrophage inflammatory protein (MIP)-2 in relative abundance. Wragg et al. then transplanted MDPC into the neurovascular bundle of ischemic rat hindlimbs. In this model, a segment of femoral artery is removed and substantial distal ischemia develops. MDPC were labeled with a β-Galexpressing retrovirus. Four weeks later, the cells were readily identified as LacZ positive. Significant engraftment of MDPC was detected around the neurovascular bundles. The cells seemed to be concentrated around arterioles. In contrast, sham-operated rats did not accumulate MDCP. Interestingly, the authors did not find that MDCP had assumed a vascular cell phenotype. MDCP did not stain positively for von Willebrand’s factor and did not resemble vascular smooth muscle cells. Nor did they express CD34. Nonetheless, MDCP resided in close proximity to CD34 positive cells. The authors were successful in measuring cytokine levels in vivo. MCP-1, SDF-1, MIP-2, and Gro/ KC again were present in increased amounts compared to animals that received vehicle. The capillary to muscle fiber ratio was increased in rats receiving MDCP into their ischemic hindlimbs; however, the effect was not dramatic. MDCP also increased muscle perfusion, as measured with microspheres. Since MDCP did not themselves differentiate into vascular structures, the question of how they may work remained. The authors were aware that SDF-1 facilitates the retention of CD11b-positive myelo-monocytic cells at the site of wound repair. This state of affairs caused the authors to focus on the spatial relationship between MDPC, infiltrating CD11bpositive cells, and proliferating endothelial cells. Indeed, about a three-fold increase in CD11b-positive cells were found in preparations that had received MDPC, compared to vehicle. Blocking the receptor for SDF-1, namely CXCR4, virtually eliminated arrival of CD11b-positive cells. The authors next performed monocyte-depletion experiments with clodronate-laden liposomes. This maneuver lowered local MIP-2 levels in tissue, but had no effect on SDF-1 or MCP-1 expression that presumably predominantly came from MDCD. Wragg et al. end their story at this point [1]. However, the questions have just started. What is the connection between monocyte-macrophage cells and angiogenesis? The authors point out that several studies have focused on monocyte recruitment to ischemic tissues and subsequent angiogenesis. For instance, Van Weel et al. studied amputated ischemic human extremities and presented evidence that bone marrow-derived cells expressing CXCR4 are retained in close proximity to angiogenic vessels by SDF-1 [2]. Arras et al. [3] investigated the association of monocyte accumulation along with cytokine production and vessel proliferJ Mol Med (2008) 86:1193–1195 DOI 10.1007/s00109-008-0401-8

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. Local infusion of low-dose MC (0.3 micromol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N-nitro-L-arginine methyl ester (L-NAME), but not by infusion of N-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 micromol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 micromol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 micromol/l MC (p<0.05), but was unaffected by 3 micromol/l MC. All increases in 2-deoxyglucose uptake by 30 micromol/l MC were blocked by 10 micromol/l L-NAME. MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 micromol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (> or =30 micromol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The low-dose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.

Blood Flow Remodels Growing Vasculature During Vascular Endothelial Growth Factor Gene Therapy and Determines Between Capillary Arterialization and Sprouting Angiogenesis

For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels. Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment. This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.

Non‐invasive monitoring of muscle blood perfusion by photoplethysmography: evaluation of a new application

To evaluate a specially developed photoplethysmographic (PPG) technique, using green and near-infrared light sources, for simultaneous non-invasive monitoring of skin and muscle perfusion. Evaluation was based on assessments of changes in blood perfusion to various provocations, such as post-exercise hyperaemia and hyperaemia following the application of liniment. The deep penetrating feature of PPG was investigated by measurement of optical radiation inside the muscle. Simultaneous measurements using ultrasound Doppler and the new PPG application were performed to elucidate differences between the two methods. Specific problems related to the influence of skin temperature on blood flow were highlightened, as well. Following static and dynamic contractions an immediate increase in muscle perfusion was shown, without increase in skin perfusion. Liniment application to the skin induced a rapid increase in skin perfusion, but not in muscle. Both similarities and differences in blood flow measured by Ultrasound Doppler and PPG were demonstrated. The radiant power measured inside the muscle, by use of an optical fibre, showed that the near-infrared light penetrates down to the vascular depth inside the muscle. The results of this study indicate the potentiality of the method for non-invasive measurement of local muscle perfusion, although some considerations still have to be accounted for, such as influence of temperature on blood perfusion.

Beneficial haemodynamic effects of insulin in chronic heart failure

OBJECTIVETo characterise the central and regional haemodynamic effects of insulin in patients with chronic heart failure.DESIGNSingle blind, placebo controlled study.SETTINGUniversity teaching hospital.PATIENTSTen patients with stable chronic heart failure.INTERVENTIONSHyperinsulinaemic euglycaemic clamp and non-invasive haemodynamic measurements.MAIN OUTCOME MEASURESChange in resting heart rate, blood pressure, cardiac output, and regional splanchnic and skeletal muscle blood flow.RESULTSInsulin infusion led to a dose dependent increase in skeletal muscle blood flow of 0.36 (0.13) and 0.73 (0.14) ml/dl/min during low and high dose insulin infusions (p &lt; 0.05 and p &lt; 0.005 v placebo, respectively). Low and high dose insulin infusions led to a fall in heart rate of 4.6 (1.4) and 5.1 (1.3) beats/min (p &lt; 0.05 and p &lt; 0.005 v placebo, respectively) and a modest increase in cardiac output. There was no significant change in superior mesenteric artery blood flow.CONCLUSIONIn patients with chronic heart failure insulin is a selective skeletal muscle vasodilator that leads to increased muscle perfusion primarily through redistribution of regional blood flow rather than by increased cardiac output. These results provide a rational haemodynamic explanation for the apparent beneficial effects of insulin infusion in the setting of heart failure.

Adenosine and nitric oxide in exercise-induced human skeletal muscle vasodilatation.

The vasoactive substances adenosine and nitric oxide (NO) are credible candidates in the local regulation of skeletal muscle blood flow. Adenosine and NO have both been shown to increase in skeletal muscle cells and interstitial fluid during exercise and the enzymes responsible for their formation, AMP 5'-nucleotidase and NO synthase (NOS), have been shown to be activated upon muscle contraction. In vitro as well as in vivo evidence suggest that the contraction-induced increase in interstitial adenosine concentration largely stems from extracellular formation via the membrane-bound ecto-form of AMP 5'-nucleotidase. It remains unclear whether the exercise-induced NO formation in muscle originates from endothelial NOS in the microvascular endothelium, or from neuronal NOS (nNOS) in nerve cells and muscle fibres. Functional evidence for the role of adenosine in muscle blood flow control stems from studies using adenosine receptor agonists and antagonists, adenosine deaminase or adenosine uptake inhibitors. The majority of these studies have been performed on laboratory animals and, although the results show some discrepancy, the majority of studies indicate that adenosine does participate in the regulation of muscle blood flow. In humans, evidence is lacking. The role of NO in the regulation of skeletal muscle blood flow has mainly been studied using NOS inhibitors. Despite a large number of studies in this area, the role of NO for the contraction-induced increase in skeletal muscle blood flow is uncertain. The majority, but not all, human and animal studies show that, whereas blockade of NOS reduces muscle blood flow at rest and in recovery from exercise, there is no effect on the exercise-induced increase in muscle perfusion. Conclusive evidence for the mechanisms underlying the precise regulation of the multiphased increase in skeletal muscle blood flow during exercise and the role and potency of various vasoactive substances, remain missing.

Vascular delay and administration of basic fibroblast growth factor augment latissimus dorsi muscle flap perfusion and function.

Ischemia of the distal latissimus dorsi muscle flap occurs when the entire muscle is acutely elevated. Although this level of ischemia may not be critical if the muscle is to be used as a conventional muscle flap, the ischemia causes decreased distal muscle function if it is used for dynamic muscle flap transfer. This experiment was designed to determine whether or not the administration of exogenous basic fibroblast growth factor (bFGF), combined with a sublethal ischemic insult (i.e., vascular delay), would further augment muscle perfusion and function. Both latissimus dorsi muscles of nine canines were subjected to a bipedicle vascular delay procedure immediately followed by thoracodorsal intraarterial injection of 100 microg of bFGF on one side and by intraarterial injection of vehicle on the other. Ten days later, both latissimus dorsi muscles were raised as thoracodorsally based island flaps, with perfusion determined by laser-Doppler fluximetry. The muscles were wrapped around silicone chambers, simulating cardiomyoplasty, and stimulating electrodes were placed around each thoracodorsal nerve. The muscles were then subjected to an experimental protocol to determine muscle contractile function. At the end of the experiment, latissimus dorsi muscle biopsies were obtained for measurement of bFGF expression. The results demonstrated that the administration of 100 microg of bFGF immediately after the vascular delay procedure increases expression of native bFGF. In the distal and middle muscle segments, it also significantly increased muscle perfusion by approximately 20 percent and fatigue resistance by approximately 300 percent. The administration of growth factors may serve as an important adjuvant to surgical procedures using dynamic muscle flap transfers.

Cardiovascular dynamics at the onset of exercise.

At the onset of exercise, the cardiovascular system adapts with a series of integrated responses to meet the metabolic demands of the exercising muscles. The importance of rapid increases in cardiac output and local muscle blood flow has been established by showing that small decreases in O2 supply at the onset of exercise cause delays in the increase in O2 utilization. With the development of techniques that can be applied to instantaneous measurement of the cardiovascular response, the mechanisms that regulate increased muscle perfusion have recently been investigated. In this introduction to the symposium, a model of the within muscle distribution of blood flow is considered as a function of the measured responses across an exercising skeletal muscle. This model demonstrates the necessity of considering the distribution of blood flow to the working fibers very early in exercise. The symposium provides insight into our current understanding of the factors involved in the regulation of skeletal muscle blood flow at the onset of exercise. Our ability to study the impact of cardiovascular disease on exercise performance has improved with the development of selective pharmacological agents to block or stimulate specific components of the cardiovascular response. These advances should provide the basis for future research.