Human femoral artery and estimated muscle capillary blood flow kinetics following the onset of exercise

The purpose of this study was to compare the kinetics of estimated capillary blood flow (Qcap) to those of femoral artery blood flow (QFA) and estimated muscle oxygen uptake (VO2m). Nine healthy subjects performed a series of transitions from rest to moderate (below estimated lactate threshold, 6 min bouts) knee extension exercise. Pulmonary oxygen uptake (VO2) was measured breath by breath, (QFA) was measured continuously using Doppler ultrasound, and deoxyhaemoglobin ([HHb]) was estimated by near-infrared spectroscopy over the rectus femoris throughout the tests. The time course of (Qcap) was estimated by rearranging the Fick equation (i.e. Qcap = VO2m/(a-v)O2), (arterio - venous O2 difference) using the primary component of VO2 to represent VO2m and [HHb] as a surrogate for (a - v)O2. The overall kinetics of QFA (mean response time, MRT, 13.7 +/- 7.0 s), VO2m (tau, 27.8 +/- 9.0 s) and Qcap (MRT, 41.4 +/- 19.0 s) were significantly (P < 0.05) different from each other. We conclude that for moderate intensity knee extension exercise, conduit artery blood flow (QFA) kinetics may not be a reasonable approximation of blood flow kinetics in the microcirculation (Qcap), the site of gas exchange. This temporal dissociation suggests that blood flow may be controlled differently at the conduit artery level than in the microcirculation.     

Proton efflux in human skeletal muscle during recovery from exercise

In recovery from exercise, phosphocreatine resynthesis results in the net generation of protons, while the net efflux of protons restores pH?to resting values. Because proton efflux rate declines as pH?increases, it appears to have an approximately linear pH-dependence. We set out to examine this in detail using recovery data from human calf muscle. Proton efflux rates were calculated from changes in pH?and phosphocreatine concentration, measured by ³¹P magnetic resonance spectroscopy, after incremental dynamic exercise to exhaustion. Results were collected post hoc into five groups on the basis of end-exercise pH. Proton efflux rates declined approximately exponentially with time. These were rather similar in all groups, even when pH?changes were small, so that the apparent rate constant (the ratio of efflux rate to pH?change) varied widely. However, all groups showed a consistent pattern of decrease with time; the halftimes of both proton efflux rate and the apparent rate constant were longer at lower pH. At each time-point, proton efflux rates showed a?significant pH-dependence [slope 17 (3)?mmol?·?l^?1?· min^?1?·?pH?unit^?1 at the start of recovery, mean (SEM)], but also a significant intercept at resting pH?[16?(3)?mmol?·?l^?1?·?min^?1 at the start of recovery]. The intercept and the slope both decreased with time, with halftimes of 0.37?(0.06) and 1.4 (0.4)?min, respectively. We conclude that over a wide range of end-exercise pH, net proton efflux during recovery comprises pH-dependent and pH-independent components, both of which decline with time. Comparison with other data in the literature suggests that lactate/proton cotransport can be only a small component of this initial recovery proton efflux.     

Effects of exhaustive stretch-shortening cycle exercise on muscle blood flow during exercise

Aim: The influence of exhaustive stretch‐shortening cycle exercise (SSC) on skeletal muscle blood flow (BF) during exercise is currently unknown. Methods: Quadriceps femoris (QF) BF was measured in eight healthy men using positron emission tomography before and 3 days after exhaustive SSC exercise. The SSC protocol consisted of maximal and submaximal drop jumps with one leg. Needle biopsies of the vastus lateralis muscles were taken immediately and 2 days after SSC for muscle endothelial nitric oxide synthase (eNOS) and interleukin‐1‐beta (IL‐1β) mRNA level determinations. Results: All subjects reported subjective muscle soreness after SSC (P < 0.001), which was well in line with a decrease in maximal isometric contraction force (MVC) and increase in serum creatine kinase activity (CK) (P = 0.018). After SSC muscle BF was 25% higher in entire QF (P = 0.043) and in its deep and superficial muscle regions, whereas oxygen uptake remained unchanged (P = 0.893). Muscle biopsies revealed increased IL‐1β (30 min: 152 ± 75%, P = 0.012 and 2 days: 108 ± 203%, P = 0.036) but decreased or unchanged eNOS (30 min; ?21 ± 57%, P = 0.050 and 2 days: +101 ± 204%, P = 0.779) mRNA levels after SSC. Conclusion: It was concluded that fatiguing SSC exercise induces increased muscle BF during exercise, which is likely to be associated with pro‐inflammatory processes in the exercised muscle.     

Matching of blood flow to metabolic rate during recovery from moderate exercise in humans

It is unclear whether measurement of limb or conduit artery blood flow during recovery from exercise provides an accurate representation of flow to the muscle capillaries where gas exchange occurs. To investigate this, we: (a) examined the kinetic responses of femoral artery blood flow (QFA), estimated muscle capillary blood flow (Qcap) and estimated muscle oxygen uptake (VO2m) following cessation of exercise; and (b) compared these responses to verify the adequacy of O2 delivery during recovery. Pulmonary VO2 (VO2p) was measured breath by breath, QFA was measured using Doppler ultrasonography, and deoxy-haemoglobin/myoglobin (deoxy-[Hb/Mb]) was estimated by near-infrared spectroscopy over the rectus femoris in nine healthy subjects during a series of transitions from moderate knee-extension exercise to rest. The time course of Qcap was estimated by rearranging the Fick equation [i.e. Qcap(t) alpha VO2m(t)/deoxy-[Hb/Mb](t)], using the primary component of Vo2p to represent VO2m and deoxy-[Hb/Mb] as a surrogate for arteriovenous O2 difference. There were no significant differences among the overall kinetics of VO2m (tau, 31.4+/-8.2 s), QFA [mean response time (MRT), 34.5+/-20.4 s] and Qcap (MRT, 31.7+/-14.7 s). The VO2m kinetics were also significantly correlated (P<0.05) with those of both QFA and Qcap. Both QFA and Qcap appear to be coupled with VO2m during recovery from moderate knee-extension exercise, such that extraction falls (thus cellular energetic state is not further compromised) throughout recovery.     

Coupling of muscle metabolism and muscle blood flow in capillary units during contraction

Muscle blood flow is tightly coupled to the level of skeletal muscle activity: Indices of skeletal muscle metabolic rate, for example oxygen consumption or muscle work, are directly related to the magnitude of the change in muscle blood flow. Despite the large amount that is known about individual aspects of local metabolic vasodilation, the mechanisms underlying integrated aspects of the response remain largely unknown. Arteriolar dilation serves both to increase blood flow through the muscle and also to recruit capillaries and control capillary blood flow distribution. Conceptually, these two apparently separate functions of larger vs. more terminal arterioles (where larger vessels subserve conductance changes while the smaller more distal vessels have a primary role in capillary blood flow control) can be met, at least in part, by differential sensitivity of large vs. small arterioles to metabolites and agonists relevant to the metabolic response. However, longitudinal differences in sensitivity through the arteriolar network will not by themselves account for observed heterogeneities in capillary perfusion or for the close matching between blood flow and metabolism that occurs even in mixed muscles. In mixed skeletal muscles, fibres of widely different metabolic profile are dispersed throughout the muscle and even fibres of a single motor unit are not perfused by common arterioles but are matched with arterioles arising from widely disparate regions within the microvascular network. In this review we present findings that support the notion that capillaries are an integral part of the mechanism underlying this close matching between blood flow and metabolism. We review studies that indicate that capillaries are capable of responding to stimuli in their immediate environment and, importantly, are able to communicate with arterioles located remotely upstream in the arteriolar tree. Not only can skeletal muscle capillary endothelial cells induce remote arteriolar vasodilatory and vasoconstrictor responses to pharmacological stimuli such as acetylcholine or noradrenaline, but they can also initiate these remote arteriolar responses in response to skeletal muscle contraction. Capillary endothelial cells respond to skeletal muscle contraction by transmitting a dilatory signal to at least three branch orders of arterioles proximal to the capillary; these upstream dilations present a mechanism whereby capillaries can initiate their own recruitment, and whereby increased blood flow can be directed only to those exchange vessels associated with the contracting muscle fibres and where, presumably, the initiating signal is sensed. This signal involves KATP channels, although their location (on endothelial, vascular smooth muscle or skeletal muscle cells) is not yet known and has a nitric oxide-dependent component. The studies reviewed here thus indicate that capillaries have the capacity to play an active role in co-ordination of muscle blood flow responses to changed muscle metabolism. Much more remains to be learned, however, about the mechanisms underlying the signals generated by the contracting muscle and the mechanisms of transmission of the signals upstream.     

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

The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l -NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5- to 10-fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)⁻¹ min⁻¹ at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)⁻¹ min⁻¹ at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively ( P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction.     

Metabolic control of muscle blood flow during exercise in humans.

During muscle contraction, several mechanisms regulate blood flow to ensure a close coupling between muscle oxygen delivery and metabolic demand. No single factor has been identified to constitute the primary metabolic regulator, yet there are signal transduction pathways between skeletal muscle and the vasculature that induce vasodilation. A link between muscle metabolic events and microvascular control of blood flow is illustrated by local dilation of terminal arterioles during contraction of muscle fibers and conduction of vasodilation upstream. Endothelial-derived vasodilator mechanisms are known to exert control of muscle vasodilation. Adenosine, nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarization factor (EDHF) are possible mediators of muscle vasodilation during exercise. In humans, adenosine has been shown to contribute to functional hyperemia as blood flow is reduced under nonselective adenosine-receptor blockade. No clear role has been demonstrated for either NO or PGI2(2), based on studies employing selective inhibition of these substances individually, suggesting a redundancy of vasodilator mechanisms. This is supported by recent work demonstrating that combined blockade of NOS and PGI2, and NOS and cytochrome P450, both attenuate exercise-induced hyperemia in humans. Combined vasodilator blockade studies offer the potential to uncover important interactions and compensatory vasodilator responses. The signaling pathways that link metabolic events evoked by muscle contraction to vasodilatory signals in the local vascular bed remains an important area of study.     

Skeletal muscle blood flow in humans and its regulation during exercise

Regional limb blood flow has been measured with dilution techniques (cardio-green or thermodilution) and ultrasound Doppler. When applied to the femoral artery and vein at rest and during dynamical exercise these methods give similar reproducible results. The blood flow in the femoral artery is ～0.3 L min^?1 at rest and increases linearly with dynamical knee-extensor exercise as a function of the power output to 6–10 L min^?1 (Q = 1.94 + 0.07 load). Considering the size of the knee-extensor muscles, perfusion during peak effort may amount to 2–3 L kg^?1 min^?1, i.e. ～100-fold elevation from rest. The onset of hyperaemia is very fast at the start of exercise with T_½ of 2–10 s related to the power output with the muscle pump bringing about the very first increase in blood flow. A steady level is reached within ～10–150 s of exercise. At all exercise intensities the blood flow fluctuates primarily due to the variation in intramuscular pressure, resulting in a phase shift with the pulse pressure as a superimposed minor influence. Among the many vasoactive compounds likely to contribute to the vasodilation after the first contraction adenosine is a primary candidate as it can be demonstrated to (1) cause a change in limb blood flow when infused i.a., that is similar in time and magnitude as observed in exercise, and (2) become elevated in the interstitial space (microdialysis technique) during exercise to levels inducing vasodilation. NO appears less likely since NOS blockade with L -NMMA causing a reduced blood flow at rest and during recovery, it has no effect during exercise. Muscle contraction causes with some delay (60 s) an elevation in muscle sympathetic nerve activity (MSNA), related to the exercise intensity. The compounds produced in the contracting muscle activating the group III–IV sensory nerves (the muscle reflex) are unknown. In small muscle group exercise an elevation in MSNA may not cause vasoconstriction (functional sympatholysis). The mechanism for functional sympatholysis is still unknown. However, when engaging a large fraction of the muscle mass more intensely during exercise, the MSNA has an important functional role in maintaining blood pressure by limiting blood flow also to exercising muscles.     

Effect of circulatory occlusion on human muscle metabolism during exercise and recovery

To assess muscle metabolism and inorganic phosphate (P_i) peak splitting during exercise, 31-phosphorus nuclear magnetic resonance spectroscopy was performed during ramp incremental and submaximal step exercise with and without circulatory occlusion. Seven healthy men performed calf flexion in a superconducting magnet. There was no P_i splitting during ramp incremental exercise with the circulation present and phosphocreatine (PCr) decreased linearly by 0.07 (SEM 0.01) mmol?·?l^?1?·?s^?1, while exercise with the circulation occluded caused the P_i peak to split into a high and a low pH peak. The rate of PCr decrease during exercise with the circulation occluded was 0.15 (SEM 0.03) mmol?·?l^?1?·?s^?1 which with the efficiency of the adenosine 5′-triphosphate (ATP) hydrolysis reaction corresponded well to the mechanical energy. Both with and without occlusion of the circulation PCr decreased with some time lag which may reflect the consumption of residual oxygen. In submaximal step exercise PCr decreased exponentially at the onset of exercise with the circulation open whereas it decreased linearly by 0.15?mmol?·?l^?1?·?s^?1 when the circulation was occluded. After exercise, occlusion of the circulation was maintained for 1 min more and there was no PCr resynthesis. It is suggested that ATP synthesis was limited by the availability of oxygen.     

Subepithelial capillary blood flow estimated from blood-to-lumen flux of barbital in ileum of rats.

The outflux of barbital from the blood into the small intestine perfused with an isosmotic buffer of pH 9.5 in anesthetized rats was measured to determine the subepithelial capillary blood flow in the gut. It was shown that barbital clearance is blood flow limited when total blood flow to the small intestine varied between 0.3 and 1.3 ml/min per g wet gut. The barbital clearance amounted to an average of 50.3% of the total blood flow. The total mucosal blood flow determined by the use of the distribution of microspheres in the layers of gut wall was 62.76% of the total blood flow. It is concluded that, because of anatomical reasons, a subepithelial blood flow available for the transport process is somewhat less than the measured total mucosal blood flow.     

Effect of heat stress on muscle blood flow during dynamic handgrip exercise

Summary During exercise in a hot environment, blood flow in the exercising muscles may be reduced in favour of the cutaneous circulation. The aim of our study was to examine whether an acute heat exposure (65–70°C) in sauna conditions reduces the blood flow in forearm muscles during handgrip exercise in comparison to tests at thermoneutrality (25° C). Nine healthy men performed dynamic handgrip exercise of the right hand by rhythmically squeezing a water-filled rubber tube at 13% (light), and at 34% (moderate) of maximal voluntary contraction. The left arm served as a control. The muscle blood flow was estimated as the difference in plethysmographic blood flow between the exercising and the control forearm. Skin blood flow was estimated by laser Doppler flowmetry in both forearms. Oesophageal temperature averaged 36.92 (SEM 0.08) ° C at thermo-neutrality, and 37.74 (SEM 0.07) ° C (P<0.01) at the end of the heat stress. The corresponding values for heart rate were 58 (SEM 2) and 99 (SEM 5) beats -min^–1 (P<0.01), respectively. At 25° C, handgrip exercise increased blood flow in the exercising forearm above the control forarm by 6.0 (SEM 0.8) ml · 100 ml^–1 · min^–1 during light exercise, and by 17.9 (SEM 2.5) ml · 100 ml^–1 · min^–1 during moderate exercise. In the heat, the increases were significantly higher: 12.5 (SEM 2:2) ml · 100 ml^–1 · min^–1 at the light exercise level (P<0.01), and 32.2 (SEM 5.9) ml · 100 ml^–1·min^–1 (P<0.05) at the moderate exercise level. Skin blood flow was not significantly different in any of the test conditions between the two forearms. These results suggested that hyperthermia of the observed magnitude did not reduce blood flow in active muscles during light or moderate levels of dynamic handgrip exercise.     

Limitations of respiratory muscle and vastus lateralis blood flow during continuous exercise

Measurement of regional blood flow to the respiratory muscles has traditionally been invasive. The blood flow index (BFI), a minimally invasive method using indocyanine green dye (ICG) and near infrared spectroscopy, allows assessment of within subject changes in regional blood flow. This study assessed regional BFI to the vastus lateralis muscle (QBFI) and the superficial respiratory muscles in the seventh intercostal space (RMBFI). Eight healthy subjects cycled continuously at incrementally more difficulty stages to exhaustion. In our subjects, QBFI declined between 83% and 100% of maximal exertion (p=0.002) and no statistically significant changes in RMBFI were seen despite steadily increasing ventilatory workloads. Post hoc pairwise comparisons demonstrated that QBFI at 83% work (0.015μmoless(-1)±0.005) was significantly higher than at maximum work output (0.011μmoless(-1)±0.004, p=0.007). There were no other significant differences of QBFI between maximum work output and different levels of work. The current study suggests that respiratory and locomotor muscle blood flow during sub-maximal and maximal exertion is unable to match increasing workloads.     

Kinetics of VO2 limb blood flow and regional muscle deoxygenation in young adults during moderate intensity, knee-extension exercise

The kinetics of pulmonary O₂ uptake ( [(V)\dot]\textO _2 \textp ), \left( {\dot{V}{{{\text{O}}_{{ 2\,{\text{p}}}} }} } \right), limb blood flow (LBF) and deoxygenation (ΔHHb) of the vastus lateralis (VL) and vastus medialis (VM) muscles during the transition to moderate-intensity knee-extension exercise (MOD) was examined. Seven males (27 ± 5 years; mean ± SD) performed repeated step transitions (n = 4) from passive exercise to MOD. Breath by breath [(V)\dot]\textO _2 \textp , \dot{V}{{{\text{O}}_{{ 2\,{\text{p}}}} }} , femoral artery LBF, and VL and VM muscle ∆HHb were measured, respectively, by mass spectrometer and volume turbine, Doppler ultrasound and near-infrared spectroscopy. Phase 2 [(V)\dot]\textO _2 \textp , \dot{V}{{{\text{O}}_{{ 2\,{\text{p}}}} }} , LBF, and ∆HHb data were fit with a mono-exponential model. The time constant (τ) of the [(V)\dot]\textO _2 \textp \dot{V}{{{\text{O}}_{{ 2\,{\text{p}}}} }} and LBF response were not different ( t[(V)\dot]\textO _2 \textp , \tau \dot{V}{{{\text{O}}_{{ 2\,{\text{p}}}} }} , 24 ± 6 s; τLBF, 23 ± 8 s). The ∆HHb response did not differ between VL and VM in amplitude (VL 6.97 ± 4.22 a.u.; VM 7.24 ± 3.99 a.u.), time delay (∆HHb_TD: VL 17 ± 2 s; VM 15 ± 1 s), time constant (τ∆HHb: VL 11 ± 6 s; VM 13 ± 4 s), or effective time constant [τ′∆HHb (= ∆HHb_TD + τ∆HHb): VL 28 ± 7 s; VM 28 ± 4 s]. Adjustments in ∆HHb in VL and VM depict a similar balance of regional O₂ delivery and utilization within the quadriceps muscle group. The τ′∆HHb and t[(V)\dot]\textO _2 \textp \tau \dot{V}{{{\text{O}}_{{ 2\,{\text{p}}}} }} were similar, however, the ∆HHb displayed an “overshoot” relative to the steady-state levels reflecting a slower alteration of microvascular blood flow (O₂ delivery) relative to O₂ utilization, necessitating a greater reliance on O₂ extraction.     

Lactate concentrations in human skeletal muscle biopsy, microdialysate and venous blood during dynamic exercise under blood flow restriction

The intramuscular microdialysate lactate concentration during dynamic exercise with various degrees of blood flow restriction and its relation to lactate concentration in skeletal muscle biopsy and venous blood were studied. Nine healthy males performed three one-legged knee extension exercises (Ex 1–3). Blood flow was restricted stepwise by applying supra-atmospheric pressure over the working leg. Microdialysate mean (range) lactate concentrations at the end of the exercise periods were 3.2 (0.5–6.6), 4.4 (1.1–9.8) and 7.9 (1.1–11.6) mmol·l^–1 during unrestricted, moderately restricted and severely restricted blood flow respectively. There was a significant correlation between microdialysate and venous lactate concentrations at the end of all three exercise periods. Microdialysate lactate concentration correlated significantly to skeletal muscle biopsy lactate concentration at the end of Ex 1. In conclusion, microdialysate lactate concentration in the working muscle increased step-wise with increasing blood flow restriction. It showed a better correlation to venous than to muscle biopsy lactate, which is possibly partly explained by the characteristics of diffusion between body compartments and differences in time resolution between the methods used.An erratum to this article can be found at     

Feeding the sleeping giant: muscle blood flow during whole body exercise

Specific anosmia, the inability to detect a particular odour, has been well documented for decades in human and animal populations. Indeed, the existence of specific anosmias was a favoured argument used to support a receptor-mediated mechanism of odourant detection prior to the molecular identification of a large family of olfactory G-protein-coupled receptors (GPCRs) in the early 1990s ( Amoore, 1974 ; Buck & Axel, 1991 ). One well known anosmia in humans is the inability to sense 5-α-androst-16-en-3-one (androstenone). Androstenone is variously described as having an unpleasant (urine, sweat) or pleasant odour (sweet, floral), yet a fraction of the population cannot detect its presence. Moreover, androstenone is a pheromone in boars and is found in urine and axillary sweat in humans, making it a prospective candidate for odour-mediated communication in humans. While a role for androstenone as a human pheromone is open to debate, a widely accepted finding is the ability of humans who are initially insensitive to androstenone to acquire sensitivity to it upon continued exposure ( Wysocki et al. 1989 ). Since the 1989 anecdotal discovery of C.J. Wysocki, several other studies have shown that humans and other species can acquire sensitivity to androstenone as well as to other odourants ( Wang et al. 1993 ; Pause et al. 1999 ; Dalton et al. 2002 ). However, the mechanism(s) of this increased sensitivity are poorly understood. In this issue of The Journal of Physiology Wang et al . (2004) provide evidence for a mechanism of increased sensitivity in the olfactory epithelium of humans.     

Leg blood flow during static exercise

Summary Leg blood flow was studied with the constant infusion dye technique during static exercise of the thigh muscles (quadriceps) and during hand-grips at 15 and 25–30% of MVC.Blood flow and oxygen uptake in the leg increased in quadriceps exercise and reached their highest values (around 1.2 l/min and 165 ml/min respectively) at 25–30% of MVC, whereas leg vascular resistance decreased. Regional circulatory adaptations and the oxygen uptake — leg blood flow relationship were in close agreement with the responses found in dynamic leg exercise. In view of the marked rise in intramuscular pressure previously observed during quadriceps contractions, a restriction of blood flow and an increased vascular resistance had been expected. Involuntary activation of leg muscles other than the quadriceps may explain the finding.Contractions of the contralateral quadriceps induced a slight increase in leg blood flow, whereas hand-grips had no influence on blood flow or vascular resistance in the leg. The distribution of the cardiac output during static contractions is discussed, and it is concluded that during hand-grips the increase in blood flow is predominantly distributed to the upper part of the body.