Muscle Blood Flow In Humans Research Articles

Cyclooxygenase inhibition does not blunt thermal hyperemia in skeletal muscle of humans.

Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. The cyclooxygenase pathway is active in skeletal muscle, is heat sensitive, and contributes to cutaneous thermal hyperemia in young healthy humans. Therefore, the purpose of this study was to test the hypothesis that cyclooxygenase inhibition would attenuate blood flow in the vastus lateralis muscle during localized heating. Twelve participants (6 women) were studied on two separate occasions: 1) time control (i.e., no ibuprofen); and 2) ingestion of 800 mg ibuprofen, a nonselective cyclooxygenase inhibitor. Experiments were randomized, counter-balanced, and separated by at least 10 days. Pulsed short-wave diathermy was used to induce unilateral deep heating of the vastus lateralis for 90 min, whereas the contralateral leg served as a thermoneutral control. Microdialysis was utilized to bypass the cutaneous circulation and directly measure local blood flow in the vastus lateralis muscle of each leg via the ethanol washout technique. Heat exposure increased muscle temperature and local blood flow (both P < 0.01 vs. baseline). However, the thermal hyperemic response did not differ between control and ibuprofen conditions (P ≥ 0.2). Muscle temperature slightly decreased for the thermoneutral leg (P < 0.01 vs. baseline), yet local blood flow remained relatively unchanged across time for control and ibuprofen conditions (both P ≥ 0.7). Taken together, our data suggest that inhibition of cyclooxygenase-derived vasodilator prostanoids does not blunt thermal hyperemia in skeletal muscle of young healthy humans.NEW & NOTEWORTHY Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. Using a pharmacological approach combined with microdialysis, we found that thermal hyperemia in the vastus lateralis muscle was well maintained despite the successful inhibition of cyclooxygenase. Our results suggest that cyclooxygenase-derived vasodilator prostanoids do not contribute to thermal hyperemia in skeletal muscle of young healthy humans.

KIR channel activation links local vasodilatation with muscle fibre recruitment during exercise in humans.

During exercise, blood flow to working skeletal muscle increases in parallel with contractile activity such that oxygen delivery is sufficient to meet metabolic demand. K+ released from active skeletal muscle fibres could facilitate vasodilatation in proportion to the degree of muscle fibre recruitment. Once released, K+ stimulates inwardly rectifying K+ (KIR ) channels on the vasculature to elicit an increase in blood flow. In the present study, we demonstrate that KIR channels mediate the rapid vasodilatory response to an increase in exercise intensity. We also show that KIR channels augment vasodilatation during exercise which demands greater muscle fibre recruitment independent of the total amount of work performed. These results suggest that K+ plays a key role in coupling the magnitude of vasodilatation to the degree of contractile activity. Ultimately, the findings from this study help us understand the signalling mechanisms that regulate muscle blood flow in humans. Blood flow to active skeletal muscle is augmented with greater muscle fibre recruitment. We tested whether activation of inwardly rectifying potassium (KIR ) channels underlies vasodilatation with elevated muscle fibre recruitment when work rate is increased (Protocol 1) or held constant (Protocol 2). We assessed forearm vascular conductance (FVC) during rhythmic handgrip exercise under control conditions and during local inhibition of KIR channels (intra-arterial BaCl2 ). In Protocol 1, healthy volunteers performed mild handgrip exercise for 3min, then transitioned to moderate intensity for 30s. BaCl2 eliminated vasodilatation during the first contraction at the moderate workload (ΔFVC, BaCl2 : -1±17 vs. control: 30±28mlmin-1 100mmHg-1 ; n=9; P=0.004) and attenuated the 30s area under the curve by 56±14% (n=9; P<0.0001). In Protocol 2, participants performed two exercise bouts in which muscle fibre recruitment was manipulated while total contractile work was held constant via reciprocal changes in contraction frequency: (1) low fibre recruitment, with contractions at 12.5% maximal voluntary contraction once every 4s and (2) high fibre recruitment, with contractions at 25% maximal voluntary contraction once every 8s. Under control conditions, steady-state FVC was augmented in high vs. low fibre recruitment (211±90 vs. 166±73mlmin-1 ⋅100mmHg-1 ; n=10; P=0.0006), whereas BaCl2 abolished the difference between high and low fibre recruitment (134±59 vs. 134±63mlmin-1 100mmHg-1 ; n=10; P=0.85). These findings demonstrate that KIR channel activation is a key mechanism linking local vasodilatation with muscle fibre recruitment during exercise.

The Effect of Passive Stretch on Vascular Control during Exercise

It has been demonstrated that daily stretching leads to an increase in blood flow to the skeletal muscle during exercise in rats; however, little is known about the effects of daily muscle stretching on adaptions of muscle blood flow in humans. PURPOSE: Therefore, the purpose of this study was to investigate the effect of passive stretch on vascular control (VC) during exercise. We tested the hypothesis that acute static stretch would not elicit changes in deoxygenated or total heme (deoxy-[heme], total-[heme] respectively) during exercise. Furthermore, we hypothesized that chronic stretch would elicit a decrease in oxygen extraction (deoxy-[heme]) through an increase in blood volume (total-[heme]). METHODS: 4 healthy males (24.8 ± 3.6 yr, 179 ± 2.2 cm, 92.1 ± 7.8 kg) completed a controlled passive stretch of the plantar flexors. 2 subjects completed 2 days of a 30 min stretching protocol, while the other 2 subjects completed 2 days of a 10 min stretching protocol. Following the first two days of stretching, all subjects completed a moderate intensity (40% PPeak) plantar flexion constant load test to determine acute effects of stretching on VC. All subjects then continued with the 10 min stretching protocol for the remainding 5 days, resulting in 7 consecutive days of stretch. Following the 7th day of stretch, subjects completed another moderate intensity (40% PPeak) constant load test to determine the chronic effects of stretching on VC. Near-infrared spectroscopy was used to continuously measure deoxy-[heme] and total-[heme] during exercise. RESULTS: Although no statistical differences were found, the 2 subjects who had completed the 30 min acute stretching protocol showed a marked decrease in deoxy-[heme] following acute stretching (5.13 ± 2.98μM to 1.40 ± 1.83μM), however no differences were observed in the 2 subjects who completed the 10 min acute stretching protocol. Following exercise in both the acute and chronic stretch protocols, no differences were observed in total-[heme]. CONCLUSIONS: The observed decrease in deoxy-[heme] lead us to believe that an acute static stretch of 30 minutes improves VC through better matching in the oxygen perfusion to extraction ratio during exercise. This VC enhancement was lost with chronic stretch, which could have been due to an insufficient stimulus on the microvasculature.

Methods for the determination of skeletal muscle blood flow: development, strengths and limitations

Since the first measurements of limb blood flow at rest and during nerve stimulation were conducted in the late 1800s, a number of methods have been developed for the determination of limb and skeletal muscle blood flow in humans. The methods, which have been applied in the study of aspects such as blood flow regulation, oxygen uptake and metabolism, differ in terms of strengths and degree of limitations but most have advantages for specific settings. The purpose of this review is to describe the origin and the basic principles of the methods, important aspects and requirements of the procedures. One of the earliest methods, venous occlusion plethysmography, is a noninvasive method which still is extensively used and which provides similar values as other more direct blood flow methods such as ultrasound Doppler. The constant infusion thermodilution method remains the most appropriate for the determination of blood flow during maximal exercise. For resting blood flow and light-to-moderate exercise, the non-invasive ultrasound Doppler methodology, if handled by a skilled operator, is recommendable. Positron emission tomography with radiolabeled water is an advanced method which requires highly sophisticated equipment and allows for the determination of muscle-specific blood flow, regional blood flows and estimate of blood flow heterogeneity within a muscle. Finally, the contrast-enhanced ultrasound method holds promise for assessment of muscle-specific blood flow, but the interpretation of the data obtained remains uncertain. Currently lacking is high-resolution methods for continuous visualization and monitoring of the skeletal muscle microcirculation in humans.

Concurrent measurement of skeletal muscle blood flow during exercise with diffuse correlation spectroscopy and Doppler ultrasound.

Noninvasive, direct measurement of local muscle blood flow in humans remains limited. Diffuse correlation spectroscopy (DCS) is an emerging technique to measure regional blood flow at the microvascular level. In order to better understand the strengths and limitations of this novel technique, we performed a validation study by comparing muscle blood flow changes measured with DCS and Doppler ultrasound during exercise. Nine subjects were measured (all males, 27.4 ± 2.9 years of age) for a rhythmic handgrip exercise at 20% and 50% of individual maximum voluntary contraction (MVC), followed by a post-exercise recovery. The results from DCS and Doppler ultrasound were highly correlated (R = 0.99 ± 0.02). DCS was more reliable and less susceptible to motion artifact.

Measurement of Skeletal Muscle Blood Flow with Near‐infrared Diffuse Correlation Spectroscopy

Direct continuous noninvasive measurement of local muscle blood flow in humans remains limited. Conventional measurements of limb blood flow, such as Doppler ultrasound or venous occlusion plethysmography, measure changes in bulk conduit flow and do not provide regional information. Near‐infrared diffuse correlation spectroscopy (DCS) is an emerging technique for non‐invasive measurement of local muscle blood flow at the microvascular level. In order to better understand the strengths and limitations of this novel approach, we performed a validation study by comparing muscle blood flow changes measured by DCS and Doppler ultrasound during exercise. Ten subjects were recruited for this study (age: 27±3 yrs; female/male: 1/9; BMI: 27.0±3.6 kg/m2). The DCS probe was affixed to the forearm over the belly of the flexor digitorum profundus. Brachial artery blood velocity and diameter were measured with Doppler ultrasound, integrated, and reported as brachial artery blood flow. After a brief period of rest, each participant performed rhythmic handgrip exercise at 20% and 50% of their maximum voluntary contraction (MVC). As expected, brachial artery blood flow increased significantly from baseline by 312±56% at 20% MVC, and 613±90% at 50% MVC. Blood flow index (BFI), the primary output from DCS, shared a similar change from baseline, increasing 112±18% and 262±35%, respectively. To more appropriately compare these two approaches, the data were normalized to each person's individual maximum for each respective technique. Remarkably, the increase in skeletal muscle blood flow was strikingly similar between the two techniques, when reported in normalized units (20%: 0.42±0.03 vs. 0.45±0.03; 50%: 0.69±0.04 vs. 0.79±0.02, DCS vs. BA flow, respectively). The change in skeletal muscle blood flow by DCS and Doppler ultrasound were also strongly correlated (r2=0.77, P&lt;0.001). Taken together, these data show that DCS and Doppler ultrasound quantify the same temporal dynamics of skeletal muscle blood flow during exercise. While these results are indeed encouraging, more work is needed to fully validate this approach for measuring local microvascular blood flow in humans.Support or Funding InformationThis work was support by an Interdisciplinary Research Program grant from the University of Texas at Arlington.

Reflex control of the circulation during exercise.

Appropriate cardiovascular and hemodynamic adjustments are necessary to meet the metabolic demands of working skeletal muscle during exercise. Alterations in the sympathetic and parasympathetic branches of the autonomic nervous system are fundamental in ensuring these adjustments are adequately made. Several neural mechanisms are responsible for the changes in autonomic activity with exercise and through complex interactions, contribute to the cardiovascular and hemodynamic changes in an intensity-dependent manner. This short review is from a presentation made at the Saltin Symposium June 2-4, 2015 in Copenhagen, Denmark. As such, the focus will be on reflex control of the circulation with an emphasis on the work of the late Dr. Bengt Saltin. Moreover, a concerted effort is made to highlight the novel and insightful concepts put forth by Dr. Saltin in his last published review article on the regulation of skeletal muscle blood flow in humans. Thus, the multiple roles played by adenosine triphosphate (ATP) including its ability to induce vasodilatation, override sympathetic vasoconstriction and stimulate skeletal muscle afferents (exercise pressor reflex) are discussed and a conceptual framework is set suggesting a major role of ATP in blood flow regulation during exercise.

Regulation of the skeletal muscle blood flow in humans.

In humans, skeletal muscle blood flow is regulated by an interaction between several locally formed vasodilators, including NO and prostaglandins. In plasma, ATP is a potent vasodilator that stimulates the formation of NO and prostaglandins and, very importantly, can offset local sympathetic vasoconstriction. Adenosine triphosphate is released into plasma from erythrocytes and endothelial cells, and the plasma concentration increases in both the feed artery and the vein draining the contracting skeletal muscle. Adenosine also stimulates the formation of NO and prostaglandins, but the plasma adenosine concentration does not increase during exercise. In the skeletal muscle interstitium, there is a marked increase in the concentration of ATP and adenosine, and this increase is tightly coupled to the increase in blood flow. The sources of interstitial ATP and adenosine are thought to be skeletal muscle cells and endothelial cells. In the interstitium, both ATP and adenosine stimulate the formation of NO and prostaglandins, but ATP has also been suggested to induce vasoconstriction and stimulate afferent nerves that signal to increase sympathetic nerve activity. Adenosine has been shown to contribute to exercise hyperaemia, whereas the role of ATP remains uncertain due to lack of specific purinergic receptor blockers for human use. The purpose of this review is to address the interaction between vasodilator systems and to discuss the multiple proposed roles of ATP in human skeletal muscle blood flow regulation.

Carotid chemoreceptor modulation of blood flow during exercise in healthy humans

Carotid chemoreceptor (CC) inhibition reduces sympathetic nervous outflow in exercising dogs and humans. We sought to determine if CC suppression increases muscle blood flow in humans during exercise and hypoxia. Healthy subjects (N = 13) were evaluated at rest and during constant-work leg extension exercise while exposed to either normoxia or hypoxia (inspired O(2) tension, F(IO(2)), ≈ 0.12, target arterial O(2) saturation = 85%). Subjects breathed hyperoxic gas (F(IO(2)) ≈ 1.0) and/or received intravenous dopamine to inhibit the CC while femoral arterial blood flow data were obtained continuously with pulsed Doppler ultrasound. Exercise increased heart rate, mean arterial pressure, femoral blood flow and conductance compared to rest. Transient hyperoxia had no significant effect on blood flow at rest, but increased femoral blood flow and conductance transiently during exercise without changing blood pressure. Similarly, dopamine had no effect on steady-state blood flow at rest, but increased femoral blood flow and conductance during exercise. The transient vasodilatory response observed by CC inhibition with hyperoxia during exercise could be blocked with simultaneous CC inhibition with dopamine. Despite evidence of dopamine reducing ventilation during hypoxia, no effect on femoral blood flow, conductance or mean arterial pressure was observed either at rest or during exercise with CC inhibition with dopamine while breathing hypoxia. These findings indicate that the carotid chemoreceptor contributes to skeletal muscle blood flow regulation during normoxic exercise in healthy humans, but that the influence of the CC on blood flow regulation in hypoxia is limited.

Influence of erythrocyte oxygenation and intravascular ATP on resting and exercising skeletal muscle blood flow in humans with mitochondrial myopathy

Oxygen (O2) extraction is impaired in exercising skeletal muscle of humans with mutations of mitochondrial DNA (mtDNA), but the muscle hemodynamic response to exercise has never been directly investigated. This study sought to examine the extent to which human skeletal muscle perfusion can increase without reductions in blood oxygenation and to determine whether erythrocyte O2 off-loading and related ATP vascular mechanisms are impaired in humans with mutations of mtDNA. Leg vascular hemodynamic, oxygenation and ATP were investigated in ten patients with mtDNA mutations and ten matched healthy control subjects: 1) at rest during normoxia, hypoxia, hyperoxia and intra-femoral artery ATP infusion, and 2) during passive and dynamic one-legged knee-extensor exercises. At rest, blood flow (LBF), femoral arterial and venous blood oxygenation and plasma ATP were similar in the two groups. During dynamic exercise, LBF and vascular conductance increased 9–10 fold in the patients despite erythrocyte oxygenation and leg O2 extraction remained unchanged (p<0.01). In the patients, workload-adjusted LBF was 28% to 62% higher during submaximal- and maximal exercises and was associated with augmented plasma ATP. The appropriate hemodynamic adjustments during severe hypoxia and ATP infusion suggest that erythrocyte O2 off-loading and related ATP vascular mechanisms are intact in patients with mtDNA mutations. Furthermore, greater increase in plasma ATP and LBF at a given metabolic demand in the patients, in concert with unchanged oxyhemoglobin, suggest that erythrocyte O2 off-loading is not obligatory for the exercise-induced increase in blood flow and intravascular ATP concentration.

Local heating, but not indirect whole body heating, increases human skeletal muscle blood flow

For decades it was believed that direct and indirect heating (the latter of which elevates blood and core temperatures without directly heating the area being evaluated) increases skin but not skeletal muscle blood flow. Recent results, however, suggest that passive heating of the leg may increase muscle blood flow. Using the technique of positron-emission tomography, the present study tested the hypothesis that both direct and indirect heating increases muscle blood flow. Calf muscle and skin blood flows were evaluated from eight subjects during normothermic baseline, during local heating of the right calf [only the right calf was exposed to the heating source (water-perfused suit)], and during indirect whole body heat stress in which the left calf was not exposed to the heating source. Local heating increased intramuscular temperature of the right calf from 33.4 ± 1.0°C to 37.4 ± 0.8°C, without changing intestinal temperature. This stimulus increased muscle blood flow from 1.4 ± 0.5 to 2.3 ± 1.2 ml·100 g⁻¹·min⁻¹ (P < 0.05), whereas skin blood flow under the heating source increased from 0.7 ± 0.3 to 5.5 ± 1.5 ml·100 g⁻¹·min⁻¹ (P < 0.01). While whole body heat stress increased intestinal temperature by ∼1°C, muscle blood flow in the calf that was not directly exposed to the water-perfused suit (i.e., indirect heating) did not increase during the whole body heat stress (normothermia: 1.6 ± 0.5 ml·100 g⁻¹·min⁻¹; heat stress: 1.7 ± 0.3 ml·100 g⁻¹·min⁻¹; P = 0.87). Whole body heating, however, reflexively increased calf skin blood flow (to 4.0 ± 1.5 ml·100 g⁻¹·min⁻¹) in the area not exposed to the water-perfused suit. These data show that local, but not indirect, heating increases calf skeletal muscle blood flow in humans. These results have important implications toward the reconsideration of previously accepted blood flow distribution during whole body heat stress.

Blood flow index using near-infrared spectroscopy and indocyanine green as a minimally invasive tool to assess respiratory muscle blood flow in humans

Near-infrared spectroscopy (NIRS) in combination with indocyanine green (ICG) dye has recently been used to measure respiratory muscle blood flow (RMBF) in humans. This method is based on the Fick principle and is determined by measuring ICG in the respiratory muscles using transcutaneous NIRS in relation to the [ICG] in arterial blood as measured using photodensitometry. This method is invasive since it requires arterial cannulation, repeated blood withdrawals, and reinfusions. A less invasive alternative is to calculate a relative measure of blood flow known as the blood flow index (BFI), which is based solely on the NIRS ICG curve, thus negating the need for arterial cannulation. Accordingly, the purpose of this study was to determine whether BFI can be used to measure RMBF at rest and during voluntary isocapnic hyperpnea at 25, 40, 55, and 70% of maximal voluntary ventilation in seven healthy humans. BFI was calculated as the change in maximal [ICG] divided by the rise time of the NIRS-derived ICG curve. Intercostal and sternocleidomastoid muscle BFI were correlated with simultaneously measured work of breathing and electromyography (EMG) data from the same muscles. BFI showed strong relationships with the work of breathing and EMG for both respiratory muscles. The coefficients of determination (R(2)) comparing BFI vs. the work of breathing for the intercostal and sternocleidomastoid muscles were 0.887 (P < 0.001) and 0.863 (P < 0.001), respectively, whereas the R(2) for BFI vs. EMG for the intercostal and sternocleidomastoid muscles were 0.879 (P < 0.001) and 0.930 (P < 0.001), respectively. These data suggest that the BFI closely reflects RMBF in conscious humans across a wide range of ventilations and provides a less invasive and less technically demanding alternative to measuring RMBF.

Blood Flow Index Using Near Infrared Spectroscopy and Indocyanine Green Dye as a Minimally Invasive Method for Assessing Respiratory Muscle Blood Flow in Humans

PURPOSE: Previous attempts at measuring respiratory muscle blood flow (RMBF) in humans have required technically demanding and invasive methods on anesthetised subjects. The purpose of this study was to determine if a less invasive method could be used to measure RMBF in conscious humans using near infrared spectroscopy (NIRS) and indocyanine green (ICG) dye.

Influence of contractile work and muscle fiber recruitment on skeletal muscle blood flow in humans

Contractile work has been considered the primary determinant of skeletal muscle oxygen consumption (VO2), which is tightly coupled with blood flow (BF). Recently it was observed that within matched work conditions, the BF response following a single contraction increased with a greater degree of muscle fiber recruitment (MFR). The purpose of this study was to determine whether the primary determinant of skeletal muscle BF was contractile work or MFR during exercise. Accordingly, we measured the forearm BF response (FBF; Doppler ultrasound) during 4 minutes of rhythmic handgrip exercise (RHE) in 9 young males. Each workload (low and high) consisted of two trials matched for total work by varying the load (% maximal voluntary contraction; %MVC) and the contraction: rest ratio (low: 20%1:7 vs 10%1:3, high: 20%1:3 vs 10%1:1). Greater MFR was attained by increasing %MVC. VO2 was calculated from FBF and deep venous blood samples. Greater MFR significantly increased the FBF response at both low and high workloads (164±16 vs 139±16 p=.03 and 270±24 vs 240±20 p=.01 (ml min−1)). Greater MFR did not significantly affect VO2 (207±19 vs 177±23 p=0.3, and 327±44 vs 305±37 p=0.4(ml min−1)) at any workload, however, the ratio of ΔFBF: ΔVO2 was unchanged. Our preliminary data suggest contractile work is not the primary determinant of FBF and greater MFR may have an independent influence on FBF during RHE in humans.Supported by HL‐087952

Measuring muscle blood flow: a key link between systemic and regional metabolism

To provide a brief overview of the main techniques to measure muscle blood flow in humans and highlight some of the strengths and weaknesses associated with each technique. Peak muscle blood flow values of 300 ml/min per 100 g are possible in humans during heavy exercise performed with small muscle mass. This value is far higher than that which appears in most textbooks. Accurate and reliable techniques are therefore essential in measuring muscle blood flow. Current invasive techniques commonly used include indicator dilution (thermodilution and dye dilution) and radiolabel tracer washout (e.g. 133Xe washout) methods. Although invasive techniques have provided valuable insight into tissue blood flow, noninvasive techniques such as venous occlusion plethysmography and Doppler ultrasound are frequently used and provide accurate measurements of blood flow. Newer imaging techniques (MRI, positron emission tomography, and contrast-enhanced ultrasonography) promise increased resolution of measurements of local blood flow, including in discrete tissues in which more classical techniques are not able to be used. Muscle blood flow is a key link in the interplay and regulation of systemic and local muscle metabolism. Recognizing the advantages and limitations of each technique is essential to translational researchers studying the effects of nutrition and metabolism on muscle blood flow.

Measurement of Respiratory Muscle Blood Flow in Humans Using Near Infrared Spectroscopy and Indocyanine Green

It has been difficult to measure respiratory muscle blood flow (RMBF) in humans because of the highly invasive measurement techniques and the need to anesthetize patients. To our knowledge, there are no methods available to accurately measure RMBF in conscious humans. PURPOSE: To develop an indicator-dilution approach to measure RMBF using near-infrared spectroscopy (NIRS) to detect indocyanine green dye (ICG) over the respiratory muscles in spontaneously breathing humans. METHODS: NIRS optodes were placed on the left 7th intercostal space at the apposition of the costal diaphragm and on an inactive control muscle (vastus lateralis) in 5 healthy male cyclists. Intravenous injection of ICG allowed cardiac output (by the conventional dye-dilution method with arterial sampling) and RMBF to be measured simultaneously. Esophageal and gastric pressures were also measured to calculate the mechanical work of breathing and trans-diaphragmatic pressure. Measurements were obtained during both resting breathing and three separate 5 minute bouts of constant isocapnic hyperventilation at 27.1±3.2, 56.0±6.1 and 75.9±5.7% of maximum minute ventilation as determined on a previous maximal exercise test. RESULTS: RMBF progressively increased (9.9±0.6, 14.8±2.7, 29.9±5.8 and 50.1±12.5 ml·100ml−1·min) with increasing levels of ventilation while blood flow to the inactive control muscle remained constant (10.39±1.4, 8.7±0.7, 12.9±1.7 and 12.2±1.8 ml·100ml−1·min−1). As ventilation rose, RMBF was closely and significantly correlated with cardiac output (r = 0.994, P = 0.006), the work of breathing (r = 0.995, P= 0.005) and trans-diaphragmatic pressure (r = 0.998, P= 0.002). CONCLUSION: To our knowledge, this is the first study to quantify RMBF in conscious humans during spontaneous hyperventilation. These data suggest that the NIRS-ICG method provides a feasible and sensitive index of respiratory muscle blood flow in humans that should be applicable to rest, light, moderate and heavy exercise.

Human Muscle Blood Flow and Metabolic Assessment Applied to Aging

Human Muscle Blood Flow and Metabolic Assessment Applied to Aging

Regulation of Muscle Blood Flow in Obesity

Obesity has been shown to impair muscle blood flow in humans. Vasodilatory control mechanisms such as metabolic control, myogenic mechanisms, conducted vasodilation, and release of endothelium-derived factors may be impaired in obesity due to insulin resistance, hyperglycemia, dyslipidemia, inflammation, oxidative stress, and endothelial dysfunction. The physiological importance of these blood flow control mechanisms has predominately been determined during the increase in blood flow (functional hyperemia) that occurs in response to the increased metabolism associated with exercise. This review examines the mechanisms by which functional hyperemia may be impaired in obesity and indicates areas where further studies are needed. The most extensively studied area of obesity-induced changes in muscle blood flow has been the role of endothelium-derived mediators during resting blood flow and exercise-induced hyperemia. Elevations in oxidative stress alter endothelium-derived factors, resulting in impaired vasodilatory responses. Alterations in metabolic and conducted vasodilatory regulation of blood flow have not been extensively studied in obesity, providing a potential area of research.

MECHANISM OF ANGIOTENSIN II VASOREACTIVITY IN RAT SOLEUS MUSCLE ARTERIOLES: EFFECTS OF AGING AND EXERCISE TRAINING

Aging appears to attenuate muscle blood flow in humans and rats, whereas exercise training ameliorates this aging effect. Because angiotensin II (Ang II) exerts a vasoconstrictor effect on the microcirculation, one possible mechanism for the aging or training associated alteration in muscle perfusion is through altered Ang II-mediated vasoconstriction. Therefore, we tested the hypothesis that, 1) aging increases Ang II vasoconstriction in rat soleus muscle arterioles, 2) the increased vasoconstriction in aged soleus arterioles is related to an endothelial nitric oxide synthase (NOS) signaling pathway, and 3) exercise training can attenuate the increased Ang II vasoconstriction in aged soleus arterioles. First-order arterioles were isolated from soleus muscles of young (4 months) and aged (24 months) male Fischer-344 rats. Ang II vasoconstrictor responses (3×10−11−3×10−5 M) were determined in arterioles with and without an intact endothelium. Ang II dose- responses were also examined in the presence of L-NAME (10−5 M), a NOS inhibitor. Ang II-mediated vasoconstriction was greater (P<0.05) in aged vs. young soleus muscle arterioles. Both the removal of the endothelium and NOS inhibition abolished this age-associated difference in Ang II vasoconstriction. Exercise training also eliminated the effects of aging on arteriolar vasoconstriction to Ang II. In conclusion, aging enhances Ang II vasoconstrictor responses through an endothelial NOS signaling mechanism, and exercise training can ameliorate the age-associated increase in Ang II vasoconstriction through an as yet unknown mechanism. Supported by NASA grants NAG2-1340 and NCC2-1166

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

Previous studies show that exercise-induced hyperaemia is unaffected by systemic inhibition of nitric oxide synthase (NOS) and it has been proposed that this may be due to compensation by other vasodilators. We studied the involvement of cytochrome P450 2C9 (CYP 2C9) in the regulation of skeletal muscle blood flow in humans and the interaction between CYP 2C9 and NOS. Seven males performed knee extensor exercise. Blood flow was measured by thermodilution and blood samples were drawn frequently from the femoral artery and vein at rest, during exercise and in recovery. The protocol was repeated three times on the same day. The first and the third protocols were controls, and in the second protocol either the CYP 2C9 inhibitor sulfaphenazole alone, or sulfaphenazole in combination with the NOS inhibitor N(omega)-monomethyl-L-arginine (L-NMMA) were infused. Compared with control there was no difference in blood flow at any time with sulfaphenazole infusion (P > 0.05) whereas with infusion of sulfaphenazole and L-NMMA, blood flow during exercise was 16 +/- 4 % lower than in control (9 min: 3.67 +/- 0.31 vs. 4.29 +/- 0.20 l min(-1); P < 0.05). Oxygen uptake during exercise was 12 +/- 3 % lower (9 min: 525 +/- 46 vs. 594 +/- 24 ml min(-1); P < 0.05) with co-infusion of sulfaphenazole and L-NMMA, whereas oxygen uptake during sulfaphenazole infusion alone was not different from that of control (P > 0.05). The results demonstrate that CYP 2C9 plays an important role in the regulation of hyperaemia and oxygen uptake during exercise. Since inhibition of neither NOS nor CYP 2C9 alone affect skeletal muscle blood flow, an interaction between CYP 2C9 and NOS appears to exist so that a CYP-dependent vasodilator mechanism takes over when NO production is compromised.