Regulation Of Muscle Blood Flow Research Articles

Advanced Age Increases the Amplitude of ATP‐sensitive K + Channel Currents in Murine Resistance Artery Smooth Muscle Cells

Advanced age impairs skeletal muscle blood flow regulation. We tested the hypothesis that advanced age decreases ATP-sensitive K+ channel (KATP) function of smooth muscle cells (SMCs) in skeletal muscle resistance arteries. Superior epigastric arteries (SEAs) were dissected from Young (Y; 蠅3 mo) or Old (O; 蠅24 mo) male C57BL/6 mice and either dissociated to yield individual SMCs for perforated patch clamp recording (holding potential, -30 mV) or cannulated and pressurized to 80 cm H20 for pressure myography. The KATP antagonist, glibenclamide (Glib, 10 µM) blocked small outward currents that were similar in Y and O (0.25±0.08 vs. 0.12±0.09 pA/pF, n = 6, p > 0.05). The KATP agonist levcromakalim (Lev, 10 µM) activated Glib-sensitive outward currents that were smaller in Y than O (0.14±0.05 vs. 1.11±0.37 pA/pF, n = 6, p < 0.05). However, Glib (10 µM) had no effect on resting diameter of SEAs from Y (control: 161±5; Glib: 166±5 μm, n=11, p>0.05) or O (control: 155±12; Glib: 155±11 μm, n=4, p>0.05). Lev induced similar maximal dilation in SEAs from Y (80±4%, n = 11) and O (74±12%, n = 7) with no difference in sensitivity (LogEC50: -6.98±0.12 vs. -6.83±0.23, p > 0.05). Thus, advanced age increases the functional expression of KATP in SEA SMCs. We suggest that this effect may not translate into a change in vasomotor function if it compensates for other age-related alterations in the regulation of SEA myogenic tone. (NIH R01-HL086483).

Adrenergic and non-adrenergic control of active skeletal muscle blood flow: implications for blood pressure regulation during exercise.

Blood flow to active skeletal muscle increases markedly during dynamic exercise. However, despite the massive capacity of skeletal muscle vasculature to dilate, arterial blood pressure is well maintained. Sympathetic nerve activity is elevated with increased intensity of dynamic exercise, and is essential for redistribution of cardiac output to active skeletal muscle and maintenance of arterial blood pressure. In addition, aside from the sympathetic nervous system, evidence from human studies is now emerging that supports roles for non-adrenergic vasoconstrictor pathways that become active during exercise and contribute to vasoconstriction in active skeletal muscle. Neuropeptide Y and adenosine triphosphate are neurotransmitters that are co-released with norepinephrine from sympathetic nerve terminals capable of producing vasoconstriction. Likewise, plasma concentrations of arginine vasopressin, angiotensin II (Ang II) and endothelin-1 (ET-1) increase during dynamic exercise, particularly at higher intensities. Ang II and ET-1 have both been shown to be important vasoconstrictor pathways for restraint of blood flow in active skeletal muscle and the maintenance of arterial blood pressure during exercise. Indeed, although both adrenergic and non-adrenergic vasoconstriction can be attenuated in exercising muscle with greater intensity of exercise, with the higher volume of blood flow, the active skeletal muscle vasculature remains capable of contributing importantly to the maintenance of blood pressure. In this brief review we provide an update on skeletal muscle blood flow regulation during exercise with an emphasis on adrenergic and non-adrenergic vasoconstrictor pathways and their potential capacity to offset vasodilation and aid in the regulation of blood pressure.

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.

Sex differences with aging in nutritive skeletal muscle blood flow: impact of exercise training, nitric oxide, and α-adrenergic-mediated mechanisms.

The incidence of cardiovascular disease increases progressively with age, but aging may affect men and women differently. Age-associated changes in vascular structure and function may manifest in impaired nutritive blood flow, although the regulation of nutritive blood flow in healthy aging is not well understood. The purpose of this study was to determine if nitric oxide (NO)-mediated or α-adrenergic-mediated regulation of nutritive skeletal muscle blood flow is impaired with advanced age, and if exercise training improves age-related deficiencies. Nutritive blood flow was monitored in the vastus lateralis of healthy young and aged men and women via the microdialysis-ethanol technique prior to and following seven consecutive days of exercise training. NO-mediated and α-adrenergic-mediated regulation of nutritive blood flow was assessed by microdialysis perfusion of acetylcholine, sodium nitroprusside, N(G)-monomethyl-L-arginine, norepinephrine, or phentolamine. Pretraining nutritive blood flow was attenuated in aged compared with young women (7.39 ± 1.5 vs. 15.5 ± 1.9 ml·100 g(−1)·min(−1), P = 0.018), but not aged men (aged 13.5 ± 3.7 vs. young 9.4 ± 1.3 ml·100 g(−1)·min(−1), P = 0.747). There were no age-associated differences in NO-mediated or α-adrenergic-mediated nutritive blood flow. Exercise training increased resting nutritive blood flow only in young men (9.4 ± 1.3 vs. 19.7 ml·100 g(−1)·min(−1), P = 0.005). The vasodilatory effect of phentolamine was significantly reduced following exercise training only in young men (12.3 ± 6.14 vs. −3.68 ± 3.26 ml·100 g(−1)·min(−1), P = 0.048). In conclusion, the age-associated attenuation of resting nutritive skeletal muscle blood flow was specific to women, while the exercise-induced alleviation of α-adrenergic mediated vasoconstriction that was specific to young men suggests an age-associated modulation of the sympathetic response to exercise training.

The effect of purinergic P2 receptor blockade on skeletal muscle exercise hyperemia in miniature swine.

ATP could play an important role in skeletal muscle blood flow regulation by inducing vasodilation via purinergic P2 receptors. This study investigated the role of P2 receptors in exercise hyperemia in miniature swine. We measured regional blood flow with radiolabeled-microsphere technique and systemic hemodynamics before and after arterial infusion of the P2 receptor antagonist reactive blue 2 during treadmill exercise (5.2 km/h, ~60 % VO2max) and arterial ATP infusion in female Yucatan miniature swine (~29 kg). Mean blood flow during exercise from the 16 sampled skeletal muscle tissues was 138 ± 18 mL/min/100 g (mean ± SEM), and it was reduced in 11 (~25 %) of the 16 sampled skeletal muscles after RB2 was infused. RB2 also lowered diaphragm blood flow and kidney blood flow, whereas lung tissue blood flow was increased (all P < 0.05). Infusion of RB2 increased arterial lactate concentration during exercise from 1.6 ± 0.5 to 3.4 ± 0.6 mmol/L and heart rate from 216 ± 12 to 230 ± 9 beats/min, whereas blood pressure was unaltered. Arterial ATP infusion caused a ~twofold increase in blood flow in 15 of the 16 sampled muscle tissues and this effect was abolished after RB2 infusion. These results indicate that P2 receptors play a role in regulating skeletal muscle blood flow during exercise in miniature swine.

Effects of oroxylin A in cerebral vascular tone regulation (841.3)

Oroxylin A, a flavonoid and an active component isolated from Scutellariae baicalensis, has been considered beneficial in preventing inflammation‐induced microglia‐mediated neurodegeneration. Its role in regulation of cerebral vascular smooth muscle tone and blood flow, however, remains unclear. This study was designed to assess possible beneficial effects of oroxylin A in cerebral blood flow and cerebral vascular smooth muscle tone regulation in vitro and in vivo. The results indicated that oroxylin A (10 mg/Kg, iv), which did not affect the systemic blood pressure, significantly increased regional cerebral blood flow in the striatum of the rat in vivo, using laser Doppler flowmetry. Results from tissue bath myography studies indicated that oroxylin A (100 nM ‐ 30 μM) in a concentration‐dependent manner relaxed U46619‐precontracted porcine isolated basilar arteries. The vasorelaxation was not affected by denudation of the endothelium, cold storage for 5 days, tetrodotoxin (0.3 μM), ODQ (10 μM, a soluble guanylate cyclase inhibitor), SQ22536 (200 μM, an adenylate cyclase inhibitor) and H89 (10 μM, an inhibitor of protein kinase A), but was blocked by iberiotoxin (100 nM). These results suggest that oroxylin A induces dilation of large pial arteries and intraparenchymal vessels. The relaxation in large basilar arteries is independent of the endothelium and is mediated by large‐conductance Ca2+‐activated K+ channels on the smooth muscle cells. The vasodilatory effect with increased regional cerebral blood flow of oroxylin A may provide additional benefits in preventing inflammation‐mediated neurodegeneration.

Short‐term naproxcinod treatment ameliorates functional muscle ischemia in dystrophin‐deficient mdx mice (1156.1)

Impaired nitric oxide (NO) signaling in the dystrophin‐deficient muscles of patients with Duchenne muscular dystrophy (DMD) and the mdx mouse model of DMD renders the diseased muscles susceptible to functional ischemia, which enhances both fatigue and exercise‐induced muscle injury. We therefore asked if short‐term treatment with naproxcinod, a NO‐donating naproxen, would prevent functional muscle ischemia and restore normal blood flow regulation in the exercising muscles of mdx mice. Norepinephrine (NE) evoked similar decreases in femoral vascular conductance (FVC) in resting and contracting hindlimbs of vehicle‐treated mdx mice, indicating functional muscle ischemia (ΔFVC contraction/rest: 0.93 ± 0.16, n=5). Naproxcinod (40 mg/kg, po) modestly reduced muscle ischemia when given as a single dose and markedly ameliorated it when treatment was extended to 1 wk (ΔFVC contraction/rest: 0.67 ± 0.18 and 0.39 ± 0.08, respectively; n=9 each), while treatment with equimolar naproxen was without effect (n=5). Daily treatment with a lower dose of naproxcinod (20 mg/kg) was equally effective in preventing functional ischemia in mdx and nNOS null mice (ΔFVC contraction/rest: 0.39 ± 0.05, n=10 and 0.31 ± 0.02, n=4, respectively). These findings suggest that naproxcinod’s ability to donate NO rather than inhibit cyclooxygenase is the main mechanism by which the drug improves muscle blood flow regulation in mdx mice.Grant Funding Source: Supported by DoD, W81XWH‐12‐1‐0256

Shear-Sensitive Regulation of Neutrophil Flow Behavior and Its Potential Impact on Microvascular Blood Flow Dysregulation in Hypercholesterolemia

Shear stress-induced pseudopod retraction is an anti-inflammatory measure that minimizes neutrophil activity and is regulated by membrane cholesterol. We tested the hypothesis that a hypercholesterolemic impairment of shear mechanotransduction alters the neutrophil flow behavior leading to microvascular dysfunction. We examined the shear effects on the flow behavior of human leukocytes. When subjected to shearing during cone-plate viscometry, leukocyte suspensions exhibited parallel time-dependent reductions in viscosity and pseudopod activity. Shear-induced reductions in suspension viscosity were attenuated by membrane cholesterol enrichment. We also showed that enhanced pseudopod activity of leukocyte suspensions in 10% hematocrit significantly (P<0.05) raised the flow resistance of microvascular mimics. These results implicate an impaired neutrophil pseudopod retraction response to shear in hypercholesterolemic microvascular dysfunction. We confirmed this using near-infrared diffuse correlation spectroscopy to assess skeletal muscle blood flow regulation in the hindlimbs of mice subjected to reactive hyperemia. Using a custom protocol for the mouse, we extrapolated an adjusted peak flow and time to adjusted peak flow to quantify the early phase of the blood flow recovery response during reactive hyperemia when shear mechanobiology likely has a maximal impact. Compared with mice on normal diet, hypercholesterolemic mice exhibited significantly (P<0.05) reduced adjusted peak flow and prolonged time to adjusted peak flow which correlated (r=0.4 and r=-0.3, respectively) with neutrophil shear responsiveness and were abrogated by neutropenia. These results provide the first evidence that the neutrophils contribute to tissue blood flow autoregulation. Moreover, a deficit in the neutrophil responsiveness to shear may be a feature of hypercholesterolemia-related microvascular dysfunction.

Aging increases the amplitude of spontaneous transient outward currents in murine resistance artery smooth muscle cells

Large conductance Ca2+‐activated K+ channels (BKCa) contribute to negative feedback regulation of microvascular tone. However, the effects of aging on BKCa function are unclear. The purpose of this study was to determine: 1) if enzymatically‐isolated smooth muscle cells (SMCs) from skeletal muscle resistance arteries display BKCa‐ and ryanodine receptor (RyR)‐dependent spontaneous transient outward currents (STOCs); and 2) whether aging affects STOC properties. Using perforated patch clamp recording, individual SMCs from Young (≥ 3 months) and Old (≥ 24 months) male C57BL/6 mice displayed STOCs at membrane potentials ≥ −30 mV, with the amplitude and frequency of STOCs increasing with membrane depolarization (n = 19–24; p &lt; 0.05). STOCs were inhibited by BKCa channel blockers (1 μM paxilline, 100 nM iberiotoxin) and by a RyR antagonist (100 μM tetracaine) (n ≥ 5; p &lt; 0.05 each). At +30 mV holding potential, STOC amplitude = 3.2 ± 0.32 pA/pF and frequency = 3.88 ± 0.41 Hz (n = 67) in SMCs from Young. STOC amplitude increased to 4.97 ± 0.5 pA/pF (n = 61; p &lt; 0.05) in SMCs from Old, with no significant difference in frequency (3.15 ± 0.31 Hz; p &gt;; 0.05). SMCs from murine resistance arteries display BKCa‐ and RyR‐dependent STOCs and aging increases STOC amplitude. Age‐related change in BKCa activity may impact the regulation of SMC function and contribute to age‐induced alterations in muscle blood flow regulation. (NIH R01HL086483).

Does a compensatory formation of nitric oxide during inhibition of prostanoid synthesis in skeletal muscle explain the redundancy between these vasoactive systems?

In skeletal muscle blood flow regulation a redundancy among vasodilators appear to exist, where a compensatory formation of one vasoactive compound may preserve adequate blood flow when the formation of another is compromised. To examine whether inhibition of prostanoid synthesis leads to a greater NO formation, skeletal muscle cells and skeletal muscle specific microvascular endothelial cells were treated with adenosine without and with inhibition of the enzyme cyclooxygenase to prevent prostanoid formation. The results showed that the adenosine‐induced formation of NO (as indicated by DAF‐FM fluorescence) was augmented (P&lt;0.001) in microvascular endothelial cells (n=10) when the formation of prostanoids was inhibited, whereas no difference was detected in skeletal muscle cells (n=10). Samples from the interstitial fluid of human skeletal muscle obtained during exercise with the microdialysis technique will reveal to what extent inhibition of prostanoid synthesis leads to a compensatory formation of NO in vivo. These results indicate that an increase in NO formation in microvascular endothelial cells could compensate for a compromised prostanoid concentration in skeletal muscle.

Mechanical effects of muscle contraction increase intravascular ATP draining quiescent and active skeletal muscle in humans

Intravascular adenosine triphosphate (ATP) evokes vasodilation and is implicated in the regulation of skeletal muscle blood flow during exercise. Mechanical stresses to erythrocytes and endothelial cells stimulate ATP release in vitro. How mechanical effects of muscle contractions contribute to increased plasma ATP during exercise is largely unexplored. We tested the hypothesis that simulated mechanical effects of muscle contractions increase [ATP](venous) and ATP effluent in vivo, independent of changes in tissue metabolic demand, and further increase plasma ATP when superimposed with mild-intensity exercise. In young healthy adults, we measured forearm blood flow (FBF) (Doppler ultrasound) and plasma [ATP](v) (luciferin-luciferase assay), then calculated forearm ATP effluent (FBF×[ATP](v)) during rhythmic forearm compressions (RFC) via a blood pressure cuff at three graded pressures (50, 100, and 200 mmHg; Protocol 1; n = 10) and during RFC at 100 mmHg, 5% maximal voluntary contraction rhythmic handgrip exercise (RHG), and combined RFC + RHG (Protocol 2; n = 10). [ATP](v) increased from rest with each cuff pressure (range 144-161 vs. 64 ± 13 nmol/l), and ATP effluent was graded with pressure. In Protocol 2, [ATP](v) increased in each condition compared with rest (RFC: 123 ± 33; RHG: 51 ± 9; RFC + RHG: 96 ± 23 vs. Mean Rest: 42 ± 4 nmol/l; P < 0.05), and ATP effluent was greatest with RFC + RHG (RFC: 5.3 ± 1.4; RHG: 5.3 ± 1.1; RFC + RHG: 11.6 ± 2.7 vs. Mean Rest: 1.2 ± 0.1 nmol/min; P < 0.05). We conclude that the mechanical effects of muscle contraction can 1) independently elevate intravascular ATP draining quiescent skeletal muscle without changes in local metabolism and 2) further augment intravascular ATP during mild exercise associated with increases in metabolism and local deoxygenation; therefore, it is likely one stimulus for increasing intravascular ATP during exercise in humans.

Taming the “sleeping giant”: the role of endothelin-1 in the regulation of skeletal muscle blood flow and arterial blood pressure during exercise

The cardiovascular response to exercise is governed by a combination of vasodilating and vasoconstricting influences that optimize exercising muscle perfusion while protecting mean arterial pressure (MAP). The degree to which endogenous endothelin (ET)-1, the body's most potent vasoconstrictor, participates in this response is unknown. Thus, in eight young (24 ± 2 yr), healthy volunteers, we examined leg blood flow, MAP, tissue oxygenation, heart rate, leg arterial-venous O(2) difference, leg O(2) consumption, pH, and net ET-1 and lactate release at rest and during knee extensor exercise (0, 5, 10, 15, 20, and 30 W) before and after an intra-arterial infusion of BQ-123 [ET subtype A (ET(A)) receptor antagonist]. At rest, BQ-123 did not evoke a change in leg blood flow or MAP. During exercise, net ET-1 release across the exercising leg increased approximately threefold. BQ-123 increased leg blood flow by ~20% across all work rates (changes of 113 ± 76, 176 ± 83, 304 ± 108, 364 ± 130, 502 ± 117, and 570 ± 178 ml/min at 0, 5, 10, 15, 20, and 30 W, respectively) and attenuated the exercise-induced increase in MAP by ~6%. The increase in leg blood flow was accompanied by a ~9% increase in leg O(2) consumption with an unchanged arterial-venous O(2) difference and deoxyhemoglobin, suggesting a decline in intramuscular efficiency after ET(A) receptor blockade. Together, these findings identify a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ET(A) receptor as an important mechanism for both the restraint of blood flow in the exercising limb and maintenance of MAP in healthy, young adults.

Vasodilator interactions in skeletal muscle blood flow regulation

During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or on the extraluminal side of the blood vessels. A number of vasodilators have been shown to bring about this increase in blood flow and, importantly, interactions between these compounds seem to be essential for the precise regulation of blood flow. Two compounds stand out as central in these vasodilator interactions: nitric oxide (NO) and prostacyclin. These two vasodilators are both stimulated by several compounds, e.g. adenosine, ATP, acetylcholine and bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other is compromised. Although numerous studies have examined the role of single and multiple pharmacological inhibition of different vasodilator systems, and important vasodilators and interactions have been identified, a large part of the exercise hyperaemic response remains unexplained. It is plausible that this remaining hyperaemia may be explained by cAMP- and cGMP-independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow regulation remain to be further explored to fully elucidate the regulation of exercise hyperaemia.

ATP as a mediator of erythrocyte‐dependent regulation of skeletal muscle blood flow and oxygen delivery in humans

In healthy human beings, blood flow to dynamically contracting skeletal muscle is regulated primarily to match oxygen (O(2)) delivery closely with utilisation. This occurs across a wide range of exercise intensities, as well as when exercise is combined with conditions that modify blood O(2) content. The red blood cells (RBCs), the primary O(2) carriers in the blood, contribute to the regulation of the local processes matching O(2) supply and demand. This is made possible by the ability of RBCs to release the vasoactive substance adenosine triphosphate (ATP) in response to reductions in erythrocyte and plasma O(2), as well as to other adjuvant metabolic and mechanical stimuli. The regulatory role of RBCs in human beings is supported by the observations that, i) exercising skeletal muscle blood flow responds primarily to changes in the amount of O(2) bound to the erythrocyte haemoglobin molecules, rather than the amount of O(2) in plasma, and ii) exercising muscle blood flow can almost double (from 260 to 460 ml min(-1) 100 g(-1)) with alterations in blood O(2) content, such that O(2) delivery and are kept constant. Besides falling blood O(2) content, RBCs release ATP when exposed to increased temperature, reduced pH, hypercapnia, elevated shear stress and augmented mechanical deformation, i.e. conditions that exist in the microcirculation of active skeletal muscle. ATP is an attractive mediator signal for skeletal muscle blood flow regulation, not only because it can act as a potent vasodilator, but also because of its sympatholytic properties in the human limb circulations. These properties are essential to counteract the vasoconstrictor effects of concurrent increases in muscle sympathetic nerve activity and circulating vasoconstrictor substances during exercise. Comparison of the relative vasoactive potencies and sympatholytic properties of ATP, other nucleotides, and adenosine in human limbs, suggests that intravascular ATP exerts its vasodilator and sympatholytic effects directly, and not via its degradation compounds. In conclusion, current evidence clearly indicates that RBCs are involved directly in the regulation of O(2) supply to human skeletal muscle during dynamic exercise. Further, intravascular ATP might be an important mediator in local metabolic sensing and signal transduction between the RBCs and the endothelial and smooth muscle cells in the vascular beds of skeletal muscle.

Alpha‐adrenergic regulation of muscle, adipose tissue and bone blood flow at rest and during exercise in humans

Positron emission tomography allows for determination of muscle and tissue‐specific blood flow in humans. Since hamstrings remain inactive during one leg exercise performed by knee extensors, the technique and model provide an opportunity to elucidate the role of nervous control of blood flow in the exercising limb in humans. Here we measured muscle and tissue‐specific blood flow in nine healthy young men under the femoral arterial infusions of norepinephrine (NE) and phentolamine. At rest, NE reduced blood flow by ~40% similarly in all muscles and in bone and adipose tissue. During exercise, NE reduced exercising muscle blood flow by 16%, but did not affect inactive muscle blood flow. Bone blood flow was not affected by NE, but blood flow in adipose tissue was reduced similarly as at rest. Phentolamine elevated blood flow similarly in different muscles and tissues of the limb at rest (by 3.5–6‐fold), and during exercise, the ratio of active‐to‐inactive muscle blood flow reduced from 18.3 ± 10.7 at control to 5.3 ± 4.0 during phentolamine, since blood flow in inactive muscles increased 3.4‐fold, but blood flow in exercising muscle remained essentially comparable to control exercise. In conclusion, the major novel finding here is that the release of á‐adrenergic tone markedly disturbs the distribution of blood flow in exercising human limb by elevating flow especially around inactive muscle fibers.

Two weeks of muscle immobilization impairs functional sympatholysis but increases exercise hyperemia and the vasodilatory responsiveness to infused ATP

During exercise, contracting muscles can override sympathetic vasoconstrictor activity (functional sympatholysis). ATP and adenosine have been proposed to play a role in skeletal muscle blood flow regulation. However, little is known about the role of muscle training status on functional sympatholysis and ATP- and adenosine-induced vasodilation. Eight male subjects (22 ± 2 yr, Vo(2max): 49 ± 2 ml O(2)·min(-1)·kg(-1)) were studied before and after 5 wk of one-legged knee-extensor training (3-4 times/wk) and 2 wk of immobilization of the other leg. Leg hemodynamics were measured at rest, during exercise (24 ± 4 watts), and during arterial ATP (0.94 ± 0.03 μmol/min) and adenosine (5.61 ± 0.03 μmol/min) infusion with and without coinfusion of tyramine (11.11 μmol/min). During exercise, leg blood flow (LBF) was lower in the trained leg (2.5 ± 0.1 l/min) compared with the control leg (2.6 ± 0.2 l/min; P < 0.05), and it was higher in the immobilized leg (2.9 ± 0.2 l/min; P < 0.05). Tyramine infusion lowers LBF similarly at rest, but, when tyramine was infused during exercise, LBF was blunted in the immobilized leg (2.5 ± 0.2 l/min; P < 0.05), whereas it was unchanged in the control and trained leg. Mean arterial pressure was lower during exercise with the trained leg compared with the immobilized leg (P < 0.05), and leg vascular conductance was similar. During ATP infusion, the LBF response was higher after immobilization (3.9 ± 0.3 and 4.5 ± 0.6 l/min in the control and immobilized leg, respectively; P < 0.05), whereas it did not change after training. When tyramine was coinfused with ATP, LBF was reduced in the immobilized leg (P < 0.05) but remained similar in the control and trained leg. Training increased skeletal muscle P2Y2 receptor content (P < 0.05), whereas it did not change with immobilization. These results suggest that muscle inactivity impairs functional sympatholysis and that the magnitude of hyperemia and blood pressure response to exercise is dependent on the training status of the muscle. Immobilization also increases the vasodilatory response to infused ATP.

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.

Ageing uncompensated: exercise, nitric oxide and hypoxia

Ageing uncompensated: exercise, nitric oxide and hypoxia

Not a fine wine: the ATP hypothesis may not get better with age

Not a fine wine: the ATP hypothesis may not get better with age

Comfortable at just below your critical speed: how is blood flow distribution coupled to muscle fibre recruitment during exercise?

Comfortable at just below your critical speed: how is blood flow distribution coupled to muscle fibre recruitment during exercise?