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Exercise hyperaemia is regulated by several factors, and one factor known to increase with exercise that evokes a powerful vasomotor action is extracellular ATP. The origin of ATP detected in plasma from exercising muscle of humans is, however, a matter of debate, and ATP has been suggested to arise from sympathetic nerves, blood sources (e.g. erythrocytes), endothelial cells and skeletal myocytes, among others. Therefore, we tested the hypothesis that acute augmentation of sympathetic nervous system activity (SNA) results in elevated plasma ATP draining skeletal muscle, and that SNA superimposition during exercise increases ATP more than exercise alone. We showed that increased SNA via -40 mmHg lower body negative pressure (LBNP) at rest did not increase plasma ATP (51±8 nmol l(-1) at rest versus 58±7 nmol l(-1) with LBNP), nor did it increase [ATP] above levels observed during rhythmic hand-grip exercise (79±11 nmol l(-1) with exercise alone versus 71±8 nmol l(-1) with LBNP). Next, we tested the hypothesis that active perfusion of skeletal muscle is essential to observe increased plasma ATP during exercise. We showed that complete obstruction of blood flow to contracting muscle abolished exercise-mediated increases in plasma ATP (from 90±19 to 49±12 nmol l(-1)), and that cessation of blood flow prior to exercise completely inhibited the typical rise in ATP (3 versus 61%, obstructed versus intact perfusion). The lack of change in ATP during occlusion occurred in the face of continued muscular work and elevated SNA, indicating that the rise of intravascular ATP did not result from these extravascular sources. Our collective observations indicated that the elevation in extracellular ATP observed in blood during exercise was unlikely to originate from sympathetic nerves or the contacting muscle itself, but rather was dependent on intact skeletal muscle perfusion. We conclude that an intravascular source for ATP is essential, which indicates an important role for blood sources (e.g. red blood cells) in augmenting and maintaining elevated plasma ATP during exercise.

We tested the hypothesis that, among conditions of matched contractile work, shorter contraction durations and greater muscle fibre recruitment result in augmented skeletal muscle blood flow and oxygen consumption ( ) during steady-state exercise in humans. To do so, we measured forearm blood flow (FBF; Doppler ultrasound) during 4 min of rhythmic hand-grip exercise in 24 healthy young adults and calculated forearm oxygen consumption ( ) via blood samples obtained from a catheter placed in retrograde fashion into a deep vein draining the forearm muscle. In protocol 1 (n = 11), subjects performed rhythmic isometric hand-grip exercise at mild and moderate intensities during conditions in which time-tension index (isometric analogue of work) was held constant but contraction duration was manipulated. In this protocol, shorter contraction durations led to greater FBF (184 ± 25 versus 164 ± 25 ml min(-1)) and (23 ± 3 versus 17 ± 2 ml min(-1); both P < 0.05) among mild workloads, whereas this was not the case for moderate-intensity exercise. In protocol 2 (n = 13), subjects performed rhythmic dynamic hand-grip exercise at mild and moderate intensities in conditions of matched total work, but muscle fibre recruitment was manipulated. In this protocol, greater muscle fibre recruitment led to significantly greater FBF (152 ± 15 versus 127 ± 13 ml min(-1)) and (20 ± 2 versus 17 ± 2 ml min(-1); both P < 0.05) at mild workloads, and there was a trend for similar responses at the moderate intensity but this was not statistically significant. In both protocols, the ratio of the change in FBF to change in was similar across all exercise intensities and manipulations, and the strongest correlation among all variables was between and blood flow. Our collective data indicate that, among matched workloads, shorter contraction duration and greater muscle fibre recruitment augment FBF and during mild-intensity forearm exercise, and that muscle blood flow is more closely related to metabolic cost ( ) rather than contractile work per se during steady-state exercise in humans.

Skeletal muscle haemodynamics and circulating adenosine triphosphate (ATP) responses during hypoxia and exercise are blunted in older (OA) vs. young (YA) adults, which may be associated with impaired red blood cell (RBC) ATP release. Rho‐kinase inhibition improves deoxygenation‐induced ATP release from OA isolated RBCs. We tested the hypothesis that Rho‐kinase inhibition (via fasudil) in vivo would improve local haemodynamic and ATP responses during hypoxia and exercise in OA. Healthy YA (25 ± 3 years; n = 12) and OA (65 ± 5 years; n = 13) participated in a randomized, double‐blind, placebo‐controlled, crossover study on two days (≥5 days between visits). A forearm deep venous catheter was used to administer saline/fasudil and sample venous plasma ATP ([ATP]V). Forearm vascular conductance (FVC) and [ATP]V were measured at rest, during isocapnic hypoxia (80% SpO2${S_{{\rm{p}}{{\rm{O}}_{\rm{2}}}}}$), and during graded rhythmic handgrip exercise that was similar between groups (5, 15 and 25% maximum voluntary contraction (MVC)). Isolated RBC ATP release was measured during normoxia/hypoxia. With saline, ΔFVC was lower (P < 0.05) in OA vs. YA during hypoxia (∼60%) and during 15 and 25% MVC (∼25–30%), and these impairments were abolished with fasudil. Similarly, [ATP]V and ATP effluent responses from normoxia to hypoxia and rest to 25% MVC were lower in OA vs. YA and improved with fasudil (P < 0.05). Isolated RBC ATP release during hypoxia was impaired in OA vs. YA (∼75%; P < 0.05), which tended to improve with fasudil in OA (P = 0.082). These data suggest Rho‐kinase inhibition improves haemodynamic responses to hypoxia and moderate intensity exercise in OA, which may be due in part to improved circulating ATP. Key points: Skeletal muscle blood flow responses to hypoxia and exercise are impaired with age. Blunted increases in circulating ATP, a vasodilator, in older adults may contribute to age‐related impairments in haemodynamics.Red blood cells (RBCs) are a primary source of circulating ATP, and treating isolated RBCs with a Rho‐kinase inhibitor improves age‐related impairments in deoxygenation‐induced RBC ATP release.In this study, treating healthy older adults systemically with the Rho‐kinase inhibitor fasudil improved blood flow and circulating ATP responses during hypoxia and moderate intensity handgrip exercise compared to young adults, and also tended to improve isolated RBC ATP release.Improved blood flow regulation with fasudil was also associated with increased skeletal muscle oxygen delivery during hypoxia and exercise in older adults.This is the first study to demonstrate that Rho‐kinase inhibition can significantly improve age‐related impairments in haemodynamic and circulating ATP responses to physiological stimuli, which may have therapeutic implications. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a paper published in "The Journal of Physiology," which determined the cardiovascular response to graded knee-extensor exercise while limiting skeletal muscle afferent feedback using a novel technique.