Key pointsr We aimed to elucidate the role of group III/IV locomotor muscle afferents in the development of central fatigue and the responsiveness of the corticospinal tract in relation to an unexercised arm muscle.r Intrathecal fentanyl, a μ-opioid receptor agonist, was employed to attenuate afferent feedback from the leg muscles during intense cycling exercise characterized by either no or severe peripheral locomotor muscle fatigue.r In the absence of locomotor muscle fatigue, group III/IV-mediated leg afferent feedback facilitates the responsiveness of the motor pathway to upper limb flexor muscles.r By contrast, in the presence of leg fatigue, group III/IV locomotor muscle afferents facilitate supraspinal fatigue in a remote muscle not involved in the exercise and disfacilitate the responsiveness of associated corticospinal projections. AbstractWe investigated the influence of group III/IV lower limb muscle afferents on the development of supraspinal fatigue and the responsiveness of corticospinal projections to an arm muscle. Eight males performed constant-load leg cycling exercise (80% peak power output) for 30 s (non-fatiguing) and to exhaustion (ß9 min; fatiguing) both under control conditions and with lumbar intrathecal fentanyl impairing feedback from μ-opioid receptor-sensitive lower limb muscle afferents. Voluntary activation (VA) of elbow flexors was assessed via transcranial magnetic stimulation (TMS) during maximum voluntary contraction (MVC) and corticospinal responsiveness was monitored via TMS-evoked potentials (MEPs) during a 25% MVC. Accompanied by a significant 5 ± 1% reduction in VA from pre-to post-exercise, elbow flexor MVC progressively decreased during the fatiguing trial (P < 0.05). By contrast, with attenuated feedback from locomotor muscle afferents, MVC and VA remained unchanged during fatiguing exercise (P > 0.3). MEPs decreased by 36 ± 6% (P < 0.05) from the start of exercise to exhaustion under control conditions, but this reduction was prevented with fentanyl blockade. Furthermore, fentanyl blockade prevented the significant increase in elbow flexor MEP observed from rest to non-fatiguing exercise under control conditions and resulted in a 14% lower corticospinal responsiveness during this short bout (P < 0.05). Taken together, in the absence of locomotor muscle fatigue, group III/IV-mediated leg muscle afferents facilitate responsiveness of the motor pathway to upper limb flexor muscles. By contrast, in the presence of cycling-induced leg fatigue, group III/IV locomotor muscle afferents facilitate supraspinal fatigue in remote muscle not involved in the exercise and disfacilitate, or inhibit, the responsiveness of corticospinal projections to upper limb muscles.

Key points• Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC) without a concomitant increase in skeletal muscle metabolism.• The peripheral vascular mechanisms associated with the increase in LBF and LVC are unknown.• Using an intra-arterial infusion of N G -monomethyl-L-arginine (L-NMMA) to inhibit nitric oxide synthase (NOS) the hyperaemic and vasodilatory response to passive limb movement was attenuated by nearly 80%.• This finding demonstrates that the increases in LBF and LVC during passive limb movement are primarily NO dependent.• Passive limb movement appears to have significant promise as a new approach to assess NO-mediated vascular function, an important predictor of cardiovascular disease risk.Abstract Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC), but the peripheral vascular mechanisms associated with this increase in LBF and LVC are unknown. This study sought to determine the contribution of nitric oxide (NO) to movement-induced LBF and LVC and document the potential for passive-limb movement to assess NO-mediated vasodilatation and therefore NO bioavailability. Six subjects underwent passive knee extension with and without nitric oxide synthase (NOS) inhibition via intra-arterial infusion of N G -monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central haemodynamics were measured by finger photoplethysmography. Although L-NMMA did not alter the immediate increase (initial ∼9 s) in LBF and LVC, NOS blockade attenuated the peak increase in LBF (control: 653 ± 81; L-NMMA: 399 ± 112 ml −1 min −1 , P = 0.03) and LVC (control: 7.5 ± 0.8; L-NMMA: 4.1 ± 1.1 ml min −1 mmHg −1 , P = 0.02) and dramatically reduced the overall vasodilatory and hyperaemic response (area under the curve) by nearly 80% (LBF: control: 270 ± 51; L-NMMA: 75 ± 32 ml, P = 0.001; LVC: control: 2.9 ± 0.5; L-NMMA: 0.8 ± 0.3 ml mmHg −1 , P < 0.001). Passive movement in control and L-NMMA trials evoked similar increases in heart rate, stroke volume, cardiac output and a reduction in mean arterial pressure. As movement-induced increases in LBF and LVC are predominantly NO dependent, passive limb movement appears to have significant promise as a new approach to assess NO-mediated vascular function, an important predictor of cardiovascular disease risk.

Objective To better understand the hemodynamic and autonomic reflex abnormalities in heart-failure patients (HF), we investigated the influence of group III/IV muscle afferents on their cardiovascular response to rhythmic exercise. Methods Nine HF-patients (NYHA class-II, mean left ventricular ejection-fraction: 27±3%) performed single leg knee-extensor exercise (25/50/80% peak-workload) under control conditions and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. Results Cardiac-output (Q) and femoral blood-flow (QL) were determined, and arterial/venous blood samples collected at each workload. Exercise-induced fatigue was estimated via pre/post-exercise changes in quadriceps strength. There were no hemodynamic differences between conditions at rest. During exercise, Q was 8–13% lower with Fentanyl-blockade, secondary to significant reductions in stroke volume and heart rate. Lower norepinephrine spillover during exercise with Fentanyl revealed an attenuated sympathetic outflow that likely contributed to the 25% increase in leg vascular conductance (p<0.05). Despite a concomitant 4% reduction in blood pressure, QL was 10–14% higher and end-exercise fatigue attenuated by 30% with Fentanyl-blockade (p<0.05). Conclusion/Practice/Implications Although group III/IV muscle afferents play a critical role for central hemodynamics in HF-patients, it also appears that these sensory neurons cause excessive sympatho-excitation impairing QL which likely contributes to the exercise intolerance in this population.

251 ± 92 Δml/min; P = 0.59). Likewise, the magnitude of the reduction in the overall (i.e., area under the curve) PLM-induced LBF response to NOS inhibition was less in the old (LBF: -31 ± 18 ml) than the young (LBF: -129 ± 21 ml; P < 0.01). These findings suggest that the age-associated reduction in PLM-induced LBF in the elderly is primarily due to a reduced contribution to vasodilation from NO and therefore support the use of PLM as a novel approach to assess NO-mediated vascular function across the lifespan.

The endothelin-1 vasoconstrictor pathway contributes to age-related elevations in resting peripheral vascular tone primarily through activation of the endothelin subtype A (ET(A)) receptor. However, the regulatory influence of ET(A)-mediated vasoconstriction during exercise in the elderly is unknown. Thus, in 17 healthy volunteers (n = 8 young, 24±2 years; n = 9 old, 70±2 years), we examined leg blood flow, mean arterial pressure, leg arterial-venous oxygen (O2) difference, and leg O2 consumption (VO2) at rest and during knee-extensor exercise before and after intra-arterial administration of the ET(A) antagonist BQ-123. During exercise, BQ-123 administration increased leg blood flow to a greater degree in the old (+29±5 mL/min/W) compared with the young (+16±3 mL/min/W). The increase in leg blood flow with BQ-123 was accompanied by an increase in leg VO2 in both groups, suggesting a reduced efficiency following ET(A) receptor blockade. Together, these findings have identified an age-related increase in ET(A)-mediated vasoconstrictor activity that persists during exercise, suggesting an important role of this pathway in the regulation of exercising skeletal muscle blood flow and maintenance of arterial blood pressure in the elderly.