Joshua J. Sebranek

Opioid‐mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans

We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development of peripheral fatigue during high‐intensity endurance exercise. In a double‐blind, placebo‐controlled design, eight cyclists randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5KPlac, L3–L4) or intrathecal fentanyl (5KFent, L3–L4) to impair cortical projection of opioid‐mediated muscle afferents. Peripheral quadriceps fatigue was assessed via changes in force output pre‐ versus postexercise in response to supramaximal magnetic femoral nerve stimulation (ΔQtw). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5KFentversus 5KPlac by 12 ± 3% (P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 ± 2% higher during the first and 11 ± 2% lower during the second 2.5 km of 5KFentversus 5KPlac (both P < 0.05). Capillary blood lactate was higher (16.3 ± 0.5 versus 12.6 ± 1.0%) and arterial haemoglobin O2 saturation was lower (89 ± 1 versus 94 ± 1%) during 5KFentversus 5KPlac. Exercise‐induced ΔQtw was greater following 5KFentversus 5KPlac (−46 ± 2 versus−33 ± 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive development of peripheral muscle fatigue.

Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans

We investigated the role of somatosensory feedback on cardioventilatory responses to rhythmic exercise in five men. In a double-blind, placebo-controlled design, subjects performed the same leg cycling exercise (50/100/150/325 ± 19 W, 3 min each) under placebo conditions (interspinous saline, L(3)-L(4)) and with lumbar intrathecal fentanyl impairing central projection of spinal opioid receptor-sensitive muscle afferents. Quadriceps strength was similar before and after fentanyl administration. To evaluate whether a cephalad migration of fentanyl affected cardioventilatory control centers in the brain stem, we compared resting ventilatory responses to hypercapnia (HCVR) and cardioventilatory responses to arm vs. leg cycling exercise after each injection. Similar HCVR and minor effects of fentanyl on cardioventilatory responses to arm exercise excluded direct medullary effects of fentanyl. Central command during leg exercise was estimated via quadriceps electromyogram. No differences between conditions were found in resting heart rate (HR), ventilation [minute ventilation (VE)], or mean arterial pressure (MAP). Quadriceps electromyogram, O(2) consumption (VO(2)), and plasma lactate were similar in both conditions at the four steady-state workloads. Compared with placebo, a substantial hypoventilation during fentanyl exercise was indicated by the 8-17% reduction in VE/CO(2) production (VCO(2)) secondary to a reduced breathing frequency, leading to average increases of 4-7 Torr in end-tidal PCO(2) (P < 0.001) and a reduced hemoglobin saturation (-3 ± 1%; P < 0.05) at the heaviest workload (∼90% maximal VO(2)) with fentanyl. HR was reduced 2-8%, MAP 8-13%, and ratings of perceived exertion by 13% during fentanyl vs. placebo exercise (P < 0.05). These findings demonstrate the essential contribution of muscle afferent feedback to the ventilatory, cardiovascular, and perceptual responses to rhythmic exercise in humans, even in the presence of unaltered contributions from other major inputs to cardioventilatory control.

Implications of group III and IV muscle afferents for high‐intensity endurance exercise performance in humans

Non‐Technical Summary  We investigated the influence of group III/IV muscle afferents on central motor drive, the development of peripheral locomotor muscle fatigue, and endurance performance time during high‐intensity constant‐load cycling exercise to exhaustion. Our findings suggest that, on the one hand, afferent feedback ensures adequate circulatory and ventilatory responses to exercise which optimizes muscle O2 transport and thereby facilitates exercise performance by preventing premature peripheral fatigue. On the other hand, afferent feedback inhibits central motor drive, which is reflected in the restriction of the neural excitation of the locomotor musculature and the reduced tolerance for peripheral muscle fatigue, and thereby limits exercise performance. Taken together, the current investigation revealed the net effects of sensory afferent feedback on time to exhaustion during high‐intensity constant‐load cycling exercise and showed that intact group III/IV muscle afferent feedback is a vital component in achieving optimal endurance performance.

Somatosensory feedback from the limbs exerts inhibitory influences on central neural drive during whole body endurance exercise

We investigated whether somatosensory feedback from contracting limb muscles exerts an inhibitory influence on the determination of central command during closed-loop cycling exercise in which the subject voluntarily determines his second-by-second central motor drive. Eight trained cyclists performed two 5-km time trials either without (5K(Ctrl)) or with lumbar epidural anesthesia (5K(Epi); 24 ml of 0.5% lidocaine, vertebral interspace L(3)-L(4)). Percent voluntary quadriceps muscle activation was determined at rest using a superimposed twitch technique. Epidural lidocaine reduced pretime trial maximal voluntary quadriceps strength (553 +/- 45 N) by 22 +/- 3%. Percent voluntary quadriceps activation was also reduced from 97 +/- 1% to 81 +/- 3% via epidural lidocaine, and this was unchanged following the 5K(Epi), indicating the presence of a sustained level of neural impairment throughout the trial. Power output was reduced by 9 +/- 2% throughout the race (P < 0.05). We found three types of significant effects of epidural lidocaine that supported a substantial role for somatosensory feedback from the exercising limbs as a determinant of central command throughout high-intensity closed-loop cycling exercise: 1) significantly increased relative integrated EMG of the vastus lateralis; 2) similar pedal forces despite the reduced number of fast-twitch muscle fibers available for activation; 3) and increased ventilation out of proportion to a reduced carbon dioxide production and heart rate and increased blood pressure out of proportion to power output and oxygen consumption. These findings demonstrate the inhibitory influence of somatosensory feedback from contracting locomotor muscles on the conscious and/or subconscious determination of the magnitude of central motor drive during high intensity closed-loop endurance exercise.

α-Adrenergic control of blood flow during exercise: effect of sex and menstrual phase

Sex differences exist in autonomic control of the cardiovascular system. This study was designed to directly test sex or female menstrual phase-related differences in α-adrenergic control of blood flow during exercise. We hypothesized that women would exhibit reduced α-adrenergic vasoconstriction compared with men during exercise; in addition, women would constrict less during the early luteal than the early follicular phase of the female menses. Young men (n = 10) were studied once and women (n = 9) studied twice, once during the early follicular phase and once during the early luteal phase of female menses. We measured forearm blood flow (FBF; Doppler ultrasound of the brachial artery) during rest and steady-state dynamic exercise (15 and 30% of maximal voluntary contraction, 20 contractions/min). A brachial artery catheter was inserted for the local administration of α-adrenergic agonists [phenylephrine (PE; α(1)) or clonidine (CL; α(2))]. Blood flow responses to exercise [forearm vascular conductance (FVC)] were similar between all groups. At rest, infusion of PE or CL decreased FVC in all groups (40-60% reduction). Vasoconstriction to PE was abolished in all groups at 15 and 30% exercise intensity. Vasoconstriction to CL was reduced at 15% and abolished at 30% intensity in all groups; women had less CL-induced constriction during the early luteal than early follicular phase (P < 0.017, 15% intensity). These results indicate that vasodilator responses to forearm exercise are comparable between men and women and are achieved through similar paths of α-adrenergic vascular control at moderate intensities; this control may differ at low intensities specific to the female menstrual phase.

Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress

Older adults with cardiovascular disease exhibit microvascular dysfunction and increased levels of reactive oxygen species (ROS). We hypothesized that microvascular impairments begin early in the disease process and can be improved by scavenging ROS. Forearm blood flow (Doppler ultrasound) was measured in 45 young (32 ± 2 yr old) adults (n = 15/group) classified as lean, obese, and metabolic syndrome (MetSyn). Vasodilation in response to endothelial (ACh) and vascular smooth muscle [nitroprusside (NTP) and epoprostenol (Epo)] agonists was tested before and after intra-arterial infusion of ascorbic acid to scavenge ROS. Vasodilation was assessed as a rise in relative vascular conductance (ml·min(-1)·dl(-1)·100 mmHg(-1)). ACh and NTP responses were preserved (P = 0.825 and P = 0.924, respectively), whereas Epo responses were lower in obese and MetSyn adults (P < 0.05) than in lean controls. Scavenging of ROS via infusion of ascorbic acid resulted in an increase in ACh-mediated (P < 0.001) and NTP-mediated (P < 0.001) relative vascular conductance across all groups, suggesting that oxidative stress influences vascular responsiveness in adults with and without overt cardiovascular disease risk. Ascorbic acid had no effect on Epo-mediated vasodilation (P = 0.267). These results suggest that obese and MetSyn adults exhibit preserved endothelium-dependent vasodilation with reduced dependence on prostacyclin and are consistent with an upregulation of compensatory vascular control mechanisms.

Altered neurovascular control of the resting circulation in human metabolic syndrome

•  Young healthy adults exhibit a balance between muscle sympathetic nerve activity (MSNA) and α‐adrenergic‐mediated vasoconstriction such that those with higher MSNA exhibit lower vascular‐adrenergic responsiveness. •  In contrast to healthy adults, the balance between MSNA and α1‐adrenergic‐mediated vasoconstriction is lost in adults with metabolic syndrome. In addition, adults with metabolic syndrome exhibit increased α2‐adrenergic responsiveness. •  This study uncovered some of the earliest sympathetic–haemodynamic changes in the progression from metabolic syndrome to cardiovascular disease and diabetes. •  Considering metabolic syndrome subjects were relatively young and free of overt cardiovascular disease, it is reasonable to speculate as the disease progresses the observed uncoupling between MSNA and α‐adrenergic responsiveness may lead to reduced whole‐limb blood flow, altered blood flow distribution, reduced glucose delivery and/or increased hypertension severity.

Neural control of blood flow during exercise in human metabolic syndrome.

What is the central question of this study? α‐Adrenergic‐mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome when compared with control animals. Whether such findings can be translated to humans was previously unexamined. What is the main finding and its importance? We observed greater muscle sympathetic nerve activity and clonidine‐mediated vasoconstriction in adults with metabolic syndrome, yet preserved exercise blood flow when compared with age‐matched healthy control subjects. These results suggest that adults with metabolic syndrome exhibit compensatory vascular control mechanisms capable of counteracting altered adrenergic responsiveness, thus preserving blood flow responses to low‐intensity, dynamic hand‐grip exercise.

β-Adrenergic-mediated vasodilation in young men and women: Cyclooxygenase restrains nitric oxide synthase

We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P < 0.01), and this effect was not different between men and women (P = 0.41). l-NMMA infusion had no effect on isoproterenol-mediated dilation in men (P > 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P < 0.01) and women (P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). β-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.

Greater Beta-Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives

Background: β-adrenergic receptors play an important role in mitigating the pressor effects of sympathetic nervous system activity in young women. Based on recent data showing oral contraceptive use in women abolishes the relationship between muscle sympathetic nervous system activity and blood pressure, we hypothesized forearm blood flow responses to a β-adrenergic receptor agonist would be greater in young women currently using oral contraceptives (OC+, n = 13) when compared to those not using oral contraceptives (OC–, n = 10). Methods: Women (18–35 years) were studied during the early follicular phase of the menstrual cycle (days 1–5) or placebo phase of oral contraceptive use. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured at baseline and during graded brachial artery infusion of the β-adrenergic receptor agonist, Isoproterenol (ISO), as well as Acetylcholine (ACH, endothelium-dependent vasodilation) and Nitroprusside (NTP, endothelium-independent vasodilation). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100 mmHg) and the rise in FVC from baseline during infusion quantified vasodilation (ΔFVC = FVCinfusion − FVCbaseline). Results: ISO increased FVC in both groups (p < 0.01) and ISO-mediated ΔFVC was greater in OC+ compared to OC– (Main effect of group, p = 0.02). Expressing data as FVC and FBF resulted in similar conclusions. FVC responses to both ACH and NTP were also greater in OC+ compared to OC–. Conclusions: These data are the first to demonstrate greater β-adrenergic receptor-mediated vasodilation in the forearm of women currently using oral contraceptives (placebo phase) when compared to those not using oral contraceptives (early follicular phase), and suggest oral contraceptive use influences neurovascular control.