RESUMO
On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11-L2) and anode (L3-L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons.NEW & NOTEWORTHY We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity.
Assuntos
Hipertonia Muscular , Traumatismos da Medula Espinal , Vértebras Torácicas , Humanos , Perna (Membro)/fisiopatologia , Hipertonia Muscular/fisiopatologia , Hipertonia Muscular/etiologia , Hipertonia Muscular/terapia , Músculo Esquelético/fisiopatologia , Pele/inervação , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/complicações , Raízes Nervosas Espinhais/fisiopatologia , Raízes Nervosas Espinhais/fisiologia , Estimulação Elétrica Nervosa Transcutânea/métodosRESUMO
We investigated the role of the exercise pressor reflex (EPR) in regulating the haemodynamic response to locomotor exercise. Eight healthy participants (23 ± 3 years, V Ì O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ : 49 ± 6 ml/kg/min) performed constant-load cycling exercise (â¼36/43/52/98% V Ì O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ; 4 min each) without (CTRL) and with (FENT) lumbar intrathecal fentanyl attenuating group III/IV locomotor muscle afferent feedback and, thus, the EPR. To avoid different respiratory muscle metaboreflex and arterial chemoreflex activation during FENT, subjects mimicked the ventilatory response recorded during CTRL. Arterial and leg perfusion pressure (femoral arterial and venous catheters), femoral blood flow (Doppler-ultrasound), microvascular quadriceps blood flow index (indocyanine green), cardiac output (inert gas breathing), and systemic and leg vascular conductance were quantified during exercise. There were no cardiovascular and ventilatory differences between conditions at rest. Pulmonary ventilation, arterial blood gases and oxyhaemoglobin saturation were not different during exercise. Furthermore, cardiac output (-2% to -12%), arterial pressure (-7% to -15%) and leg perfusion pressure (-8% to -22%) were lower, and systemic (up to 16%) and leg (up to 27%) vascular conductance were higher during FENT compared to CTRL. Leg blood flow, microvascular quadriceps blood flow index, and leg O2 -transport and utilization were not different between conditions (P > 0.5). These findings reflect a critical role of the EPR in the autonomic control of the heart, vasculature and, ultimately, arterial pressure during locomotor exercise. However, the lack of a net effect of the EPR on leg blood flow challenges the idea of this cardiovascular reflex as a key determinant of leg O2 -transport during locomotor exercise in healthy, young individuals. KEY POINTS: The role of the exercise pressor reflex (EPR) in regulating leg O2 -transport during human locomotion remains uncertain. We investigated the influence of the EPR on the cardiovascular response to cycling exercise. Lumbar intrathecal fentanyl was used to block group III/IV leg muscle afferents and debilitate the EPR at intensities ranging from 30% to 100% V Ì O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . To avoid different respiratory muscle metaboreflex and arterial chemoreflex activation during exercise with blocked leg muscle afferents, subjects mimicked the ventilatory response recorded during control exercise. Afferent blockade increased leg and systemic vascular conductance, but reduced cardiac output and arterial-pressure, with no net effect on leg blood flow. The EPR influenced the cardiovascular response to cycling exercise by contributing to the autonomic control of the heart and vasculature, but did not affect leg blood flow. These findings challenge the idea of the EPR as a key determinant of leg O2 -transport during locomotor exercise in healthy, young individuals.
Assuntos
Perna (Membro) , Músculo Esquelético , Masculino , Humanos , Perna (Membro)/irrigação sanguínea , Músculo Esquelético/fisiologia , Reflexo , Fentanila , Vasoconstritores/farmacologia , PerfusãoRESUMO
The role played by the transient receptor potential vanilloid 1 (TRPV1) channel on the thin fibre afferents evoking the exercise pressor reflex is controversial. To shed light on this controversy, we compared the exercise pressor reflex between newly developed TRPV1+/+ , TRPV1+/- and TRPV1-/- rats. Carotid arterial injection of capsaicin (0.5 µg), evoked significant pressor responses in TRPV1+/+ and TRPV1+/- rats, but not in TRPV1-/- rats. In acutely isolated dorsal root ganglion neurons innervating the gastrocnemius muscles, capsaicin evoked inward currents in neurons isolated from TRPV1+/+ and TRPV1+/- rats but not in neurons isolated from TRPV1-/- rats. The reflex was evoked by stimulating the tibial nerve in decerebrated rats whose femoral artery was either freely perfused or occluded. We found no difference between the reflex in the three groups of rats regardless of the patency of the femoral artery. For example, the peak pressor responses to contraction in TRPV1+/+ , TRPV1+/- and TRPV1-/- rats with patent femoral arteries averaged 17.1 ± 7.2, 18.9 ± 12.4 and 18.4 ± 8.6 mmHg, respectively. Stimulation of the tibial nerve after paralysis with pancuronium had no effect on arterial pressure, findings which indicated that the pressor responses to contraction were not caused by electrical stimulation of afferent tibial nerve axons. We also found that expression levels of acid-sensing ion channel 1 and endoperoxide 4 receptor in the L4 and 5 dorsal root ganglia were not upregulated in the TRPV1-/- rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex in rats whose contracting muscles have either a patent or an occluded arterial blood supply. KEY POINTS: A reflex arising in contracting skeletal muscle contributes to the increases in arterial blood pressure, cardiac output and breathing evoked by exercise. The sensory arm of the reflex comprises both mechanoreceptors and metaboreceptors, of which the latter signals that blood flow to exercising muscle is not meeting its metabolic demand. The nature of the channel on the metaboreceptor sensing a mismatch between supply and demand is controversial; some believe that it is the transient receptor potential vanilloid 1 (TRPV1) channel. Using genetically engineered rats in which the TRPV1 channel is rendered non-functional, we have shown that it is not needed to evoke the metaboreflex.
Assuntos
Capsaicina , Canais de Potencial de Receptor Transitório , Animais , Ratos , Pressão Sanguínea , Capsaicina/farmacologia , Artéria Femoral/metabolismo , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Ratos Sprague-Dawley , Reflexo/fisiologia , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
Mechanical distortion of working skeletal muscle induces sympathoexcitation via thin fibre afferents, a reflex response known as the skeletal muscle mechanoreflex. However, to date, the receptor ion channels responsible for mechanotransduction in skeletal muscle remain largely undetermined. Transient receptor potential vanilloid 4 (TRPV4) is known to sense mechanical stimuli such as shear stress or osmotic pressure in various organs. It is hypothesized that TRPV4 in thin-fibre primary afferents innervating skeletal muscle is involved in mechanotransduction. Fluorescence immunostaining revealed that 20.1 ± 10.1% of TRPV4 positive neurons were small dorsal root ganglion (DRG) neurons that were DiI-labelled, and among them 9.5 ± 6.1% of TRPV4 co-localized with the C-fibre marker peripherin. In vitro whole-cell patch clamp recordings from cultured rat DRG neurons demonstrated that mechanically activated current amplitude was significantly attenuated after the application of the TRPV4 antagonist HC067047 compared to control (P = 0.004). Such reductions were also observed in single-fibre recordings from a muscle-nerve ex vivo preparation where HC067047 significantly decreased afferent discharge to mechanical stimulation (P = 0.007). Likewise, in an in vivo decerebrate rat preparation, the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch of hindlimb muscle were significantly reduced by intra-arterial injection of HC067047 (ΔRSNA: P = 0.019, ΔMAP: P = 0.002). The findings suggest that TRPV4 plays an important role in mechanotransduction contributing to the cardiovascular responses evoked by the skeletal muscle mechanoreflex during exercise. KEY POINTS: Although a mechanical stimulus to skeletal muscle reflexively activates the sympathetic nervous system, the receptors responsible for mechanotransduction in skeletal muscle thin fibre afferents have not been fully identified. Evidence suggests that TRPV4 is a mechanosensitive channel that plays an important role in mechanotransduction within various organs. Immunocytochemical staining demonstrates that TRPV4 is expressed in group IV skeletal muscle afferents. In addition, we show that the TRPV4 antagonist HC067047 decreases the responsiveness of thin fibre afferents to mechanical stimulation at the muscle tissue level as well as at the level of dorsal root ganglion neurons. Moreover, we demonstrate that intra-arterial HC067047 injection attenuates the sympathetic and pressor responses to passive muscle stretch in decerebrate rats. These data suggest that antagonism of TRPV4 attenuates mechanotransduction in skeletal muscle afferents. The present study demonstrates a probable physiological role for TRPV4 in the regulation of mechanical sensation in somatosensory thin fibre muscle afferents.
Assuntos
Canais de Cátion TRPV , Canais de Potencial de Receptor Transitório , Ratos , Animais , Canais de Cátion TRPV/metabolismo , Ratos Sprague-Dawley , Mecanotransdução Celular , Músculo Esquelético/fisiologia , Reflexo/fisiologia , Contração Muscular/fisiologia , Pressão Sanguínea/fisiologiaRESUMO
Male and female rats differ in muscle fibre composition, related motor unit contractile properties, and muscle spindle density but not number. On the other hand, their motoneurons' intrinsic properties, excitability and firing properties are similar. The aim of this study was to investigate whether apparent sex differences in body mass and muscle force influence the proprioceptive input from muscle spindles to motoneurons. Medial gastrocnemius motoneurons were investigated intracellularly in deeply anaesthetised male and female rats. Monosynaptic Ia excitatory postsynaptic potentials (EPSPs) were evoked using electrical stimulation of primary afferents from homonymous muscle. Data were analysed using a mixed linear model. The central latencies of EPSPs were 0.38-0.80 ms, with no differences in means between males and females. The maximum EPSP amplitude varied between 2.03 and 8.09 mV in males and 1.24 and 6.79 mV in females. The mean maximum EPSP amplitude was 26% higher in males than in females. The mean EPSP rise time, half-decay time and total duration did not differ between the sexes. EPSP amplitudes correlated with the resting membrane potential, input resistance and EPSP rise time in both sexes. The observed sex differences in the Ia proprioceptive input may be related either to mechanical loading differences in males and females associated with their different body mass or hormonal differences influencing the levels of neuromodulation in spinal circuits. The results highlight the importance of taking sex into consideration in the studies on the influence of afferent inputs on MN excitability.
Assuntos
Potenciais Evocados , Medula Espinal , Feminino , Masculino , Animais , Ratos , Medula Espinal/fisiologia , Neurônios Motores/fisiologia , Contração Muscular/fisiologia , Músculo Esquelético , Sinapses/fisiologiaRESUMO
We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce simulated peripheral artery disease (PAD). We hypothesized that in decerebrate, unanesthetized rats with a ligated femoral artery, hindlimb arterial injection of HOE-140 (100 ng, B2 receptor antagonist) would reduce the pressor response to 30 s of electrically induced 1 Hz hindlimb skeletal muscle contraction, and 30 s of 1 Hz hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). We hypothesized no effect of HOE-140 in sham-operated "freely perfused" rats. In both freely perfused (n = 4) and "ligated" (n = 4) rats, we first confirmed efficacious B2 receptor blockade by demonstrating that HOE-140 injection significantly reduced (P < 0.05) the peak increase in mean arterial pressure (peak ΔMAP) in response to hindlimb arterial injection of bradykinin. In subsequent experiments, we found that HOE-140 reduced the peak ΔMAP response to muscle contraction in ligated (n = 14; control: 23 ± 2; HOE-140: 17 ± 2 mmHg; P = 0.03) but not freely perfused rats (n = 7; control: 17 ± 3; HOE-140: 18 ± 4 mmHg; P = 0.65). Furthermore, HOE-140 had no effect on the peak ΔMAP response to stretch in ligated rats (n = 14; control: 37 ± 4; HOE-140: 32 ± 5 mmHg; P = 0.13) but reduced the integrated area under the blood pressure signal over the final â¼20 s of the maneuver. The data suggest that B2 receptors contribute to the exaggerated exercise pressor reflex in rats with simulated PAD, and that contribution includes a modest role in the chronic sensitization of the mechanically activated channels/afferents that underlie mechanoreflex activation.
Assuntos
Doença Arterial Periférica , Reflexo , Ratos , Animais , Reflexo/fisiologia , Músculo Esquelético/metabolismo , Receptores da Bradicinina/metabolismo , Ratos Sprague-Dawley , Bradicinina/farmacologia , Contração Muscular/fisiologia , Pressão Sanguínea/fisiologia , Artéria Femoral , Membro Posterior/metabolismoRESUMO
Skeletal muscle reflexes play a crucial role in determining the magnitude of the cardiovascular response to exercise. However, evidence supporting an association between the magnitude of the pressor response and the velocity of muscle deformation has remained to be elucidated. Thus, we investigated the impact of different muscle deformation rates on the neural discharge of muscle afferents and pressor and sympathetic responses in Sprague-Dawley rats. In an ex vivo muscle-nerve preparation, action potentials elicited by sinusoidal mechanical stimuli (137 mN) at different frequencies (0.01, 0.05, 0.1, 0.2, and 0.25 Hz) were recorded in mechanosensitive group III and IV fibers. The afferent response magnitude to sine-wave stimulation significantly varied at different frequencies (ANOVA, P = 0.01). Specifically, as compared with 0.01 Hz (0.83 ± 0.96 spikes/s), the response magnitudes were significantly greater at 0.20 Hz (4.07 ± 5.04 spikes/s, P = 0.031) and 0.25 Hz (4.91 ± 5.30 spikes/s, P = 0.014). In an in vivo decerebrated rat preparation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch (1 kg) of hindlimb skeletal muscle at different velocities of loading (slow, medium, and fast) were measured. Pressor responses to passive stretch were significantly associated with the velocity of muscle deformation (ANOVA, P < 0.001). The MAP response to fast stretch (Δ 56 ± 12 mmHg) was greater than slow (Δ 33 ± 11 mmHg, P = 0.006) or medium (Δ 30 ± 11 mmHg, P < 0.001) stretch. Likewise, the RSNA response was related to deformation velocity (ANOVA, P = 0.024). These findings suggest that the muscle neural afferent discharge and the cardiovascular response to mechanical stimulation are associated with muscle deformation velocity.
Assuntos
Contração Muscular , Alta do Paciente , Ratos , Animais , Humanos , Ratos Sprague-Dawley , Contração Muscular/fisiologia , Reflexo/fisiologia , Músculo Esquelético/inervação , Pressão Sanguínea/fisiologiaRESUMO
PURPOSE: The aim of the present study was to investigate whether exercise-induced muscle damage (EIMD) influences cardiovascular responses to isometric exercise and post-exercise circulatory occlusion (PECO). We hypothesized that EIMD would increase muscle afferent sensitivity and, accordingly, increase blood pressure responses to exercise and PECO. METHODS: Eleven male and nine female participants performed unilateral isometric knee extension at 30% of maximal voluntary contraction (MVC) for 3-min. A thigh cuff was rapidly inflated to 250 mmHg for two min PECO, followed by 3 min recovery. Heart rate and blood pressure were monitored beat-by-beat, with stroke volume and cardiac output estimated from the Modelflow algorithm. Measurements were taken before and 48 h after completing eccentric knee-extension contractions to induce muscle damage (EIMD). RESULTS: EIMD caused 21% decrease in MVC (baseline: 634.6 ± 229.3 N, 48 h: 504.0 ± 160 N), and a 17-fold increase in perceived soreness using a visual-analogue scale (0-100 mm; VASSQ) (both p < 0.001). CV responses to exercise and PECO were not different between pre and post EIMD. However, mean arterial pressure (MAP) was higher during the recovery phase after EIMD (p < 0.05). Significant associations were found between increases in MAP during exercise and VASSQ, Rate of Perceived Exertion (RPE) and Pain after EIMD only (all p < 0.05). CONCLUSION: The MAP correlations with muscle soreness, RPE and Pain during contractions of damaged muscles suggests that higher afferent activity was associated with higher MAP responses to exercise.
Assuntos
Sistema Cardiovascular , Músculo Esquelético , Humanos , Masculino , Feminino , Músculo Esquelético/fisiologia , Contração Isométrica/fisiologia , Mialgia , Pressão Sanguínea/fisiologia , Contração Muscular/fisiologiaRESUMO
Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fibre muscle afferents, which, in turn, generates reflex increases in sympathetic nerve activity (SNA) and blood pressure (the exercise pressor reflex; EPR). EPR activation in patients and animals with heart failure with reduced ejection fraction (HF-rEF) results in exaggerated increases in SNA and promotes exercise intolerance. In the healthy decerebrate rat, a subtype of acid sensing ion channel (ASIC) on the sensory endings of thin fibre muscle afferents, namely ASIC1a, has been shown to contribute to the metabolically sensitive portion of the EPR (i.e. metaboreflex), but not the mechanically sensitive portion of the EPR (i.e. the mechanoreflex). However, the role played by ASIC1a in evoking the EPR in HF-rEF is unknown. We hypothesized that, in decerebrate, unanaesthetized HF-rEF rats, injection of the ASIC1a antagonist psalmotoxin-1 (PcTx-1; 100 ng) into the hindlimb arterial supply would reduce the reflex increase in renal SNA (RSNA) evoked via 30 s of electrically induced static hindlimb muscle contraction, but not static hindlimb muscle stretch (model of mechanoreflex activation isolated from contraction-induced metabolite-production). We found that PcTx-1 reduced the reflex increase in RSNA evoked in response to muscle contraction (n = 8; mean (SD) ∫ΔRSNA pre: 1343 (588) a.u.; post: 816 (573) a.u.; P = 0.026) and muscle stretch (n = 6; ∫ΔRSNA pre: 688 (583) a.u.; post: 304 (370) a.u.; P = 0.025). Our data suggest that, in HF-rEF rats, ASIC1a contributes to activation of the exercise pressor reflex and that contribution includes a novel role for ASIC1a in mechanosensation that is not present in healthy rats. KEY POINTS: Skeletal muscle contraction results in exaggerated reflex increases in sympathetic nerve activity in heart failure patients compared to healthy counterparts, which likely contributes to increased cardiovascular risk and impaired tolerance for even mild exercise (i.e. activities of daily living) for patients suffering with this condition. Activation of acid sensing ion channel subtype 1a (ASIC1a) on the sensory endings of thin fibre muscle afferents during skeletal muscle contraction contributes to reflex increases in sympathetic nerve activity and blood pressure, at least in healthy subjects. In this study, we demonstrate that ASIC1a on the sensory endings of thin fibre muscle afferents plays a role in both the mechanical and metabolic components of the exercise pressor reflex in male rats with heart failure. The present data identify a novel role for ASIC1a in evoking the exercise pressor reflex in heart failure and may have important clinical implications for heart failure patients.
Assuntos
Canais Iônicos Sensíveis a Ácido , Insuficiência Cardíaca , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/metabolismo , Membro Posterior , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Ratos , Ratos Sprague-Dawley , Reflexo/fisiologiaRESUMO
The cardiovascular response resulting from the individual activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) is different between men and women. Whether the haemodynamic consequence resulting from the interaction of these sympathoexcitatory reflexes is also sex-dependent remains unknown. MMR and CR were activated by passive leg movement (LM) and exposure to hypoxia (O2 -CR) or hypercapnia (CO2 -CR), respectively. Twelve young men and 12 young women completed two experimental protocols: (1) resting in normoxia (PET O2 : â¼83 mmHg, PET CO2 : â¼34 mmHg), normocapnic hypoxia (PET O2 : â¼48 mmHg, PET CO2 : â¼34 mmHg) and hyperoxic hypercapnia (PET O2 : â¼524 mmHg, PET CO2 : â¼44 mmHg); (2) LM under the same gas conditions. During the MMR:O2 -CR coactivation, in men, the observed mean arterial pressure (MAP) and cardiac output (CO) were not different (additive effect), while the observed leg blood flow (LBF) and vascular conductance (LVC) were significantly lower (hypo-additive), compared with the sum of the responses elicited by each reflex alone. In women, the observed MAP was not different (additive) while the observed CO, LBF and LVC were significantly greater (hyper-additive), compared with the summated responses. During the MMR:CO2 -CR coactivation, in men, the observed MAP, CO and LBF were not different (additive), while the observed LVC was significantly lower (hypo-additive), compared with the summated responses. In women, the observed MAP was significantly higher (hyper-additive), while the observed CO, LBF and LVC were not different (additive), compared with the summated responses. The interaction of the MMR and CR has a pronounced influence on the autonomic cardiovascular control, with the haemodynamic consequences differing between men and women. KEY POINTS: The cardiovascular response resulting from the activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) was previously shown to be different between women and men; this study focused on the haemodynamic consequence of the interaction of these two sympathoexcitatory reflexes. MMR and CR were activated by passive leg movement and exposure to hypoxia (O2 -CR) or hypercapnia (CO2 -CR), respectively. Individual and interactive reflex effects on central and peripheral haemodynamics were quantified in healthy young women and men. In men, the MMR:O2 -CR and MMR:CO2 -CR interactions restricted peripheral haemodynamics, likely by potentiating sympathetic vasoconstriction. In women, the MMR:O2 -CR interaction facilitated central and peripheral haemodynamics, likely by potentiating sympathetic vasodilatation; however, the MMR:CO2 -CR interaction was simply additive for the central and peripheral haemodynamics. The interaction between the MMR and the CR exerts a profound influence on the autonomic control of cardiovascular function in humans, with the haemodynamic consequences differing between women and men.
Assuntos
Dióxido de Carbono , Hipercapnia , Feminino , Hemodinâmica , Humanos , Hipóxia , Masculino , MúsculosRESUMO
Systemic insulin administration evokes sympathoexcitatory actions, but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserves them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole-cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n = 13) was significantly (P < 0.05) higher than with a vehicle control (n = 14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n = 9 per group, P < 0.05). Furthermore, insulin receptor blockade with GSK1838705 significantly suppressed the insulin-induced augmentation in CAP-activated currents (n = 13) as well as the response magnitude of CAP-induced action potentials (n = 9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n = 8) was significantly (P < 0.05) greater compared to vehicle (n = 9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. KEY POINTS: Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical-sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, it is demonstrated that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, it is demonstrated that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggest that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.
Assuntos
Capsaicina , Gânglios Espinais , Animais , Capsaicina/farmacologia , Gânglios Espinais/fisiologia , Insulina/farmacologia , Camundongos , Fibras Musculares Esqueléticas , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Roedores , Canais de Cátion TRPV/fisiologiaRESUMO
The sense of force is suggested to rely in part on proprioceptive inputs when assessed with a force reproduction task. The age-related alterations in proprioceptive system could, therefore, alter the sense of force. This study investigated the effects of tendon vibration on a force reproduction task performed with the wrist flexors in 18 young (20-40 year) and 18 older adults (60-90 year). Participants matched a target force (5% or 20% of their maximal force) with visual feedback of the force produced (target phase), and reproduced the target force without visual feedback (reproduction phase) after a 5-s rest period with or without vibration. The force reproduction error was expressed as the ratio between the force produced during the reproduction and the target phases. For the trials with vibration, the error was expressed as the ratio between the force produced during the reproduction phase performed with and without vibration. Tactile acuity was assessed with a two-point discrimination test. The error was greater at 5% than at 20% contraction intensity (p < 0.001), and in older [56.5 (32.2)%; mean (SD)] than in young adults [33.5 (13.6)%] at 5% (p = 0.002) but not 20% target (p = 0.46). Tendon vibration had a greater effect at 5% than 20% contraction intensity, and in older [41.7 (32.4)%, p < 0.001] than young adults [20.0 (16.1)%]. Tactile acuity was lesser in older than young adults (p < 0.001). The results support the contribution of proprioception in the sense of force, and highlight a decrease in performance with ageing restricted to low-force contractions.
Assuntos
Vibração , Punho , Idoso , Eletromiografia , Humanos , Músculo Esquelético , Propriocepção , Reprodução , Tendões , Adulto JovemRESUMO
Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.
Assuntos
Metabolismo Energético , Exercício Físico , Mitocôndrias Musculares/metabolismo , Contração Muscular , Músculo Quadríceps/metabolismo , Adulto , Analgésicos Opioides/administração & dosagem , Ciclismo , Respiração Celular , Fentanila/administração & dosagem , Voluntários Saudáveis , Humanos , Injeções Espinhais , Masculino , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Músculo Quadríceps/inervação , Distribuição Aleatória , Adulto JovemRESUMO
The exercise pressor reflex is a feedback autonomic and cardiovascular control mechanism evoked by mechanical and metabolic signals within contracting skeletal muscles. The mechanically sensitive component of the reflex (the mechanoreflex) is exaggerated in patients with peripheral artery disease (PAD) and in a rat model of simulated PAD in which a femoral artery is chronically ligated. Products of cyclooxygenase enzyme activity have been shown to chronically sensitize the mechanoreflex in PAD, but the identity of the muscle afferent receptors that mediate the sensitization is unclear. We hypothesized that injection of the endoperoxide 4 receptor (EP4-R) antagonist L161982 or the thromboxane A2 receptor (TxA2-R) antagonist daltroban into the arterial supply of the hindlimb would reduce the pressor response to repetitive, dynamic hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in rats with a femoral artery that was ligated ~72 h before the experiment but not in rats with freely perfused femoral arteries. We found that EP4-R blockade had no effect on the pressor response (peak Δmean arterial pressure) to stretch in freely perfused (n = 6, pre: 14 ± 2, post: 15 ± 2 mmHg, P = 0.97) or ligated (n = 8, pre: 29 ± 4, post: 29 ± 6 mmHg, P = 0.98) rats. In contrast, TxA2-R blockade had no effect on the pressor response to stretch in freely perfused rats (n = 6, pre: 16 ± 3, post: 17 ± 4 mmHg, P = 0.99) but significantly reduced the response in ligated rats (n = 11, pre: 29 ± 4, post: 17 ± 5 mmHg, P < 0.01). We conclude that TxA2-Rs contribute to chronic mechanoreflex sensitization in the chronic femoral artery-ligated rat model of simulated PAD.NEW & NOTEWORTHY We demonstrate that thromboxane A2 receptors, but not endoperoxide 4 receptors, on the sensory endings of thin fiber muscle afferents contribute to the chronic sensitization of the muscle mechanoreflex in rats with a ligated femoral artery (a model of simulated peripheral artery disease). The data may have important implications for our understanding of blood pressure control during exercise in patients with peripheral artery disease.
Assuntos
Mecanorreceptores/metabolismo , Contração Muscular , Músculo Esquelético/inervação , Doença Arterial Periférica/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Reflexo , Animais , Pressão Arterial , Modelos Animais de Doenças , Masculino , Mecanorreceptores/efeitos dos fármacos , Mecanotransdução Celular , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/fisiopatologia , Fenilacetatos/farmacologia , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Reflexo/efeitos dos fármacos , Sulfonamidas/farmacologia , Fatores de TempoRESUMO
The exercise pressor reflex arises from contracting muscle and is manifested by increases in arterial pressure, heart rate, and cardiac contractility. In patients with peripheral artery disease, the exercise pressor reflex is exaggerated. This effect is believed to be caused by a metabolite whose concentration is increased when the working muscles are inadequately perfused. Previous work in rats with simulated peripheral artery disease has shown that pharmacological blockade of acid-sensing ion channel 3 (ASIC3), which is found on group III and IV afferents, prevented the exaggeration of the exercise pressor reflex. Blockade of ASIC3, however, may have off-target effects that preclude a conclusion that ASIC3 plays a role in evoking the reflex in rats with simulated peripheral artery disease. In the present experiments performed in decerebrated rats with simulated peripheral artery disease, we compared the exercise pressor reflex in rats with a functional knockout of the ASIC3 (KO) with the reflex in their wild-type counterparts (WT). We found that the exercise pressor reflex in ASIC3 KO rats was significantly lower than the exercise pressor reflex in their WT counterparts (P < 0.05). ASIC 3 KO rats demonstrated lower pressor responses to intra-arterial injection of diprotonated phosphate (86 mM; pH 6.0), lactic acid (12 mM; pH 2.85), and capsaicin (0.2 µg; pH 7.2) (P < 0.05). In contrast, both ligated WT and ASIC3 KO rats displayed similar pressor responses to tendon stretch (P > 0.05). We conclude that ASIC3 play an important role in evoking the exaggerated exercise pressor reflex in rats with peripheral artery disease.NEW & NOTEWORTHY We used a genetic approach to test the hypothesis that the magnitude of the exercise pressor reflex evoked in ligated ASIC3 KO rats was significantly lower than the magnitude of the exercise pressor reflex evoked in their ligated wild-type (WT) counterparts. The pressor response to contraction in ligated ASIC3 KO rats was significantly smaller than was the pressor response to contraction in ligated WT rats.
Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Artéria Femoral/fisiopatologia , Contração Muscular , Doença Arterial Periférica/metabolismo , Reflexo , Canais Iônicos Sensíveis a Ácido/genética , Animais , Pressão Sanguínea , Masculino , Doença Arterial Periférica/fisiopatologia , Ratos , Ratos WistarRESUMO
The aim of the present study was to determine the magnitude of the maximal level of peripheral fatigue attainable (fatigue threshold) during an all-out intermittent isometric knee-extensor protocol in both younger (24 ± 1 yr, n = 12) and older (60 ± 2 yr, n = 12) participants to provide new insights into the effects of aging on neuromuscular function. Participants performed two experimental sessions, in which they performed 60 maximal voluntary contractions (MVCs; 3 s of contraction, 2 s of relaxation). One trial was performed in the unfatigued state (CTRL) and one other following fatiguing neuromuscular electrical stimulation of the quadriceps (FNMES). Peripheral fatigue was quantified via pre/postexercise decrease in quadriceps twitch force (∆Ptw). Critical force (CF) was determined as the mean force output of the last 12 contractions, whereas W' was calculated as the area above CF. Although FNMES led to a significant decrease in Ptw before performing the 60-MVCs protocol (P = 0.024), ∆Ptw was not different between CTRL and FNMES for both the young group (P = 0.491) and the old group (P = 0.523). However, this peripheral fatigue threshold was significantly greater in young versus old participants (∆Ptw = -48 ± 10% vs. -29 ± 13%, respectively, P = 0.028). In CTRL, W' was 55 ± 13% lower in the old group than in the young group (P < 0.001), but CF was similar (326 ± 10 N vs. 322 ± 12 N, respectively, P = 0.941). ∆Ptw was correlated with W', independently of age (r2 = 0.84, P < 0.001). Exercise performance decreases with aging consequent to a lower tolerance to peripheral fatigue. However, the peripheral fatigue threshold mechanism persists with healthy aging and continues to play a protective role in preserving locomotor muscle function during exercise.
Assuntos
Envelhecimento , Tolerância ao Exercício , Contração Muscular , Fadiga Muscular , Músculo Quadríceps/fisiologia , Adulto , Fatores Etários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Fatores de Tempo , Adulto JovemRESUMO
NEW FINDINGS: What is the central question of this study? How do locomotor muscle metabo- and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase-2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure. ABSTRACT: Heart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo- and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase-2 (COX-2), purinergic 2X3 (P2X3 ), transient receptor potential vanilloid type 1 (TRPV 1), acid-sensing ion channel 3 (ASIC3 ), Piezo 1 and Piezo 2 protein expression. TRPV 1 and COX-2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X3 , ASIC3 , and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX-2 protein expression was related to the percentage change in ventilation (r = -0.66) and mean arterial pressure (MAP) (r = -0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRPV 1 protein expression was related to the percentage change in systolic blood pressure (r = -0.77, P = 0.02) and MAP (r = -0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRPV 1 and COX-2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRPV 1 and COX-2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF.
Assuntos
Vias Aferentes , Exercício Físico , Insuficiência Cardíaca/fisiopatologia , Mecanorreceptores/metabolismo , Músculo Quadríceps/fisiologia , Canais Iônicos Sensíveis a Ácido , Idoso , Estudos de Casos e Controles , Ciclo-Oxigenase 2 , Feminino , Fentanila/administração & dosagem , Humanos , Canais Iônicos , Masculino , Pessoa de Meia-Idade , Receptores Purinérgicos P2X3 , Canais de Cátion TRPVRESUMO
KEY POINTS: Insulin is known to activate the sympathetic nervous system centrally. A mechanical stimulus to tissues activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, we report the novel finding that insulin augments the mechanical responsiveness of thin fibre afferents not only at dorsal root ganglion, but also at muscle tissue levels. Our data suggest that sympathoexcitation is mediated via the insulin-induced mechanical sensitization peripherally. The present study proposes a novel physiological role of insulin in the regulation of mechanical sensitivity in somatosensory thin fibre afferents. ABSTRACT: Insulin activates the sympathetic nervous system, although the mechanism underlying insulin-induced sympathoexcitation remains to be determined. A mechanical stimulus to tissues such as skin and/or skeletal muscle, no matter whether the stimulation is noxious or not, activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion (DRG) neurons of these afferents. Accordingly, we investigated whether insulin augments whole-cell current responses to mechanical stimuli in small DRG neurons of normal healthy mice. We performed whole-cell patch clamp recordings using cultured DRG neurons and observed mechanically-activated (MA) currents induced by mechanical stimuli applied to the cell surface. Local application of vehicle solution did not change MA currents or mechanical threshold in cultured DRG neurons. Insulin (500 mU mL-1 ) significantly augmented the amplitude of MA currents (P < 0.05) and decreased the mechanical threshold (P < 0.05). Importantly, pretreatment with the insulin receptor antagonist, GSK1838705, significantly suppressed the insulin-induced potentiation of the mechanical response. We further examined the impact of insulin on thin fibre muscle afferent activity in response to mechanical stimuli in normal healthy rats in vitro. Using a muscle-nerve preparation, we recorded single group IV fibre activity to a ramp-shaped mechanical stimulation. Insulin significantly decreased mechanical threshold (P < 0.05), although it did not significantly increase the response magnitude to the mechanical stimulus. In conclusion, these data suggest that insulin augments the mechanical responsiveness of small DRG neurons and potentially sensitizes group IV afferents to mechanical stimuli at the muscle tissue level, possibly contributing to insulin-induced sympathoexcitation.
Assuntos
Potenciais de Ação/fisiologia , Gânglios Espinais/citologia , Insulina/farmacologia , Mecanotransdução Celular/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Neurônios/fisiologia , Vias Aferentes/efeitos dos fármacos , Animais , Gânglios Espinais/fisiologia , Insulina/fisiologia , Masculino , Mecanotransdução Celular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptor de Insulina/antagonistas & inibidoresRESUMO
Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in patients with peripheral artery disease (PAD) and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery ("ligated" rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1-Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats (n = 7), indomethacin reduced the pressor response during stretch (control: 30 ± 4; indomethacin: 12 ± 3 mmHg; P < 0.01), whereas there was no effect in rats with "freely perfused" femoral arteries (n = 6, control: 18 ± 5; indomethacin: 17 ± 5 mmHg; P = 0.87). In ligated rats (n = 4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity or concentration of the COX metabolite prostaglandin E2. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A2-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents, which occurs principally as a result of increased expression of COX metabolite receptors.NEW & NOTEWORTHY We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.
Assuntos
Mecanorreceptores/metabolismo , Mecanotransdução Celular , Contração Muscular , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Doença Arterial Periférica/enzimologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Reflexo , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Artéria Femoral/fisiopatologia , Artéria Femoral/cirurgia , Gânglios Espinais/metabolismo , Membro Posterior , Indometacina/farmacologia , Ligadura , Masculino , Doença Arterial Periférica/fisiopatologia , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismoRESUMO
KEY POINTS: This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise. Firing of these interneurons probably contributes to the development of central fatigue during physical activity. ABSTRACT: We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus-lateralis EMG signal (â¼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant-load cycling exercise (80% Wpeak; 221 ± 10 W; â¼8 min). During, PRE and POST cycling, single and paired-pulse (100 ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor-evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100 ms interval) cervicomedullary motor-evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P < 0.05). This paralleled a reduction in conditioned MEP (P < 0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P > 0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABAB intracortical interneurons.