ABSTRACT
Patients with hypertension (HTN) are characterized by exaggerated vascular resistance and mean arterial pressure (MAP), and a compromised leg blood flow (QL) response to exercise recruiting a small muscle mass. However, the impact of hypertension on peripheral hemodynamics and the development of neuromuscular fatigue during locomotor activities, which critically depends on QL, remain unknown. Eight HTN (143±11mmHg / 95±6mmHg; 45±13years) and 8 matched (age, activity) controls (120±6mmHg / 77±7mmHg; CTRL) performed constant-load cycling exercise at 25, 50, and 75W (for 4-min each), and at 165±41W (for 5-min). Exercise-induced locomotor muscle fatigue was quantified as the pre- to post-exercise change in quadriceps twitch-torque (∆Qtw, peripheral fatigue) and voluntary activation (∆VA%, central fatigue). QL (Doppler-ultrasound) and leg vascular conductance (LVC) were determined during cycling at 25, 50, and 75W. Heart Rate and ventilatory responses were recorded during all intensities. MAP during exercise was, on average, ~21mmHg higher (P=0.002) and LVC ~39% lower (P=0.001) in HTN compared to CTRL. QL was consistently between 20-30% lower (P=0.004) and heart rate was significantly higher in HTN. Exercise-induced peripheral (∆Qtw: -53±19% vs -25±23%) and central (∆VA%: -7±5% vs -3±2%) fatigue were significantly greater in HTN compared to CTRL. In addition to an exaggerated MAP, LVC and QL were lower during exercise in HTN compared to CTRL. Given the critical role of QL in determining the development of neuromuscular fatigue, these hemodynamic impairments likely accounted for the faster development of neuromuscular fatigue characterizing hypertensive individuals during locomotor exercise.
ABSTRACT
Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.
Subject(s)
Exercise , Heart Failure , Muscle, Skeletal , Stroke Volume , Humans , Male , Female , Heart Failure/physiopathology , Heart Failure/metabolism , Aged , Muscle, Skeletal/blood supply , Exercise/physiology , Middle Aged , Phentolamine/pharmacology , Regional Blood Flow , Phenylephrine/pharmacology , Oxygen Consumption , Adrenergic alpha-Antagonists/pharmacology , Leg/blood supplyABSTRACT
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.
Subject(s)
Leg , Muscle, Skeletal , Male , Humans , Leg/blood supply , Muscle, Skeletal/physiology , Reflex , Fentanyl , Vasoconstrictor Agents/pharmacology , PerfusionABSTRACT
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.
Subject(s)
Carbon Dioxide , Hypercapnia , Female , Hemodynamics , Humans , Hypoxia , Male , MusclesABSTRACT
Intramuscular hydrogen ion (H+ ) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P-MRS) was used to continuously quantify intramuscular [H+ ] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw ) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+ ] (ß coefficient: -0.9, P < 0.0001) and [Pi] (-1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+ ] (-0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+ ] in Trial 1 vs. Trial 2. VA was related to [H+ ] (-0.3, P < 0.0001), but not [Pi] (-0.2, P = 0.243), across trials and there was no effect of trial (-0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. KEY POINTS: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee-extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+ ) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch-force (Qtw ) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P-MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+ ] did not. Qtw was strongly related to both [H+ ] and [Pi] across both trials. However, the relationship between Qtw and [H+ ] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+ ], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.
Subject(s)
Acidosis , Phosphates , Electromyography , Fatigue , Humans , Male , Muscle Contraction , Muscle Fatigue/physiology , Muscle, Skeletal/physiology , PhosphorusABSTRACT
The exercise pressor reflex (EPR), a neurocirculatory control mechanism, is exaggerated in hypertensive humans and rats. Disease-related abnormalities within the afferent arm of the reflex loop, including mechano- and metabosensitive receptors located at the terminal end of group III/IV muscle afferents, may contribute to the dysfunctional EPR in hypertension. Using control (WKY) and spontaneous hypertensive (SHR) rats, we examined dorsal root ganglion (DRG) gene and protein expression of molecular receptors recognized as significant determinants of the EPR. Twelve lumbar DRGs (6 left, 6 right) were harvested from each of 10 WKY [arterial blood pressure (MAP): 96 ± 9 mmHg] and 10 SHR (MAP: 144 ± 9 mmHg). DRGs from the left side were used for protein expression (Western blotting; normalized to GAPDH), whereas right-side DRGs (i.e., parallel structure) were used to determine mRNA levels (RNA-sequencing, normalized to TPM). Analyses focused on metabosensitive (ASIC3, Bradykinin receptor B2, EP4, P2X3, TRPv1) and mechanosensitive (Piezo1/2) receptors. Although Piezo1 was similar in both groups (P = 0.75), protein expression for all other receptors was significantly higher in SHR compared with WKY. With the exception of a greater Bradykinin-receptor B2 in SHR (P < 0.05), mRNA expression of all other receptors was not different between groups (P > 0.18). The higher protein content of these sensory receptors in SHR indirectly supports the previously proposed hypothesis that the exaggerated EPR in hypertension is, in part, due to disease-related abnormalities within the afferent arm of the reflex loop. The upregulated receptor content, combined with normal mRNA levels, insinuates that posttranscriptional regulation of sensory receptor protein expression might be impaired in hypertension.
Subject(s)
Ganglia, Spinal , Hypertension , Animals , Blood Pressure , Ganglia, Spinal/metabolism , Humans , Ion Channels , Male , RNA, Messenger/genetics , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Sensory Receptor Cells/metabolismABSTRACT
The role of nitric oxide (NO) as a modulator of functional sympatholysis has been debated in the literature, but the preponderance of evidence suggests that the magnitude of NO-mediated dilation is restrained by sympathetic vasoconstriction. Therefore, we hypothesized that passive leg movement (PLM)-induced vasodilation, which is predominantly NO-mediated, would be attenuated by an exercise-induced increase in muscle sympathetic nerve activity (MSNA). To test this hypothesis, MSNA, leg blood flow (LBF), and mean arterial blood pressure (MAP) were measured and leg vascular conductance (LVC) calculated in 9 healthy subjects (30 ± 3 yr), during PLM with and without sympathoexcitation evoked by arm-cranking exercise (ACE), at 25, 50, and 75% of maximal capacity. During this incremental intensity ACE, MSNA increased significantly (26 ± 2, 34 ± 3, and 41 ± 5 bursts/100 HB, respectively). LVC during PLM fell markedly (~1.2 ml/min/mmHg) with each increase in ACE intensity, and there was a strong relationship (r = 0.92; p < 0.05) between ∆MSNA and ∆Peak LVC induced by the three intensities of ACE. Thus, as anticipated, this study reveals that the, NO-mediated, PLM-induced vasodilation, is significantly and proportionally attenuated by exercise-induced MSNA. This finding highlights the dominant role of MSNA in regulating skeletal muscle vascular conductance.
Subject(s)
Hypotension , Vasodilation , Blood Pressure , Humans , Leg , Muscle, Skeletal/innervation , Nitric Oxide , Regional Blood Flow/physiology , Sympathetic Nervous System/physiology , VasoconstrictionABSTRACT
This study examined the impact of aging on the elastic and resistive components of the work of breathing (Wb) during locomotor exercise at a given 1) ventilatory rate, 2) metabolic rate, and 3) operating lung volume. Eight healthy younger (25 ± 4 yr) and 8 older (72 ± 6 yr) participants performed incremental bicycle exercise, from which retrospective analyses identified similar ventilatory rates (approximately 40, 70, and 100 L·min-1), similar metabolic rates (VÌo2: approximately 1.2, 1.6, and 1.9 L·min-1), and similar lung volumes [inspiratory and expiratory reserve volumes (IRV/ERV: approximately 25/34%, 16/33%, and 13-34% of vital capacity]. Wb at each level was quantified by integrating the averaged esophageal pressure-volume loop, which was then partitioned into elastic and resistive components of inspiratory and expiratory work using the modified Campbell diagram. IRV was smaller in the older participants during exercise at ventilations of 70 and 100 L·min-1 and during exercise at the three metabolic rates (P < 0.05). Mainly because of a greater inspiratory elastic and resistive Wb in the older group (P < 0.05), total Wb was augmented by 40%-50% during exercise at matched ventilatory and matched metabolic rates. When examined during exercise evoking similar lung volumes, total Wb was not different between the groups (P = 0.86). Taken together, although aging exaggerates total Wb during locomotor exercise at a given ventilatory or a given metabolic rate, this difference is abolished during exercise at a given operating lung volume. These findings highlight the significance of operating lung volume in determining the age-related difference in Wb during locomotor exercise.NEW & NOTEWORTHY This study evaluated the impact of aging on the work of breathing (Wb) during locomotor exercise evoking similar ventilatory rates, metabolic rates, and operating lung volumes in young and older individuals. Mainly because of a greater inspiratory elastic and resistive Wb in older participants, total Wb was higher during exercise at any given ventilatory and metabolic rate with aging. However, this age-related difference was abolished during exercise evoking similar operating lung volumes in both age groups. These findings highlight the significance of lung volumes in determining the age-related difference in total Wb.
Subject(s)
Exercise , Work of Breathing , Aged , Aging , Humans , Male , Respiration , Retrospective StudiesABSTRACT
This study investigated the impact of dietary nitrate supplementation on peripheral hemodynamics, the development of neuromuscular fatigue, and time to task failure during cycling exercise. Eleven recreationally active male participants (27 ± 5 yr, VÌo2max: 42 ± 2 mL/kg/min) performed two experimental trials following 3 days of either dietary nitrate-rich beetroot juice (4.1 mmol NO3-/day; DNS) or placebo (PLA) supplementation in a blinded, counterbalanced order. Exercise consisted of constant-load cycling at 50, 75, and 100 W (4 min each) and, at â¼80% of peak power output (218 ± 12 W), to task-failure. All participants returned to repeat the shorter of the two trials performed to task failure, but with the opposite supplementation regime (iso-time comparison; ISO). Mean arterial pressure (MAP), leg blood flow (QL; Doppler ultrasound), leg vascular conductance (LVC), and pulmonary gas exchange were continuously assessed during exercise. Locomotor muscle fatigue was determined by the change in pre to postexercise quadriceps twitch-torque (ΔQtw) and voluntary activation (ΔVA; electrical femoral nerve stimulation). Following DNS, plasma [nitrite] (â¼670 vs. â¼180 nmol) and [nitrate] (â¼775 vs. â¼11 µmol) were significantly elevated compared with PLA. Unlike PLA, DNS lowered both QL and MAP by â¼8% (P < 0.05), but did not alter LVC (P = 0.31). VÌO2 across work rates, as well as cycling time to task-failure (â¼7 min) and locomotor muscle fatigue following the ISO-time comparison were not different between the two conditions (ΔQtw â¼42%, ΔVA â¼4%). Thus, despite significant hemodynamic changes, DNS did not alter the development of locomotor muscle fatigue and, ultimately, cycling time to task failure.NEW & NOTEWORTHY This study sought to characterize the impact of dietary nitrate supplementation on the hemodynamic response, locomotor muscle fatigue, and time to task failure during cycling exercise. Although nitrate supplementation lowered mean arterial pressure and exercising leg blood flow, leg vascular conductance and oxygen utilization were unaffected. Despite significant hemodynamic changes, there was no effect of dietary nitrate on neuromuscular fatigue development and, ultimately, cycling time to task failure.
Subject(s)
Beta vulgaris , Nitrates , Cross-Over Studies , Dietary Supplements , Double-Blind Method , Exercise , Hemodynamics , Humans , Male , Muscle Fatigue , Muscle, SkeletalABSTRACT
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.
Subject(s)
Energy Metabolism , Exercise , Mitochondria, Muscle/metabolism , Muscle Contraction , Quadriceps Muscle/metabolism , Adult , Analgesics, Opioid/administration & dosage , Bicycling , Cell Respiration , Fentanyl/administration & dosage , Healthy Volunteers , Humans , Injections, Spinal , Male , Neurons, Afferent/drug effects , Neurons, Afferent/physiology , Quadriceps Muscle/innervation , Random Allocation , Young AdultABSTRACT
We examined the effect of intravenous ascorbate (VitC) administration on exercise-induced redox balance, inflammation, exertional dyspnea, neuromuscular fatigue, and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Eight COPD patients completed constant-load cycling (â¼80% of peak power output, 83 ± 10 W) to task failure after intravenous VitC (2 g) or saline (placebo, PL) infusion. All participants repeated the shorter of the two exercise trials (isotime) with the other infusate. Quadriceps fatigue was determined by pre- to postexercise changes in quadriceps twitch torque (ΔQtw, electrical femoral nerve stimulation). Corticospinal excitability before, during, and after exercise was assessed by changes in motor evoked potentials triggered by transcranial magnetic stimulation. VitC increased superoxide dismutase (marker for endogenous antioxidant capacity) by 129% and mitigated C-reactive protein (marker for inflammation) in the plasma during exercise but failed to alter the exercise-induced increase in lipid peroxidation (malondialdehyde) and free radicals [electron paramagnetic resonance (EPR)-spectroscopy]. Although VitC did, indeed, decrease neuromuscular fatigue (ΔQtw: PL -29 ± 5%, VitC -23 ± 6%, P < 0.05), there was no impact on corticospinal excitability and time to task failure (â¼8 min, P = 0.8). Interestingly, in terms of pulmonary limitations to exercise, VitC had no effect on perceived exertional dyspnea (â¼8.5/10) and its determinants, including oxygen saturation ([Formula: see text]) (â¼92%) and respiratory muscle work (â¼650 cmH2O·s·min-1) (P > 0.3). Thus, although VitC facilitated indicators for antioxidant capacity, diminished inflammatory markers, and improved neuromuscular fatigue resistance, it failed to improve exertional dyspnea and cycling exercise tolerance in patients with COPD. As dyspnea is recognized to limit exercise tolerance in COPD, the otherwise beneficial effects of VitC may have been impacted by this unaltered sensation.NEW & NOTEWORTHY We investigated the effect of intravenous vitamin C on redox balance, exertional dyspnea, neuromuscular fatigue, and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. Acute vitamin C administration increased superoxide dismutase (marker of antioxidant capacity) and attenuated fatigue development but failed to improve exertional dyspnea and exercise tolerance. These findings suggest that a compromised redox balance plays a critical role in the development of fatigue in COPD but also highlight the significance of exertional dyspnea as an important symptom limiting the patients' exercise tolerance.
Subject(s)
Exercise Tolerance , Pulmonary Disease, Chronic Obstructive , Ascorbic Acid , Dyspnea , Exercise Test , Humans , Muscle FatigueABSTRACT
We examined the interactive influence of the muscle reflex (MR) and the chemoreflex (CR) on the ventilatory response to exercise. Eleven healthy subjects (5 women/6 men) completed three bouts of constant-load single-leg knee-extension exercise in a control trial and an identical trial conducted with lumbar intrathecal fentanyl to attenuate neural feedback from lower-limb group III/IV muscle afferents. The exercise during the two trials was performed while breathing ambient air ([Formula: see text] ~97%, [Formula: see text]~84 mmHg, [Formula: see text] ~32 mmHg, pH ~7.39), or under normocapnic hypoxia ([Formula: see text] ~79%, [Formula: see text] ~43 mmHg, [Formula: see text] ~33 mmHg, pH ~7.39) or normoxic hypercapnia ([Formula: see text] ~98%, [Formula: see text] ~105 mmHg, [Formula: see text] ~50 mmHg, pH ~7.26). During coactivation of the MR and the hypoxia-induced CR (O2-CR), minute ventilation (VÌe) and tidal volume (VT) were significantly greater compared with the sum of the responses to the activation of each reflex alone; there was no difference between the observed and summated responses in terms of breathing frequency (fB; P = 0.4). During coactivation of the MR and the hypercapnia-induced CR (CO2-CR), the observed ventilatory responses were similar to the summated responses of the reflexes (P ≥ 0.1). Therefore, the interaction between the MR and the O2-CR exerts a hyperadditive effect on VÌe and VT and an additive effect on fB, whereas the interaction between the MR and the CO2-CR is simply additive for all ventilatory parameters. These findings reveal that the MR:CR interaction further augments the ventilatory response to exercise in hypoxia.NEW & NOTEWORTHY Although the muscle reflex and the chemoreflex are recognized as independent feedback mechanisms regulating breathing during exercise, the ventilatory implications resulting from their interaction remain unclear. We quantified the individual and interactive effects of these reflexes during exercise and revealed differential modes of interaction. Importantly, the reflex interaction further amplifies the ventilatory response to exercise under hypoxemic conditions, highlighting a potential mechanism for optimizing arterial oxygenation in physically active humans at high altitude.
Subject(s)
Exercise , Hypercapnia , Female , Humans , Male , Muscles , Reflex , RespirationABSTRACT
This review discusses evidence suggesting that group III/IV muscle afferents affect locomotor performance by influencing neuromuscular fatigue. These neurons regulate the hemodynamic and ventilatory response to exercise and, thus, assure appropriate locomotor muscle O2 delivery, which optimizes peripheral fatigue development and facilitates endurance performance. In terms of central fatigue, group III/IV muscle afferents inhibit motoneuronal output and thereby limit exercise performance.
Subject(s)
Exercise/physiology , Motor Neurons/physiology , Muscle, Skeletal/innervation , Neurons, Afferent/physiology , Physical Endurance/physiology , Fatigue/physiopathology , Hemodynamics , Humans , Muscle Fatigue/physiology , Muscle, Skeletal/metabolism , Oxygen Consumption , RespirationABSTRACT
KEY POINTS: Although the exercise pressor reflex (EPR) and the chemoreflex (CR) are recognized for their sympathoexcitatory effect, the cardiovascular implication of their interaction remains elusive. We quantified the individual and interactive cardiovascular consequences of these reflexes during exercise and revealed various modes of interaction. The EPR and hypoxia-induced CR interaction is hyper-additive for blood pressure and heart rate (responses during co-activation of the two reflexes are greater than the summation of the responses evoked by each reflex) and hypo-additive for peripheral haemodynamics (responses during co-activation of the reflexes are smaller than the summated responses). The EPR and hypercapnia-induced CR interaction results in a simple addition of the individual responses to each reflex (i.e. additive interaction). Collectively, EPR:CR co-activation results in significant cardiovascular interactions with restriction in peripheral haemodynamics, resulting from the EPR:CR interaction in hypoxia, likely having the most crucial impact on the functional capacity of an exercising human. ABSTRACT: We investigated the interactive effect of the exercise pressor reflex (EPR) and the chemoreflex (CR) on the cardiovascular response to exercise. Eleven healthy participants (5 females) completed a total of six bouts of single-leg knee-extension exercise (60% peak work rate, 4 min each) either with or without lumbar intrathecal fentanyl to attenuate group III/IV afferent feedback from lower limbs to modify the EPR, while breathing either ambient air, normocapnic hypoxia (Sa O2 â¼79%, Pa O2 â¼43 mmHg, Pa CO2 â¼33 mmHg, pH â¼7.39), or normoxic hypercapnia (Sa O2 â¼98%, Pa O2 â¼105 mmHg, Pa CO2 â¼50 mmHg, pH â¼7.26) to modify the CR. During co-activation of the EPR and the hypoxia-induced CR (O2 -CR), mean arterial pressure and heart rate were significantly greater, whereas leg blood flow and leg vascular conductance were significantly lower than the summation of the responses evoked by each reflex alone. During co-activation of the EPR and the hypercapnia-induced CR (CO2 -CR), the haemodynamic responses were not different from the summated responses to each reflex response alone (P ≥ 0.1). Therefore, while the interaction resulting from the EPR:O2 -CR co-activation is hyper-additive for blood pressure and heart rate, and hypo-additive for peripheral haemodynamics, the interaction resulting from the EPR:CO2 -CR co-activation is simply additive for all cardiovascular parameters. Thus, EPR:CR co-activation results in significant interactions between cardiovascular reflexes, with the impact differing when the CR activation is achieved by hypoxia or hypercapnia. Since the EPR:CR co-activation with hypoxia potentiates the pressor response and restricts blood flow to contracting muscles, this interaction entails the most functional impact on an exercising human.
Subject(s)
Exercise , Reflex , Blood Pressure , Female , Humans , Hypercapnia , HypoxiaABSTRACT
Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s-1·mg-1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s-1·mg-1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated (r = 0.49-0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals.NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.
Subject(s)
Aging/physiology , Free Radicals/metabolism , Mitochondria/physiology , Oxygen Consumption/physiology , Vasodilation/physiology , Acetylcholine/metabolism , Adult , Aged , Aged, 80 and over , Antioxidants/metabolism , Humans , Middle AgedABSTRACT
We investigated the impact of hypertension on circulatory responses to exercise and the role of the exercise pressor reflex in determining the cardiovascular abnormalities characterizing patients with hypertension. After a 7-day drug washout, 8 hypertensive (mean arterial pressure [MAP] 130±4 mm Hg; 65±3 years) and 8 normotensive (MAP 117±2 mm Hg; 65±2 years) individuals performed single-leg knee-extensor exercise (7 W, 15 W, 50%, 80%-Wpeak) under control conditions and with lumbar intrathecal fentanyl impairing feedback from µ-opioid receptor-sensitive leg muscle afferents. Femoral artery blood flow (QL), MAP (femoral artery), leg vascular conductance, and changes in cardiac output were continuously measured. While the increase in MAP from rest to control exercise was significantly greater in hypertension compared with normotension, the exercise-induced increase in cardiac output was comparable between groups, and QL and leg vascular conductance responses were ≈18% and ≈32% lower in the hypertensive patients (P<0.05). The blockade-induced decreases in MAP were significantly larger during exercise in hypertensive (≈11 mm Hg) compared with normotensive (≈6 mm Hg). Afferent blockade attenuated the central hemodynamic response to exercise similarly in both groups resulting in a ≈15% lower cardiac output at each workload. With no effect in normotensive, afferent blockade significantly raised the peripheral hemodynamic response to exercise in hypertensive, resulting in ≈14% and ≈23% higher QL and leg vascular conductance during exercise. Finally, QL and MAP during fentanyl-exercise in hypertensive were comparable to that of normotensive under control conditions (P>0.2). These findings suggest that exercise pressor reflex abnormalities largely account for the exaggerated MAP response and the impaired peripheral hemodynamics during exercise in hypertension.
Subject(s)
Blood Flow Velocity/physiology , Cardiovascular Abnormalities/diagnosis , Exercise/physiology , Hypertension/diagnosis , Pressoreceptors/physiopathology , Aged , Arterial Pressure/physiology , Blood Pressure Determination/methods , Case-Control Studies , Female , Hemodynamics/physiology , Humans , Hypertension/epidemiology , Male , Middle Aged , Muscle Contraction/physiology , Reference Values , Regional Blood Flow/physiology , Severity of Illness Index , Stroke VolumeABSTRACT
We sought to investigate the role of group III/IV muscle afferents in limiting endurance exercise performance, independently of their role in optimizing locomotor muscle O2 delivery. While breathing 100% O2 to ensure a similar arterial O2 content ([Formula: see text]) in both trials, eight male cyclists performed 5-km time trials under control conditions (HCTRL) and with lumbar intrathecal fentanyl (HFENT) impairing neural feedback from the lower limbs. After each time trial, common femoral artery blood flow (FBF) was quantified (Doppler ultrasound) during constant-load cycling performed at the average power of the preceding time trial. The assessment of end-tidal gases, hemoglobin content and saturation, and FBF facilitated the calculation of leg O2 delivery. Locomotor muscle activation during cycling was estimated from vastus lateralis EMG. With electrical femoral nerve stimulation, peripheral and central fatigue were quantified by pre- to postexercise decreases in quadriceps twitch torque (ΔQtw) and voluntary activation (ΔVA), respectively. FBF (~16 mL·min-1·W-1; P = 0.6), [Formula: see text] (~24 mL O2/dL; P = 0.9), and leg O2 delivery (~0.38 mL O2·min-1·W-1; P = 0.9) were not different during HCTRL and HFENT. Mean power output and time to completion were significantly improved by 9% (~310 W vs. ~288 W) and 3% (~479 s vs. ~463 s), respectively, during HFENT compared with HCTRL. Quadriceps muscle activation was 9 ± 7% higher during HFENT compared with HCTRL (P < 0.05). ΔQtw was significantly greater in HFENT compared with HCTRL (54 ± 8% vs. 39 ± 9%), whereas ΔVA was not different (~5%; P = 0.3) in both trials. These findings reveal that group III/IV muscle afferent feedback limits whole body endurance exercise performance and peripheral fatigue by restricting neural activation of locomotor muscle.NEW & NOTEWORTHY Group III/IV muscle afferent feedback facilitates endurance performance by optimizing locomotor muscle O2 delivery but also limits performance by restricting neural drive to locomotor muscle. To isolate the performance-limiting effect of these sensory neurons, we pharmacologically attenuated their central projection during a cycling time trial while controlling for locomotor muscle O2 delivery. With no difference in leg O2 delivery, afferent blockade attenuated the centrally mediated restriction in motoneuronal output and improved cycling performance.
Subject(s)
Afferent Pathways/physiology , Bicycling/physiology , Nerve Fibers, Unmyelinated/physiology , Physical Endurance , Quadriceps Muscle/physiology , Adult , Electromyography , Femoral Artery/physiology , Fentanyl , Humans , Injections, Spinal , Male , Muscle Contraction , Muscle Fatigue , Oxygen/metabolism , Quadriceps Muscle/innervation , Regional Blood Flow , Young AdultABSTRACT
This short review offers a general summary of the consequences of whole body exercise on neuromuscular fatigue pertaining to the locomotor musculature. Research from the past two decades have shown that whole body exercise causes considerable peripheral and central fatigue. Three determinants characteristic for locomotor exercise are discussed, namely, pulmonary system limitations, neural feedback mechanisms, and mental/psychological influences. We also discuss existing data suggesting that the impact of whole body exercise is not limited to locomotor muscles, but can also impair non-locomotor muscles, such as respiratory and cardiac muscles, and other limb muscles not directly contributing to the task.
ABSTRACT
The corticospinal pathway is considered the primary conduit for voluntary motor control in humans. The efficacy of the corticospinal pathway to relay neural signals from higher brain areas to the locomotor muscle, i.e., corticospinal excitability, is subject to alterations during exercise. While the integrity of this motor pathway has historically been examined during single-joint contractions, a small number of investigations have recently focused on whole body exercise, such as cycling or rowing. Although differences in methodologies employed between these studies complicate the interpretation of the existing literature, it appears that the net excitability of the corticospinal pathway remains unaltered during fatiguing whole body exercise. Importantly, this lack of an apparent effect does not designate the absence of change, but a counterbalance of excitatory and inhibitory influences on the two components of the corticospinal pathway, namely the motor cortex and the spinal motoneurons. Specific emphasis is put on group III/IV afferent feedback from locomotor muscle which has been suggested to play a significant role in mediating these changes. Overall, this review aims at summarizing our limited understanding of how fatiguing whole body exercise influences the corticospinal pathway.