Respiratory and cardiovascular responses to muscle mechanoreflex (passive calf stretch) and metaboreflex activation (local circulatory occlusion) were examined during inhalation of a hypercapnic gas mixture in four trials. These controlled for the effects of central command, metabolite sensitization of muscle afferents and hypercapnia-induced elevation of central respiratory drive. In an isokinetic dynamometer, with circulation through the right leg occluded by inflation of a thigh cuff, 13 participants either rested (control trial; CON) or plantarflexed their ankle at 50% maximal force for 1.5 min (voluntary exercise trial; EX). Thereafter, circulatory occlusion was maintained and the calf passively stretched before return to the resting position. Both trials were performed while breathing air, as well as while breathing a normoxic, hypercapnic (5% CO 2 ) gas mixture (CO 2 trial and CO 2 +EX trial). Hypercapnic gas inhalation increased baseline minute ventilation (V ), heart rate and mean arterial pressure (+27.67 ± 1.74 l min −1 , +7 ± 0.85 beats min −1 and +13 ± 3.41 mmHg, respectively; means ± SEM) above control values (9.78 ± 0.86 l min −1 , 62 ± 2.3 beats min −1 and 88 ± 2.6 mmHg, respectively). Voluntary exercise further increased these variables from baseline during both trials (P < 0.05). During the continued circulatory occlusion after voluntary exercise, mean arterial pressure remained significantly elevated (P < 0.05). Minute ventilation returned to baseline during circulatory occlusion following exercise in the EX trial, but in the CO 2 +EX trial theV remained elevated at end-exercise levels during this period (+7.12 ± 1.13 l min −1 ). Passive stretch caused further increases inV during CO 2 +EX and CO 2 trials but not in CON and EX. These results indicate that in the absence of central command, either muscle metaboreflex and/or mechanoreflex activation stimulates ventilation during concurrent hypercapnia.

Key pointsr Recent evidence indicates a role for group III/IV muscle afferents in reflex control of the human ventilatory response to exercise.r Dyspnoea in chronic obstructive pulmonary disease (COPD) may be linked to this reflex response.r This study shows that activation of the muscle metaboreflex causes a ventilatory response in COPD patients but not in healthy controls.r This indicates abnormal involvement of muscle afferents in the control of ventilation in COPD which may be a contributing factor to exercise dyspnoea.Abstract Blockade of thin fibre muscle afferent feedback during dynamic exercise reduces exercise hyperpnoea in health and chronic obstructive pulmonary disease (COPD). Therefore, we hypothesised that activation of the muscle metaboreflex at rest would cause hyperpnoea. We evaluated the effect of muscle metaboreflex activation on ventilation, in resting COPD patients and healthy participants. Following a bout of rhythmic hand grip exercise, post exercise circulatory occlusion (PECO) was applied to the resting forearm to sustain activation of the muscle metaboreflex, in 18 COPD patients (FEV 1 /FVC ratio < 70%), 9 also classified as chronically hypercapnic, and 9 ageand gender-matched controls. The cardiovascular response to exercise and the sustained blood pressure elevation during PECO was similar in patients and controls. During exercise ventilation increased by 6.64 ± 0.84 in controls and significantly (P < 0.05) more, 8.38 ± 0.81 l min −1 , in patients. During PECO it fell to baseline levels in controls but remained significantly (P < 0.05) elevated by 2.78 ± 0.51 l min −1 in patients until release of circulatory occlusion, with no significant difference in responses between patient groups. Muscle metaboreflex activation causes increased ventilation in COPD patients but not in healthy participants. Chronic hypercapnia in COPD patients does not exaggerate this response. The muscle metaboreflex appears to be abnormally involved in the control of ventilation in COPD and may be a contributing factor to exercise dyspnoea.

New Findings What is the central question of this study?Classically, the stimulation of thin‐fibre skeletal muscle afferents, via the application of postexercise circulatory occlusion (PECO) at rest, fails to generate ventilatory responses. We used a new experimental protocol to examine whether the involvement of these metabosensitive afferents in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. What is the main finding and its importance?We found that PECO of one leg augmented the ventilatory and heart rate responses to single‐legged exercise of the contralateral leg, suggesting that metaboreceptive muscle afferents contribute to the control of the exercise hyperpnoea. Abstract Inhibition of thin‐fibre skeletal muscle afferent neurotransmission attenuates ventilatory and cardiovascular responses to exercise. However, stimulation of muscle metaboreceptive afferents at rest, via postexercise circulatory occlusion (PECO), classically fails to generate increases in ventilation or heart rate. It is possible that the involvement of muscle afferent feedback in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. Therefore, we assessed the cardiorespiratory responses to single‐legged cycling exercise with or without PECO of the contralateral leg. Thirteen healthy participants performed left‐legged cycling exercise (40 or 60 W) followed by either: (i) no PECO (Con trial); or (ii) PECO (PECO trial) of the left leg for 3 min. During this 3 min period, right‐legged cycling exercise was performed at the same workload as the preceding left‐legged exercise (40 or 60 W). During 60 W right‐legged cycling, ventilation relative to baseline was significantly higher in the PECO versus Con trial (22.9 ± 2 versus 18.7 ± 1.8 l min−1; P < 0.05), but there was no difference between the trials performed at 40 W. The change in heart rate was significantly greater during right‐legged cycling in the PECO versus Con trial in the 40 (41.2 ± 4 versus 34.1 ± 3.1 beats min−1; P < 0.05) and 60 W trials (49.7 ± 2.7 versus 43.4 ± 3.7 beats min−1; P < 0.05). There were no differences in oxygen uptake, carbon dioxide production and ratings of perceived exertion between trials. These findings suggest that stimulation of muscle metaboreceptive afferents can drive increases in ventilation and heart rate during dynamic exercise.

The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO 2 /H + ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients. K E Y W O R D Sexercise, muscle afferent feedback, respiratory control

The inspired sine-wave technique (IST) is a new method that can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal breaths, the concentration of a tracer gas (i.e. nitrous oxide, N O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sine wave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV /FRC , ELV /FRC and ELV /ELV ). This investigation aimed to determine the repeatability and agreement of ELV with FRC and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent. Forty-eight healthy never-smoker participants (20-86 years) underwent traditional pulmonary function testing (e.g. spirometry, body plethysmography) and the IST test, which consisted of 4 min of quiet breathing through a face mask while inspired N O concentrations were oscillated in a sine-wave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 or 60 s. The ELV /FRC and ELV /FRC were age dependent (average decreases of 0.58 and 0.48% year ), suggesting an increase in VH with advancing age. The ELV showed a mean bias of -1.09 litres versus FRC , but when normalized for the effects of age this bias reduced to -0.35 litres. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be taken into account in clinical investigations.

New Findings r What is the central question of this study?During hypercapnia but not normocapnia, activation of muscle afferents by postexercise circulatory occlusion increases ventilation, possibly due to additional activation of metabolite-stimulated muscle afferents. Alternatively, chemoreflex activation caused by hypercapnia may have a synergistic interaction with muscle afferent feedback, so stimulating breathing. r What is the main finding and its importance?Muscle afferent activation during muscle hypercapnia with concurrent systemic normocapnia did not increase breathing. With systemic hypercapnia, there was a response that did not change with hyperoxic hypercapnia. A synergistic interaction between central chemoreception and muscle afferent feedback is therefore indicated.During hypercapnia, activation of thin-fibre muscle afferents using postexercise circulatory occlusion (PECO) provokes a ventilatory response not seen in normocapnia. We investigated the ventilatory responses to PECO when hypercapnia was restricted to the active muscle ('Local' trial) or during systemic hypercapnia ('Systemic' trial). In the Local trial, a hypercapnic gas mixture (5% CO 2 in air) was inhaled for 5 min when circulation to the active calf muscle was open, then rapidly closed by thigh-cuff inflation (200 mmHg), immediately before a return to breathing room air and performance of isometric exercise and PECO. In the Systemic trial, circulation through the muscle was closed throughout the exercise and PECO phases, performed during the hypercapnic gas inhalation. In a third trial, in Systemic conditions a hyperoxic hypercapnic gas mixture (95% O 2 and 5% CO 2 ) was breathed for 1 min during PECO ('Hyperoxia' trial). The increase in ventilation during calf muscle exercise was not different between trials. In the Local trial, ventilation fell to pre-exercise levels during PECO, but in the Systemic trial it remained at end-exercise levels (4.9 ± 0.8 l min

Mechanically and metabolically sensitive thin fibre (group III and IV) muscle afferents are activated during exercise, causing reflex cardiovascular responses that are essential to normal cardiovascular control. Impaired exercise performance in some disease states can be linked to abnormal muscle mechanoreflex and muscle metaboreflex activity. A role for this same afferent feedback in contributing to the How to cite this article: White M, Bruce R. The role of muscle mechano and metaboreflexes in the control of ventilation:

Background Cardiac output monitoring can support the management of high-risk surgical patients, but the pulmonary artery catheterisation required by the current ‘gold standard’—bolus thermodilution —has the potential to cause life-threatening complications. We present a novel noninvasive and fully automated method that uses the inspired sinewave technique to continuously monitor cardiac output . Methods Over successive breaths the inspired nitrous oxide (N 2 O) concentration was forced to oscillate sinusoidally with a fixed mean (4%), amplitude (3%), and period (60 s). was determined in a single-compartment tidal ventilation lung model that used the resulting amplitude/phase of the expired N 2 O sinewave. The agreement and trending ability of were compared with during pharmacologically induced haemodynamic changes, before and after repeated lung lavages, in eight anaesthetised pigs. Results Before lung lavage, changes in and from baseline had a mean bias of –0.52 L min −1 (95% confidence interval [CI], –0.41 to –0.63). The concordance between and was 92.5% as assessed by four-quadrant analysis, and polar plot analysis revealed a mean angular bias of 5.98° (95% CI, –24.4°–36.3°). After lung lavage, concordance was slightly reduced (89.4%), and the mean angular bias widened to 21.8° (–4.2°, 47.6°). Impaired trending ability correlated with shunt fraction ( r =0.79, P <0.05). Conclusions The inspired sinewave technique provides continuous and noninvasive monitoring of cardiac output, with a ‘marginal–good’ trending ability compared with cardiac output based on thermodilution. However, the trending ability can be reduced with increasing shunt fraction, such as in acute lung injury.