194 Exp Physiol 95.1 pp 194–201 Experimental Physiology – Research Paper A respiratory response to the activation of the muscle metaboreflex during concurrent hypercapnia in man Christos K. Lykidis 1 , Prem Kumar 2 , Lauro C. Vianna 1 , Michael J. White 1 and George M. Balanos 1 1 School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK 2 Department of Physiology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK In this study, we aimed to assess the ventilatory and cardiovascular responses to the combined activation of the muscle metaboreflex and the ventilatory chemoreflex, achieved by postexercise circulatory occlusion (PECO) and euoxic hypercapnia (end-tidal partial pressure of CO 2 7 mmHg above normal), respectively. Eleven healthy subjects (4 women and 7 men; 29 ± 4.4 years old; mean ± s.d.) undertook the following four trials, in random order: 2 min of isometric handgrip exercise followed by 2 min of PECO with hypercapnia; 2 min of isometric handgrip exercise followed by 2 min of PECO while breathing room air; 4 min of rest with hypercapnia; and 4 min of rest while breathing room air. Ventilation was significantly increased during exercise in both the hypercapnic (+3.17 ± 0.82 l min -1 ) and the room air breathing trials (+2.90 ± 0.26 l min -1 ; all P < 0.05). During PECO, ventilation returned to pre-exercise levels when breathing room air (+0.52 ± 0.37 l min -1 ; P > 0.05), but it remained elevated during hypercapnia (+3.77 ± 0.23 l min -1 ; P < 0.05). The results indicate that the muscle metaboreflex stimulates ventilation with concurrent chemoreflex activation. These findings have implications for disease states where effort intolerance and breathlessness are linked. (Received 22 July 2009; accepted after revision 1 October 2009; first published online 2 October 2009) Corresponding author G. M. Balanos: School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Email: g.m.balanos@bham.ac.uk The involvement of muscle reflexes in the control of the cardiovascular system during exercise is well known (Alam & Smirk 1937; Coote et al. 1971; Rowell & O’Leary, 1990). Likewise, chemoreceptors have been implicated in the regulation of ventilation at rest and during exercise (Dejours, 1962; Whipp, 1994), and signals from both control systems are known to be carried to common areas of the brain where interaction could occur (Spyer, 1994; Smith et al. 2006). Such an interaction was suggested by Ponikowski et al . (2001), who reported that the activity of the muscle metaboreflex was a strong and independent predictor of the exaggerated ventilatory responses to both inhalation of CO 2 and to dynamic exercise in chronic heart failure (CHF) patients. Likewise, it has been shown that the sympathoexcitatory stimuli of lower body negative pressure and head-up tilt have no effect on ventilation in eucapnic conditions, but they significantly enhance ventilation when imposed against a hypercapnic background (Jordan et al. 2000; Howden et al. 2004). However, despite the likelihood that muscle reflexes and the chemoreflex interact during exercise this area has received little direct attention (Makeham et al. 2004). Indeed, in man an interaction between the muscle metaboreflex and the ventilatory chemoreflex has never been demonstrated. Therefore, the aim of this study was to assess human respiratory and cardiovascular responses to the separate activation of the ventilatory chemoreflex and the muscle metaboreflex and definitively, their combined activation. This was achieved by comparison of ventilatory responses to the application of hypercapnia alone and post-isometric exercise circulatory occlusion (PECO) alone, respectively, with the response to PECO applied during hypercapnia. Circulatory occlusion following isometric exercise is known to maintain muscle metaboreflex activation at the levels seen during exertion without having an effect on ventilation, which returns to pre-exercise levels (Rowell et al. 1976; Innes et al. 1989; Haouzi et al. 2001; Fukuba et al. 2007). We hypothesized that during chemoreflex stimulation concurrent activation of the muscle metaboreflex by PECO would sustain ventilation at levels seen during exercise. DOI: 10.1113/expphysiol.2009.049999 C  2009 The Authors. Journal compilation C  2010 The Physiological Society