One and one is not always two: hypo‐ and hyper‐additive effects of the chemoreflex during exercise

The physiological sciences are focused on complex systems, and models are generated to make sense of what is known and what requires further attention. With advances in the study of a given problem, new components are incorporated into existing models and other disproven components are removed. Dr George Box, a British statistician, is credited with the following: ‘All models are wrong but some models are useful.’ With remarkable clarity and brevity, this colourful expression emphasizes the need for a cautionary approach to interpreting models across most scientific fields. Nowhere is this sentiment more applicable than the myriad of models used to understand human cardiovascular and respiratory control during exercise where conflicting and contradictory conclusions can be drawn depending upon what is, and what isn't, included in a physiological model. To meet the metabolic demands of working muscle during exercise, a number of cardiovascular and haemodynamic adjustments are required, which are largely governed by alterations in the sympathetic and parasympathetic branches of the autonomic nervous system. In general terms (i.e. a simplified model), the adjustments are brought about by central command, the exercise pressor reflex (EPR), the arterial baroreflex and the cardiopulmonary baroreflex. Recent work has added to the model by demonstrating that the chemoreflex (CR) via the arterial chemoreceptors makes an important contribution to the feedback sympathetic control of skeletal muscle blood flow during exercise (Stickland et al. 2011). Specifically, stimulation of the O2-sensitive arterial chemoreceptors increases sympathetic outflow, mean arterial pressure, and vascular resistance during exercise and restricts blood flow to active skeletal muscle. In this issue of the Journal, Wan et al. (2020) have provided an important advance to the model of cardiovascular control and have exceeded the ‘useful’ designation in fine form! Their careful and clever approach has provided new information about how the EPR and CR interact during exercise and exert influences on cardiovascular regulation. Submaximal one-legged knee extension, used as a model of exercise, was performed by healthy young male and female participants. The six experimental conditions consisted of control trials or manipulation of EPR by lumbar intrathecal fentanyl to attenuate group III/IV afferent feedback from the working leg. To assess the CR contribution, the trials were performed while (i) breathing normoxia (control inspirate), (ii) normocapnic hypoxia (to modulate the O2-CR), and (iii) normoxic hypercapnia (to modulate the CO2-CR). By systematically altering the EPR and CR, it was possible to make conclusions regarding the individual and interactive effects of the EPR and CR reflexes. Activation and attenuation of the EPR during normoxic exercise elicited the expected cardiac and vascular responses. Co-activation of the EPR and the O2-CR resulted in increases in mean arterial pressure and heart rate that were larger than the summation of the individual reflexes (i.e. a hyper-additive interaction). The leg blood flow and conductance values were lower during EPR:O2-CR co-activation relative to the sum of the responses of each reflex (i.e. a hypo-additive interaction). Co-activation of the EPR:CO2-CR elicited a simple addition of the haemodynamic response evoked by each reflex in isolation. The authors interpreted these observations to mean that in exercising humans the type of CR will dictate the magnitude of the EPR:CR interaction and the corresponding cardiovascular changes. There is accumulating evidence to show that the CR plays an important role in cardiovascular control during exercise in health (Stickland et al. 2011; Wan et al. 2020). It should now be clear that the activation of the CR, along with the type of activation, should be considered within a ‘useful’ model of cardiovascular control during dynamic exercise. Under what ‘naturally occurring’ circumstances might the EPR:CR interaction be relevant to the human performing dynamic exercise? Chronic heart failure (CHF) is characterized by exercise intolerance and both human and experimental animal models have shown the independent effects of an altered EPR and CR. First, during exercise in CHF there is an increased reliance on glycolytic vs. oxidative metabolism along with alterations in muscle fibre type and mitochondrial function. The fast depletion of high-energy phosphates and early onset of acidosis causes stimulation of type III/IV afferent fibres within working skeletal muscle leading to a triggering of the EPR and sympathetic overactivation. As suggested elsewhere (Ponikowski et al. 2001), stimulation of the EPR in CHF is likely to be important in the origin of the symptoms limiting exercise as well as in the progression of the disease. Second, there is a growing appreciation that the sensitivity of the carotid chemoreceptors (CCs) is increased in CHF both at rest and during exercise and contributes to increased sympathetic activity. It is important to recognize that while the CCs are sensitive to changes in O2 they are also sensitive to several other metabolites produced with exercise. As such, increases in exercise-induced metabolite production in CHF may be ‘sensed’ by the CCs and in turn contribute to a greater sympathetic vasoconstrictor activity and sympathetic restraint of blood flow. Physical training is a cornerstone of patient management and unravelling the complexities of EPR:CR interactions may lead to more specific and effective exercise interventions and rehabilitation strategies for CHF patients (Marcus et al. 2015), although much additional work is required. The work of Wan et al. (2020) demonstrates the importance of including chemoreceptors when creating a framework to understand the physiological adjustments to exercise. Their work highlights the need to appreciate the integrative nature of whole-body exercise in healthy humans as well as other states such as CHF and metabolic disorders (Limberg, 2018). The authors have no conflicts of interests related to this paper. AWS and CMP conceptualized and designed the work. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. 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