Our colleagues skillfully addressed how peripheral chemoreceptors interact with systemic effects of CO2. Unfortunately, systemic CO2 affects oxyhaemoglobin dissociation, sympathetic, endocrine and cardiovascular systems, and afferents from lungs and CO2-sensitive upper airway receptors – all capable of having effects on ventilation independent of central chemoreceptors. Duffin's ingenious rebreathing studies add further concerns, namely psychological and physiological aspects of voluntary hyperventilation (e.g. Steinback et al. 2011). Similarly, carotid body denervation (CBD) studies acclaimed by Teppema & Smith (2013) introduce complications including disruption of baroreflex, abolition of central carotid body regulation of sympathetic and parasympathetic outputs, and unknown contribution of changes associated with long-term plasticity. To mitigate these issues, we developed an artificially perfused rat preparation devoid of intact autonomic and respiratory feedback loops, descending and vagal influences (Day & Wilson, 2009).
Demonstrations of hypoadditivity in our preparation are reconcilable with work in humans summarized by Duffin & Mateika (2013). While Duffin & Mateika favour the conclusion of additive interactions, simple addition in ventilation mathematically necessitates hypoadditivity in frequency and/or tidal volume (Mitchell, 1990). Moreover, stimulus and state specific parcelling of responses into frequency and tidal volume suggests hypoadditivity translates to ventilation in certain circumstances. However, our findings are not easily reconciled with a hyperadditive system, as argued by Teppema & Smith (2013). So how do we move forward?
Pigeonholed discussions addressing the nature of interaction have illustrated the importance of type, magnitude, order and pattern of stimulus, and species and preparation used, but have yet to reconcile hypoadditive and hyperadditive camps. Therefore, we suggest the need for a new paradigm: a hybrid model incorporating multiple forms of interaction depending on systemic CO2 and/or physiological state. In support of this new paradigm, we note (a) even the hyperadditive O2–CO2 carotid body interaction transitions to hypoadditive at severe levels (Fitzgerald & Parks, 1971), (b) the additive-to-hyperadditive transition with long term facilitation cited by Duffin & Mateika (2013), and (c) Hodges et al. (2005), cited by Teppema & Smith (2013), is only partly consistent with hyperadditivity. Hodges et al. show that, while both mild and severe hypercapnic brainstem aCSF cause increased ventilation, only responses to severe hypercapnic aCSF were reduced by CBD. Thus, while Teppema & Smith considered only the blunted responses to severe hypercapnic aCSF, lack of CBD effect on responses to mild hypercapnic aCSF argues for hypoadditivity. These data are therefore consistent with a hybrid system that endows respiratory chemosensitivity with redundancy and a large dynamic range.