VCO: The Essential Underpinning to Homeostatic Control of Breathing.

Abstract

This essay addresses the fundamental mechanism underlying the precise regulation of PaCO2 during steady states of air-breathing eupnea and hyperpnea. First, an argument is made for CO2/Hchemoreception as an important compensatory feedback regulator of breathing and breathing stability, especially during NREM sleep. Tonic contributions to respiratory drive occur from the carotid chemoreceptors and retrotrapezoid nucleus (RTN). A case against chemoreception of PCO2 as the primary homeostatic PaCO2 regulator is made based on conditions where precise PaCO2 control during air-breathing exists even when ventilatory responsiveness to raised PCO2 is markedly subnormal or when a measurable PaCO2 error signal is nonexistent. Alternatively, a case is made that homeostatic ventilatory control incorporates information critically dependent on pulmonary CO2 exchange, as revealed when: a) VCO2, per se, is altered at rest or exercise; b) Vd/VT is raised or lowered; and c) the resting PaCO2 set point is changed, thereby changing respiratory system plant gains. In each of these common conditions, substantial ventilatory adjustments occur to achieve near proportional VA:VCO2 linkages at rest and/or exercise with no coincidence changes in CO2 chemoreception. We view this VCO2-mediated mechanism as a dedicated tracking system for alveolar ventilation that provides an essential underpinning in a traditional hybrid model of homeostatic ventilatory control. While some potential mediators of these VCO2 effects have been suggested, such as an integrative role for the RTN, they remain inadequately explored. It is time to restart enquiry, using modern neuroscience approaches, into the mediation of VCO2 as the critical underpinning to PaCO2 homeostasis. Major advances in our understanding of the neuroscience of cardiorespiratory regulation have been made over the past few decades (1). However, we still do not have consensus on the major tonic drive(s) to breathe which underlie our homeostatic regulation of PaCO2 under most physiologic, air-breathing conditions while at rest or during exercise. This essay addresses the evidence, controversies, unknowns and future needs concerning this fundamental problem. Our primary proposal is that respiratory CO2 exchange serves as the critical determinant and underpinning of eupneic and hyperpneic drives to breathe and does so in the absence of significant influences or dependance on CO2 sensitive chemoreception.