Is the hypoxic ventilatory response driven by blood oxygen concentration?

Vertebrates breathe faster and deeper when confronted with low oxygen levels in the inspired water or air. The underlying mechanisms for this ubiquitous hypoxic ventilatory response, and the attendant cardiovascular responses, received considerable attention in the latter half of the 19th century. Indeed, the 1938 Nobel Prize in Physiology or Medicine was awarded to Corneille Jean François Heymans for ‘the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration’ (De Castro, 2009). This seminal research established that oxygensensitive chemoreceptors within the carotid body, a small and heavily vascularized structure at the bifurcation of the carotid artery, sense oxygen and relay information on arterial blood gas composition to the central nervous system via the afferent fibres of the glossopharyngeal nerve (also called the sinus nerve). This led to renewed interest in hypoxic reflexes by the biomedical community, but precious little was known about the comparative physiology of hypoxia responses by the time of the Second World War. As part of the ‘Golden Era’ of comparative physiology (1960–1980), many studies began to characterize the ventilatory responses of different vertebrate classes with descriptions of changes in tidal volume, breathing frequency and overall ventilation pattern. It became clear that the magnitude of the ventilatory response and the threshold at which it was elicited differed considerably amongst species. In many cases, such differences in response could be related to the species’ natural environments, i.e. many species living in hypoxic burrows or at high altitude had muted responses that appeared to reflect adaptations that enhance oxygen uptake and delivery. From this, it became clear that the underlying regulation was complex, such that the breathing pattern at any given inspired oxygen level was the end result of a cascade of events (Weibel, 1984). Inmost cases, the actual stimulus to the oxygen-sensitive chemoreceptors was unknown, because few studies measured blood gases. The lack of blood gas measurements posed a particularly pertinent problem in amphibians and reptiles. This is because their undivided heart allows for large cardiac shunts where some systemic blood bypasses the lungs and re-enters the systemic circulation, which means that the partial pressure of oxygen (PO2) in the arterial blood can be considerably lower than inspired levels or even the PO2 within the lungs (Shelton and Burggren, 1976). The actual stimulus to the chemoreceptors (i.e. the PO2 at the chemoreceptor sites) therefore remained uncertain and it was clear that any interpretation of similarities and differences in the ventilatory responses amongst vertebrates required that the relationship between inspired O2, oxygen uptake, blood oxygen levels and acid–base status be clarified.