Brainstem P_CO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation

Abstract

Inputs from central (brainstem) and peripheral (carotid body) respiratory chemoreceptors are coordinated to protect blood gases against potentially deleterious fluctuations. However, the mathematics of the steady-state interaction between chemoreceptors has been difficult to ascertain. Further, how this interaction affects time-dependent phenomena (in which chemoresponses depend upon previous experience) is largely unknown. To determine how central P CO 2 modulates the response to peripheral chemostimulation in the rat, we utilized an in situ arterially perfused, vagotomized, decerebrate preparation, in which central and peripheral chemoreceptors were perfused separately (i.e. dual perfused preparation (DPP)). We carried out two sets of experiments: in Experiment 1, we alternated steady-state brainstem P CO 2 between 25 and 50 Torr in each preparation, and applied specific carotid body hypoxia (60 Torr P O 2 and 40 Torr P CO 2 ) under both conditions; in Experiment 2, we applied four 5 min bouts (separated by 5 min) of specific carotid body hypoxia (60 Torr P O 2 and 40 Torr P CO 2 ) while holding the brainstem at either 30 Torr or 50 Torr P CO 2 . We demonstrate that the level of brainstem P CO 2 modulates (a) the magnitude of the phrenic responses to a single step of specific carotid body hypoxia and (b) the magnitude of time-dependent phenomena. We report that the interaction between chemoreceptors is negative (i.e. hypo-additive), whereby a lower brainstem P CO 2 augments phrenic responses resulting from specific carotid body hypoxia. A negative interaction may underlie the pathophysiology of central sleep apnoea in populations that are chronically hypocapnic.

Hypocapnia increases the prevalence of hypoxia-induced augmented breaths

“…While this specific hypothesis remains to be tested, an interaction between central and peripheral chemoreflexes has already been demonstrated by several other investigators. It has been found that central hypocapnia, or alkalosis, results in an augmented respiratory response to peripheral chemoreceptor stimulation (5,17,66). In other words, when hypoxia is accompanied by central hypocapnia, ventilation is greater than it is when central isocapnia is maintained.…”

Neonatal stress and attenuation of the hypercapnic ventilatory response in adult male rats: the role of carotid chemoreceptors and baroreceptors

“…Nevertheless, these data suggest that results obtained in isolated organs, such as the in vitro carotid body preparation may not always apply to the ventilatory response observed at the whole animal level. There is growing evidence indicating that peripheral and central chemoreceptors are interdependent, such that the sensitivity of the medullary chemoreceptors is highly determined by input from carotid bodies and perhaps by other sensory afferents (4,10,11,57). Although difficult to explain and reconcile with current knowledge, one must keep in mind that the nature of the interdependence between central and peripheral chemoreceptors remains controversial as various types of interactions (e.g., hypoadditive and hyperadditive) have been reported, owing, in part, to differences in experimental approaches used (57).…”

“…On the basis of indirect evidence indicating that NMS augments carotid body's responsiveness to hypoxia (35,36), it was proposed that the relative hyperoxia that occurs during hypercapnic hyperpnea [ϳ20 mmHg increase (34)] is sufficient to attenuate the CO 2 response of NMS rats (21). However, the recent evidence indicating that central and peripheral chemoreceptors are interdependent and influence each other's sensitivity (4,10,11,57) raises the possibility that NMS disrupts this interaction.…”

AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea

“…Ventilatory movements are delivered by respiratory central pattern generators (rCPGs) distributed bilaterally in the pons and ventral medulla. These semiautonomous neural networks comprise core circuits of excitatory and inhibitory interneurons that deliver rhythmic patterns of activity (10) and confer a set point about which respiratory rhythm is continuously modulated through the integration of inputs from those central (10,11) and peripheral (12) chemosensors that monitor O 2 , CO 2 , and pH. It is generally accepted that the carotid bodies represent the primary arterial chemoreceptors (12) and that the acute hypoxic ventilatory response (HVR) is delivered by increased afferent discharge from the carotid bodies to the rCPGs via, in great part, catecholaminergic networks within the caudal brainstem (13,14).…”