Abstract
Complex mechanisms that detect changes in brainstem parenchymal PCO2/[H+] and trigger adaptive changes in lung ventilation are responsible for central respiratory CO2 chemosensitivity. Previous studies of chemosensory signalling pathways suggest that at the level of the ventral surface of the medulla oblongata (VMS), CO2-induced changes in ventilation are (at least in part) mediated by the release and actions of ATP and/or acetylcholine (ACh). Here we performed simultaneous real-time biosensor recordings of CO2-induced ATP and ACh release from the VMS in vivo and in vitro, to test the hypothesis that central respiratory CO2 chemosensory transduction involves simultaneous recruitment of purinergic and cholinergic signalling pathways. In anaesthetised and artificially ventilated rats, an increase in inspired CO2 triggered ACh release on the VMS with a peak amplitude of ~5 μM. Release of ACh was only detected after the onset of CO2-induced activation of the respiratory activity and was markedly reduced (by ~70%) by ATP receptor blockade. In horizontal slices of the VMS, CO2-induced release of ATP was reliably detected, whereas CO2 or bath application of ATP (100 μM) failed to trigger release of ACh. These results suggest that during hypercapnia locally produced ATP induces or potentiates the release of ACh (likely from the medullary projections of distal groups of cholinergic neurones), which may also contribute to the development and/or maintenance of the ventilatory response to CO2.
Highlights
Breathing is a vital physiological function that maintains constant levels of the arterial and brain PCO2/pH to support metabolic demands under ever-changing physiological and environmental conditions
In horizontal slices of the VMS, CO2-induced release of ATP was reliably detected, whereas CO2 or bath application of ATP (100 μM) failed to trigger release of ACh. These results suggest that during hypercapnia locally produced ATP induces or potentiates the release of ACh, which may contribute to the development and/or maintenance of the ventilatory response to CO2
ACh Release from the Medulla Oblongata models of central respiratory CO2 chemosensitivity have centred around the function of the so-called retrotrapezoid nucleus (RTN) located near the ventral surface of the medulla (VMS) oblongata, as loss of RTN neurons abolishes CO2-induced recruitment of the expiratory activity and significantly reduces CO2-induced enhancement of the inspiratory activity [11,12,13]
Summary
Breathing is a vital physiological function that maintains constant levels of the arterial and brain PCO2/pH to support metabolic demands under ever-changing physiological and environmental conditions. Investigations of the signalling mechanisms underlying central respiratory CO2 chemosensitivity suggested that at the VMS, acidification-induced changes in breathing are mediated by the release and actions of acetylcholine (ACh) [14, 15]. Central respiratory CO2 chemosensory transduction may involve simultaneous recruitment of purinergic and cholinergic signalling pathways similar to those employed for chemosensory transduction in the carotid body [22,23,24]. We tested this hypothesis by making simultaneous real-time biosensor recordings of CO2-evoked release of ATP and ACh from the VMS in anaesthetised and artificially ventilated rats, and reduced preparations of the VMS in vitro. We determined the effect of ATP receptor blockade on ACh release during systemic hypercapnia
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