Respiratory diseases such as chronic obstructive pulmonary disease (COPD) often lead to chronic hypercapnia which may exacerbate progression of the disease, increase risk of mortality and contribute to comorbidities such as cognitive dysfunction. Determining the contribution of hypercapnia per se to adaptations in ventilation and cognitive dysfunction within this patient population is complicated by the presence of multiple comorbidities. Herein, we sought to determine the role of chronic hypercapnia per se on the temporal pattern of ventilation and the ventilatory CO /H chemoreflex by exposing healthy goats to either room air or an elevated inspired CO (InCO ) of 6% for 30 days. A second objective was to determine whether chronic hypercapnia per se contributes to cognitive dysfunction. During 30 days of exposure to 6% InCO , steady-state (SS) ventilation ( ) initially increased to 335% of control, and then within 1-5 days decreased and stabilized at ∼230% of control. There was an initial respiratory acidosis that was partially mitigated over time due to increased arterial [HCO ]. There was a transient decrease in the ventilatory CO /H chemoreflex, followed by return to pre-exposure levels. The SS during chronic hypercapnia was greater than predicted from the acute CO /H chemoreflex, suggesting separate mechanisms regulating SS and the chemoreflex. Finally, as assessed by a shape discrimination test, we found a sustained decrease in cognitive function during chronic hypercapnia. We conclude that chronic hypercapnia per se results in: (1) a disconnect between SS and the CO /H chemoreflex, and (2) deterioration of cognitive function.

Patients that retain CO2 with respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. However, little is known about the effects of chronic hypercapnia on the neurochemical mechanisms controlling brainstem respiratory nuclei (BRN). Common mechanisms of neuroplasticity involve changes in glutamate receptor expression/phosphorylation to modulate synaptic strength and network excitability, driven by changes in both AMPA (GluR) and NMDA (GluN) glutamate receptors. Accordingly, herein we tested the hypothesis that changes occur in glutamatergic signaling within the BRN during exposure to chronically elevated inspired CO2 (InCO2) induced hypercapnia. Healthy goats were euthanized after either 24 hours or 30 days of chronic exposure to 6% InCO2 or room air. The brainstems were extracted for western blot analyses to assess GluR and GluN receptor expression and phosphorylation state within the BRN. Compared to room air control goats, the following significant (P<0.05) changes were found after 24 hours of exposure to chronic hypercapnia: 1) AMPA receptor expression was greater, and NMDA receptor expression lower within the rostral solitary complex. 2) NMDA receptor expression/phosphorylation and APMA receptor phosphorylation were lower within the rostral ventrolateral medulla (VLM), while AMPA receptor expression/phosphorylation were greater in the caudal VLM. 3) AMPA receptor expression/phosphorylation were lower within the rostral retrotrapezoid nucleus. And, 4) NMDA receptor expression was greater within the caudal Raphe nucleus. The data indicate that within 24 hours of chronic hypercapnia changes have occurred in four BRN in GluR/GluN signaling which may contribute to an attenuated CO2‐induced hyperpnea and attenuated CO2 chemoreflex between 1 and 24 hours of hypercapnia (J. Physiol. 2018). GluR/GluN changes found at 24 hours of hypercapnia had returned to control levels after 30 days of hypercapnia. However, compared to room air control goats, the following significant (P<0.05) changes were found following 30 days of hypercapnia: 1) NMDA receptor phosphorylation was greater in the caudal ventral respiratory column, and 2) AMPA receptor expression was greater in the caudal RTN. The changes in GluR/GluN signaling between 24 hours and 30 days of chronic InCO2 may contribute to a sustained hyperpnea and normalization of the CO2 chemoreflex at 30 days. Support or Funding Information ‐Department of Veteran Affairs ‐NIH Grant 007852 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Despite the prevalence of CO 2 retention in human disease, little is known about the adaptive neurobiological effects of chronic hypercapnia. We have recently shown 30-d exposure to increased inspired CO 2 (InCO 2 ) leads to a steady-state ventilation that exceeds the level predicted by the sustained acidosis and the acute CO 2 /H + chemoreflex, suggesting plasticity within respiratory control centers. Based on data showing brainstem changes in aminergic and inflammatory signaling during carotid body denervation-induced hypercapnia, we hypothesized chronic hypercapnia per se will lead to similar changes. We found that: 1) increased InCO 2 increased IL-1b in the medullary raphe (MR), ventral respiratory column, and cuneate nucleus after 24 h, but not after 30 d of hypercapnia; 2) the number of serotonergic and total neurons were reduced within the MR and ventrolateral medulla following 30 d of increased InCO 2 ; 3) markers of tryptophan metabolism were altered following 24 h, but not 30 d of InCO 2 ; and 4) there were few changes in brainstem amine levels following 24 h or 30 d of increased InCO 2 . We conclude that these changes may contribute to initiating or maintaining respiratory neuroplasticity during chronic hypercapnia but alone do not account for ventilatory acclimatization to chronic increased InCO 2 .-Burgraff, N.

Patients that retain CO2 with respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. However, little is known about the effects of chronic hypercapnia on the neurochemical mechanisms controlling brainstem respiratory nuclei (BRN). Common mechanisms of neuroplasticity involve changes in glutamate receptor expression/phosphorylation to modulate synaptic strength and network excitability, driven by changes in both AMPA (GluR) and NMDA (GluN) glutamate receptors. Accordingly, herein we tested the hypothesis that changes occur in glutamatergic signaling within the BRN during exposure to chronically elevated inspired CO2 (InCO2) induced hypercapnia. Healthy goats were euthanized after either 24 hours or 30 days of chronic exposure to 6% InCO2 or room air. The brainstems were extracted for western blot analyses to assess GluR and GluN receptor expression and phosphorylation state within the BRN. Compared to room air control goats, the following significant (P<0.05) changes were found after 24 hours of exposure to chronic hypercapnia: 1) AMPA receptor expression was greater, and NMDA receptor expression lower within the rostral solitary complex. 2) NMDA receptor expression/phosphorylation and APMA receptor phosphorylation were lower within the rostral ventrolateral medulla (VLM), while AMPA receptor expression/phosphorylation were greater in the caudal VLM. 3) AMPA receptor expression/phosphorylation were lower within the rostral retrotrapezoid nucleus. And, 4) NMDA receptor expression was greater within the caudal Raphe nucleus. The data indicate that within 24 hours of chronic hypercapnia changes have occurred in four BRN in GluR/GluN signaling which may contribute to an attenuated CO2‐induced hyperpnea and attenuated CO2 chemoreflex between 1 and 24 hours of hypercapnia (J. Physiol. 2018). GluR/GluN changes found at 24 hours of hypercapnia had returned to control levels after 30 days of hypercapnia. However, compared to room air control goats, the following significant (P<0.05) changes were found following 30 days of hypercapnia: 1) NMDA receptor phosphorylation was greater in the caudal ventral respiratory column, and 2) AMPA receptor expression was greater in the caudal RTN. The changes in GluR/GluN signaling between 24 hours and 30 days of chronic InCO2 may contribute to a sustained hyperpnea and normalization of the CO2 chemoreflex at 30 days.Support or Funding Information‐Department of Veteran Affairs ‐NIH Grant 007852This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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