Role of hyperpnea in the relaxant effect of inspired CO2 on methacholine-induced bronchoconstriction

: Inhaling carbon dioxide (CO2) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO2 on airway smooth muscle or to changes in minute ventilation (e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy and mild asthmatics while breathing air or gas mixtures containing 2% or 4% CO2. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R5) was significantly higher in asthmatics (2.53±0.38 cm H2O•L-1•s) than healthy subjects (2.11±0.42 cm H2O•L-1•s) (p=0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. e, tidal volume (VT), and breathing frequency (BF) significantly increased with CO2-containing mixtures (p<0.001) with insignificant differences between groups. After methacholine, the increase in R5 and the decrease in respiratory reactance (X5) were significantly attenuated up to about 50% with CO2-containing mixtures instead of room air in both asthmatic (p<0.001) and controls (p<0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO2 was due to the increase in e (p=0.006 for R5 and p=0.014 for X5) independently of the increase in VT or BF, rather than a direct effect of CO2. These findings suggest that the increased stretching of airway smooth muscle by the CO2-induced increase in e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy and mild asthmatic subjects.