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 (<(V)over dot> E). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma 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 (R-5) was significantly higher in subjects with asthma (2.53 +/- 0.38 cmH(2)O.L-1.s) than healthy subjects (2.11 +/- 0.42 cmH(2)O.L-1.s) (P = 0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. <(V)over dot>E , tidal volume (V-T), and breathing frequency (BF) significantly increased with CO2-containing mixtures (P < 0.001) with insignificant differences between groups. After methacholine, the increase in R-5 and the decrease in respiratory reactance (X-5) 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 <(V)over dot>E (P = 0.006 for R-5 and P = 0.014 for X-5) independently of the increase in V-T 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 <(V)over dot>E is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma. NEW & NOTEWORTHY The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2 significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2 was significantly mediated via an indirect effect of the increment of <(V)over dot>E in response to intrapulmonary hypercapnia.