Chronic moderate hypercapnia suppresses ventilatory responses to acute CO<sub>2</sub> challenges.

Chronic hypercapnia (CH) is a hallmark of chronic lung disease, and CH increases the risk for acute-on-chronic exacerbations leading to greater hypoxemia/hypercapnia and poor health outcomes. However, the role of hypercapnia per se (duration and severity) in determining an individual's ability to tolerate further hypercapnic exacerbations is unknown. Our primary objective herein was to test the hypothesis that mild-to-moderate CH (arterial [Formula: see text] ∼50-70 mmHg) increases susceptibility to pathophysiological responses to severe acute CO<sub>2</sub> challenges. Three groups (GR) of adult female goats were studied during 14 days of exposure to room air (<i>GR 1</i>; control) or 6% inspired CO<sub>2</sub> (<i>GR 2</i>; mild CH), or 7 days of 6% inspired CO<sub>2</sub> followed by 7 days of 8% inspired CO<sub>2</sub> (<i>GR 3</i>; moderate CH). Consistent with previous reports, there were no changes in physiological parameters in <i>GR 1</i> (RA control), but mild CH (<i>GR 2</i>) increased steady-state ventilation and transiently suppressed CO<sub>2</sub>/[H<sup>+</sup>] chemosensitivity. Further increasing InCO<sub>2</sub> from 6% to 8% (<i>GR 3</i>) transiently increased ventilation and arterial [H<sup>+</sup>]. Similar to mild CH, moderate CH increased ventilation to levels greater than predicted. However, in contrast to mild CH, acute ventilatory chemosensitivity was suppressed throughout the duration of moderate CH, and the arterial - mixed expired CO<sub>2</sub> gradient became negative. These data suggest that moderate CH limits physiological responses to acute severe exacerbations and provide evidence of recruitment of extrapulmonary systems (i.e., gastric CO<sub>2</sub> elimination) during times of moderate-severe hypercapnia.<b>NEW & NOTEWORTHY</b> Moderate levels of chronic hypercapnia (CH; ∼70 mmHg) in healthy adult female goats elicited similar steady-state physiological adaptations compared with mild CH (∼55 mmHg). However, unlike mild CH, moderate CH chronically suppressed acute CO<sub>2</sub>/[H<sup>+</sup>] chemosensitivity and reversed the arterial to mixed expired CO<sub>2</sub> gradient. These findings suggest that moderate CH suppresses vital mechanisms of ventilatory control and recruits additional physiological systems (i.e., gastric CO<sub>2</sub> release) to help buffer excess CO<sub>2</sub>.