Influence of indomethacin on ventilatory and cerebrovascular responsiveness to CO2 and breathing stability: The influence of PCO2 gradients

Indomethacin (INDO), a reversible cyclooxygenase inhibitor, is a useful tool for assessing the role of cerebrovascular reactivity on ventilatory control. Despite this, the effect of INDO on breathing stability during wakefulness has yet to be examined. Although the effect of reductions in cerebrovascular CO₂ reactivity on ventilatory CO₂ sensitivity is likely dependent upon the method used, no studies have compared the effect of INDO on steady-state and modified rebreathing estimates of ventilatory CO₂ sensitivity. The latter method includes the influence of PCO₂ gradients and cerebral perfusion, whereas the former does not. We examined the hypothesis that INDO-induced reduction in cerebrovascular CO₂ reactivity would 1) cause unstable breathing in conscious humans and 2) increase ventilatory CO₂ sensitivity during the steady-state method but not during rebreathing methods. We measured arterial blood gases, ventilation (V̇E), and middle cerebral artery velocity (MCAv) before and 90 min following INDO ingestion (100 mg) or placebo in 12 healthy participants. There were no changes in resting arterial blood gases or V̇E following either intervention. INDO increased the magnitude of V̇E variability (index of breathing stability) during spontaneous air breathing (+4.3 ± 5.2 Δl/min, P = 0.01) and reduced MCAv (-25 ± 19%, P < 0.01) and MCAv-CO₂ reactivity during steady-state (-47 ± 27%, P < 0.01) and rebreathing (-32 ± 25%, P < 0.01). The V̇E-CO ₂ sensitivity during the steady-state method was increased with INDO (+0.5 ± 0.5 l·min^-1·mmHg^-1, P < 0.01), while no changes were observed during rebreathing (P > 0.05). These data indicate that the net effect of INDO on ventilatory control is an enhanced ventilatory loop gain resulting in increased breathing instability. Our findings also highlight important methodological and physiological considerations when assessing the effect of INDO on ventilatory CO₂ sensitivity, whereby the effect of INDO-induced reduction of cerebrovascular CO₂ reactivity on ventilatory CO₂ sensitivity is unmasked with the rebreathing method.