Mediator mechanisms involved in TRPV1 and P2X receptor-mediated, ROS-evoked bradypneic reflex in anesthetized rats

Inhalation of H₂O₂ is known to evoke bradypnea followed by tachypnea, which are reflexes resulting from stimulation by reactive oxygen species of vagal lung capsaicin-sensitive and myelinated afferents, respectively. This study investigated the pharmacological receptors and chemical mediators involved in triggering these responses. The ventilatory responses to 0.2% aerosolized H₂O₂ were studied before and after various pharmacological pretreatments in anesthetized rats. The initial bradypneic response was reduced by a transient receptor potential vanilloid 1 (TRPV1) receptor antagonist [capsazepine; change (Δ) = -53%] or a P2X purinoceptor antagonist [iso-pyridoxalphosphate-6-azophenyl-2′,5′- disulphonate (PPADS); Δ = -47%] and was further reduced by capsazepine and iso-PPADS in combination (Δ = -78%). The initial bradypneic response was reduced by a cyclooxygenase inhibitor (indomethacin; Δ = -48%), ATP scavengers (apyrase and adenosine deaminase in combination; Δ = -50%), or capsazepine and indomethacin in combination (Δ = -47%), was further reduced by iso-PPADS and indomethacin in combination (Δ = -75%) or capsazepine and ATP scavengers in combination (Δ = -83%), but was not affected by a lipoxygenase inhibitor (nordihydroguaiaretic acid) or by any of the various vehicles. No pretreatment influenced delayed tachypnea. We concluded that 1) the initial bradypneic response to H₂O₂ results from activation of both TRPV1 and P2X receptors, possibly located at terminals of vagal lung capsaicin-sensitive afferent fibers; 2) the functioning of the TRPV1 and P2X receptors in triggering the initial bradypnea is, in part, mediated through the actions of cyclooxygenase metabolites and ATP, respectively; and 3) these mechanisms do not contribute to the H ₂O₂-evoked delayed tachypnea.