Mediator mechanisms involved in TRPV1 and P2X receptor-mediated, ROS-evoked bradypneic reflex in anesthetized rats. Inhalation of H 2O2 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 H

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... O2 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 (⌬) ϭ Ϫ53%] or a P2X purinoceptor antagonist [iso-pyridoxalphosphate-6-azophenyl-2Ј,5Ј-disulphonate (PPADS); ⌬ ϭ Ϫ47%] and was further reduced by capsazepine and iso-PPADS in combination (⌬ ϭ Ϫ78%). The initial bradypneic response was reduced by a cyclooxygenase inhibitor (indomethacin; ⌬ ϭ Ϫ48%), ATP scavengers (apyrase and adenosine deaminase in combination; ⌬ ϭ Ϫ50%), or capsazepine and indomethacin in combination (⌬ ϭ Ϫ47%), was further reduced by iso-PPADS and indomethacin in combination (⌬ ϭ Ϫ75%) or capsazepine and ATP scavengers in combination (⌬ ϭ Ϫ83%), 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 H 2O2 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 H2O2-evoked delayed tachypnea. lung; vagal sensory receptors; sensory transduction; cyclooxygenase metabolites; adenosine 5Ј-triphosphate VARIOUS LUNG DISEASES ARE manifested by increased production of pulmonary reactive oxygen species (ROS) (10, 13, 14, 44, 46, 48, 62) . Excess pulmonary ROS have been suggested to stimulate vagal lung afferent fibers and trigger respiratory reflexes under pathological conditions, such as pulmonary air embolism or sepsis