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

Departments of 1 Physiology and 4 Pharmacology, School of Medicine, National Yang-Ming University, Taipei; 2 Department of Physiology, College of Medicine, Chung-Shan Medical University, Taichung; and 3 Department of Physiology, Taipei Medical University, Taipei, Taiwan Submitted 15 February 2006 ; accepted in final form 11 April 2006 Inhalation of H 2 O 2 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 2 O 2 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 ( ) = –53%] or a P2X purinoceptor antagonist [ iso -pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (PPADS); = –47%] and was further reduced by capsazepine and iso -PPADS in combination ( = –78%). The initial bradypneic response was reduced by a cyclooxygenase inhibitor (indomethacin; = –48%), ATP scavengers (apyrase and adenosine deaminase in combination; = –50%), or capsazepine and indomethacin in combination ( = –47%), was further reduced by iso -PPADS and indomethacin in combination ( = –75%) or capsazepine and ATP scavengers in combination ( = –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 H 2 O 2 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 2 O 2 -evoked delayed tachypnea. lung; vagal sensory receptors; sensory transduction; cyclooxygenase metabolites; adenosine 5'-triphosphate Address for reprint requests and other correspondence: Y. R. Kou, Dept. of Physiology, School of Medicine, National Yang-Ming Univ., Shih-Pai, Taipei 112, Taiwan (e-mail: yrkou{at}ym.edu.tw )