title: Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats.
abstract: Capsaicin-sensitive lung vagal afferents (CSLVAs) are important in detecting pulmonary reactive oxygen species (ROS). We investigated the mechanisms underlying the stimulation of CSLVAs by inhaled cigarette smoke (CS) in 216 anesthetized rats. In spontaneously breathing rats, CS evoked a CSLVA-mediated reflex bradypnea that was prevented by N-acetyl-L-cysteine (NAC; an antioxidant), HC-030031 [a transient receptor potential ankyrin 1 (TRPA1) receptor antagonist], and iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate (iso-PPADS; a P2X receptor antagonist). In paralyzed, artificially ventilated rats, CS evoked an increase in CSLVA fiber activity (DeltaFA) that was abolished by NAC and was attenuated by HC-030031, iso-PPADS, indomethacin (Indo; a cyclooxygenase inhibitor), and a combination of apyrase and adenosine deaminase (ADA) (ATP scavengers); the response to CS was reduced to 11.7+/-4.0%, 39.5+/-10.0%, 52.9+/-14.4%, 68.7+/-10.1%, and 47.2+/-12.9% of control, respectively. The suppressive effect on this afferent response was not improved by a combination of HC-030031 and Indo (DeltaFA=39.5+/-10.1% of control) compared with that induced by HC-030031 alone. In contrast, the suppressive effect was enhanced by a combination of HC-030031 and apyrase+ADA (DeltaFA=5.3+/-4.9% of control) or a combination of iso-PPADS and Indo (DeltaFA=23.3+/-7.7% of control) compared with that induced by HC-030031 alone or iso-PPADS alone. This afferent response was not altered by the vehicles for these drugs. These results suggest that activations of TRPA1 receptors by cyclooxygenase metabolites and P2X receptors by ATP are both necessary for the ROS-mediated stimulation of CSLVA fibers by CS in rats.
authors.affiliation: Graduate Institute of Medical Sciences, Department of Physiology, School of Respiratory Therapy, College of Medicine, Taipei Medical University, and Neuroscience Research Center, Department of Respiratory Therapy, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: You Shuei
authors.initials: YS
authors.lastname: Lin
authors.forename: Chun-Chun
authors.initials: CC
authors.lastname: Hsu
authors.forename: Mauo-Ying
authors.initials: MY
authors.lastname: Bien
authors.forename: Hui-Chi
authors.initials: HC
authors.lastname: Hsu
authors.forename: Hsu-Ting
authors.initials: HT
authors.lastname: Weng
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017487:Ankyrins / Q000819:agonists* / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001081:Apyrase / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D019570:Inhalation Exposure; D008168:Lung / Q000294:innervation*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D012018:Reflex / Q000187:drug effects; D012121:Respiration, Artificial; D015656:Respiratory Mechanics / Q000187:drug effects; D018689:Sensory System Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism
chemical_list: D017487:Ankyrins; D000975:Antioxidants; D015220:Calcium Channels; D016861:Cyclooxygenase Inhibitors; D058910:Purinergic P2 Receptor Agonists; D017382:Reactive Oxygen Species; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D018689:Sensory System Agents; D012906:Smoke; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D000243:Adenosine Deaminase; D001081:Apyrase; D002211:Capsaicin; D000111:Acetylcysteine; D007213:Indomethacin