Sensitization of vagal lung C-fibers (VLCFs) induced by mediators contributes to the pathogenesis of airway hypersensitivity, which is characterized by exaggerated sensory and reflex responses to stimulants. Reactive oxygen species (ROS) are mediators produced during airway inflammation. However, the role of ROS in VLCF-mediated airway hypersensitivity has remained elusive. Here, we report that inhalation of aerosolized 0.05% H2O2 for 90 s potentiated apneic responses to intravenous capsaicin (a TRPV1 receptor agonist), α,β-methylene-ATP (a P2X receptor agonist), and phenylbiguanide (a 5-HT3 receptor agonist) in anesthetized rats. The apneic responses to these three stimulants were abolished by vagatomy or by perivagal capsaicin treatment, a procedure that blocks the neural conduction of VLCFs. The potentiating effect of H2O2 on the apneic responses to these VLCF stimulants was prevented by catalase (an enzyme that degrades H2O2) and by dimethylthiourea (a hydroxyl radical scavenger). The potentiating effect of H2O2 on the apneic responses to capsaicin was attenuated by HC-030031 (a TRPA1 receptor antagonist) and by iso-pyridoxalphosphate-6-azophenyl-2′,5′-disulphonate (a P2X receptor antagonist). The potentiating effect of H2O2 on the apneic responses to α,β-methylene-ATP was reduced by capsazepine (a TRPV1 receptor antagonist), and by HC-030031. The potentiating effect of H2O2 on the apneic responses to phenylbiguanide was totally abolished when all three antagonists were combined. Consistently, our electrophysiological studies revealed that airway delivery of aerosolized 0.05% H2O2 for 90 s potentiated the VLCF responses to intravenous capsaicin, α,β-methylene-ATP, and phenylbiguanide. The potentiating effect of H2O2 on the VLCF responses to phenylbiguanide was totally prevented when all antagonists were combined. Inhalation of 0.05% H2O2 indeed increased the level of ROS in the lungs. These results suggest that 1) increased lung ROS sensitizes VLCFs, which leads to exaggerated reflex responses in rats and 2) the TRPV1, TRPA1, and P2X receptors are all involved in the development of this airway hypersensitivity.

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The effects of an acute increase in intraureteral pressure (IUP) on pelvic-urethra reflex potentiation were examined in urethane-anesthetized rats by recording the external urethral sphincter electromyogram activities evoked by the pelvic afferent stimulation. Compared with a single action potential elicited by the test stimulation (TS; characterized by an intensity that evoked a constant reflex response without facilitation, 1/30 Hz, 1.03 +/- 0.12 spikes/stimulation, n = 7), the repetitive stimulation [RS; identical stimulation intensity as the TS (1 Hz)] significantly induced spinal reflex potentiation (SRP; 16.90 +/- 2.00 spikes/stimulation, P < 0.01, n = 7). Such SRP was significantly attenuated by intrathecal 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline [NBQX; a glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionat (AMPA) receptor antagonist] and d-2-amino-5-phosphonovalerate [APV; a glutamatergic N-methyl-d-aspartate (NMDA) antagonist; the spike number per stimulation: 11.0 +/- 0.70 for NBQX, 1.01 +/- 0.30 for APV, and 16.90 +/- 2.0 for RS, respectively, n = 7, P < 0.01]. Acute stepwise elevations of IUP gradually attenuated and eventually abolished the RS-induced SRP (16.80 +/- 1.30, 17.00 +/- 1.30, 16.30 +/- 1.30, 10.50 +/- 1.80, 8.80 +/- 1.90, 3.50 +/- 1.60, 0.80 +/- 0.20, 0.70 +/- 0.20, and 0.20 +/- 0.10 spikes/stimulation at intraureteral pressure of 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 cmH(2)O, respectively, n = 7). Intrathecal NMDA (a glutamatergic NMDA receptor agonist) and bicuculline (a GABA receptor antagonist) both reversed the abolition of RS-induced SRP caused by unilateral ureteral distension (14.0 +/- 4.04 and 8.00 +/- 1.53 spikes/stimulation, respectively, n = 7, P < 0.01). All the results suggested unilateral ureteral distension might compensatorily relax the urethra via GABAergic inhibition of NMDA-dependent SRP.

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