Abstract
The activation of capsaicin-sensitive lung vagal (CSLV) afferents can elicit airway reflexes. Hypersensitivity of these afferents is known to contribute to the airway hypersensitivity during airway inflammation. Hydrogen sulfide (H2S) has been suggested as a potential therapeutic agent for airway hypersensitivity diseases, such as asthma, because of its relaxing effect on airway smooth muscle and anti-inflammatory effect. However, it is still unknown whether H2S affects airway reflexes. Our previous study demonstrated that exogenous application of H2S sensitized CSLV afferents and enhanced Ca2+ transients in CSLV neurons. The present study aimed to determine whether the H2S-induced sensitization leads to functional changes in airway reflexes and elevates the electrical excitability of the CSLV neurons. Our results showed that, first and foremost, in anesthetized, spontaneously breathing rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a donor of H2S; 5 mg/mL, 3 min) caused an enhancement in apneic response evoked by several stimulants of the CSLV afferents. This enhancement effect was found 5 min after NaHS inhalation and returned to control 30 min later. However, NaHS no longer enhanced the apneic response after perineural capsaicin treatment on both cervical vagi that blocked the conduction of CSLV fibers. Furthermore, the enhancing effect of NaHS on apneic response was totally abolished by pretreatment with intravenous HC-030031 (a TRPA1 antagonist; 8 mg/kg), whereas the potentiating effect was not affected by the pretreatment with the vehicle of HC-030031. We also found that intracerebroventricular infusion pretreated with HC-030031 failed to alter the potentiating effect of NaHS on the apneic response. Besides, the cough reflex elicited by capsaicin aerosol was enhanced by inhalation of NaHS in conscious guinea pigs. Nevertheless, this effect was entirely eliminated by pretreatment with HC-030031, not by its vehicle. Last but not least, voltage-clamp electrophysiological analysis of isolated rat CSLV neurons showed a similar pattern of potentiating effects of NaHS on capsaicin-induced inward current, and the involvement of TRPA1 receptors was also distinctly shown. In conclusion, these results suggest that H2S non-specifically enhances the airway reflex responses, at least in part, through action on the TRPA1 receptors expressed on the CSLV afferents. Therefore, H2S should be used with caution when applying for therapeutic purposes in airway hypersensitivity diseases.
Highlights
Hydrogen sulfide (H2S) is a colorless gas with an odor of rotten eggs and a potent inhaled irritant
We demonstrated that H2S induces hypersensitivity of capsaicin-sensitive lung vagal (CSLV) afferents via TRPA1 receptors [15], which is a potent leading cause of airway hypersensitivity [16]
A right atrial bolus injection of capsaicin (1 μg/kg) elicited an inhibitory breathing pattern that was characterized by an apnea and reduced respiratory frequency
Summary
Hydrogen sulfide (H2S) is a colorless gas with an odor of rotten eggs and a potent inhaled irritant. The inhalation of H2S might lead to several adverse airway responses, such as cough, airway irritation, airway hypersensitivity, and lung inflammation [1,2]. H2S is involved in a variety of functions, such as vasodilation [3], neuronal function regulation [4], inflammation [5], cellular signaling, and smooth muscle relaxation [6]. In 1996, Abe and Kimura first reported that, as an endogenous mediator, H2S regulates the neuronal function in CNS [7]. H2S might play a role in the pathogenesis of asthma, and its level could be a biomarker of asthma. H2S was reported to cause relaxation in mouse bronchial smooth muscle [6]. H2S was suggested as a treatment of asthma, its role is still controversial
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