Abstract
KEY POINTS: Brief inhalation of SO(2) of concentration >500 p.p.m. triggered a pronounced stimulatory effect on vagal bronchopulmonary C-fibres in anaesthetized rats. This stimulatory effect was drastically diminished by a pretreatment with NaHCO(3) that raised the baseline arterial pH, suggesting a possible involvement of acidification of airway fluid and/or tissue generated by inhaled SO(2) . The stimulation was completely abolished by pretreatment with antagonists of both acid-sensing ion channels and transient receptor potential vanilloid type-1 receptors, indicating that this effect was caused by acid activation of these cation channels expressed in airway sensory nerves. This conclusion was further supported by the results obtained from studies in isolated rat vagal bronchopulmonary sensory neurones and also in the cough response to SO(2) inhalation challenge in awake mice. These results provide new insight into the underlying mechanism of harmful irritant effects in the respiratory tract caused by accidental exposure to a high concentration of SO(2) . ABSTRACT: Inhalation of sulfur dioxide (SO(2) ) triggers coughs and reflex bronchoconstriction, and stimulation of vagal bronchopulmonary C-fibres is primarily responsible. However, the mechanism underlying this stimulatory effect is not yet fully understood. In this study, we tested the hypothesis that the C-fibre stimulation was caused by SO(2) -induced local tissue acidosis in the lung and airways. Single-unit activities of bronchopulmonary C-fibres in response to inhalation challenges of SO(2) (500-1500 p.p.m., 10 breaths) were measured in anaesthetized rats. Inhalation of SO(2) reproducibly induced a pronounced and sustained stimulation (lasting for 15-60 s) of pulmonary C-fibres in a concentration-dependent manner. This stimulatory effect was significantly attenuated by an increase in arterial pH generated by infusion of sodium bicarbonate (NaHCO(3) ), and completely abrogated by a combined pretreatment with amiloride (an antagonist of acid-sensing ion channels, ASICs) and AMG8910 (a selective antagonist of the transient receptor potential vanilloid type-1 receptor, TRPV1). Furthermore, in isolated rat vagal pulmonary sensory neurones, perfusion of an aqueous solution of SO(2) evoked a transient increase in the intracellular Ca(2+) concentration; this response was also markedly diminished by a pretreatment with amiloride and AMG8910. In addition, inhalation of SO(2) consistently evoked coughs in awake mice; responses were significantly smaller in TRPV1(-/-) mice than in wild-type mice, and almost completely abolished after a pretreatment with amiloride in TRPV1(-/-) mice. These results suggested that the stimulatory effect of inhaled SO(2) on bronchopulmonary C-fibres was generated by acidification of fluid and/or tissue in the lung and airways, which activated both ASICs and TRPV1 expressed in these sensory nerves.