Mechanisms underlying the stimulatory effect of inhaled sulfur dioxide on vagal bronchopulmonary C‐fibres

Abstract

Inhalation of sulfur dioxide (SO₂ ) 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 SO₂ -induced local tissue acidosis in the lung and airways. Single-unit activities of bronchopulmonary C-fibres in response to inhalation challenges of SO₂ (500-1500 p.p.m., 10 breaths) were measured in anaesthetized rats. Inhalation of SO₂ 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 (NaHCO₃ ), 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 SO₂ evoked a transient increase in the intracellular Ca²⁺ concentration; this response was also markedly diminished by a pretreatment with amiloride and AMG8910. In addition, inhalation of SO₂ 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 SO₂ 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.