The mechanisms underlying the response of airway afferent nerves to low pH were investigated in an isolated guinea-pig airway nerve preparation. Extracellular recordings were made from single jugular or nodose vagal ganglion neurons that projected their sensory fibers into the airways. The airway tissue containing the mechanically sensitive receptive fields was exposed into acidic solutions. Rapid and transient (approximately 3 s) administration of 1 mM citric acid to the receptive field consistently induced action potential discharge in nociceptive C-fibers (41/44) and nodose Adelta fibres (29/30) that are rapidly adapting low threshold mechanosensors (RAR-like fibres). In contrast, citric acid activated only 8/17 high threshold mechanosensitive jugular Adelta fibres. The RAR-like fibres were slightly more sensitive than C-fibres to acidic solutions (pH threshold > 6.7). The RAR-like fibres response to the approximately 3 s acid treatment was not affected by a vanilloid receptor 1 (VR1) antagonist, capsazepine (10 microM), and was rapidly inactivating (action potential discharge terminated before the acid administration was completed). Gradual reduction of pH did not activate the RAR-like fibres even when the pH was reduced to approximately 5.0. The C-fibres responded to the gradual reduction of pH with persistent action potential discharge that was nearly abolished by capsazepine (10 microM) and inhibited by over 70 % with another VR1 antagonist iodo-resiniferatoxin (1 microM). In contrast the C-fibre response to the transient approximately 3 s exposure to pH approximately 5.0 was not affected by the VR1 antagonists. We conclude that activation of guinea-pig airway afferents by low pH is mediated by both slowly and rapidly inactivating mechanisms. We hypothesize that the slowly inactivating mechanism, present in C-fibres but not in RAR-like fibres, is mediated by VR1. The rapidly inactivating mechanism acts independently of VR1, has characteristics similar to acid sensing ion channels (ASICs) and is found in the airway terminals of both C-fibres and RAR-like fibres.