Characterization of non‐adrenergic, non‐cholinergic inhibitory responses of the isolated guinea‐pig trachea: differences between pre‐ and post‐ganglionic nerve stimulation

1 Differences in the mechanism of non-adrenergic, non-cholinergic (NANC) inhibitory responses to preganglionic- and post-ganglionic nerve stimulation were investigated in the guinea-pig isolated trachea. 2 Stimulation of the vagus nerve at frequencies above 4 Hz elicited NANC relaxation of the trachealis muscle. Responses to low frequencies of stimulation (4-8 Hz) were abolished by the nitric oxide (NO) synthase inhibitor L-NOARG (10 microM), while a L-NOARG resistant component was observed at higher stimulus frequencies. The L-NOARG-resistant component of NANC inhibitory responses to higher frequencies of vagus nerve stimulation were significantly attenuated by the proteinase alpha-chymotrypsin (2 U/ml), suggesting that a neuropeptide such as VIP may contribute to NANC responses. 3 When postganglionic nerves were stimulated by electrical field stimulation (EFS), responses were readily elicited at frequencies below 4 Hz. Like responses to vagus nerve stimulation, responses to low frequency (<4 Hz) EFS were abolished by L-NOARG while a L-NOARG-resistant component was apparent at higher stimulus frequencies. 4 The L-NOARG-resistant component of NANC inhibitory responses to EFS was sensitive to alpha-chymotrypsin only if stimuli were delivered in either long trains at a low frequency (4 Hz for 10-30 s) or short trains of high frequency (16 Hz for 2.5-7.5 s). 5 Responses to preganglionic nerve stimulation were approximately 35% of the amplitude of responses to EFS in the same preparations. 6 In conclusion, responses to preganglionic and postganglionic NANC inhibitory nerve stimulation in the guinea-pig trachea differ in maximum amplitude, frequency-response characteristics and the contributions of cotransmitters. We suggest that these differences may be explained by filtering of preganglionic input to postganglionic NANC neurons. These results have implications in all studies where EFS is considered to be representative of physiological stimulation of post-ganglionic nerve stimulation.