Epithelial influence on the tracheal nonadrenergic inhibitory response.

1. The role of epithelium in the non-adrenergic non-cholinergic (NANC) inhibitory response to electrical nerve stimulation as well as to the putative neurotransmitter, vasoactive intestinal polypeptide (VIP), was evaluated in guinea-pigs anaesthetized with chloralose-urethane. 2. The tracheal pouch, an in vivo method to demonstrate the NANC inhibitory response, was used in all experiments. The relaxation response was measured as a pressure drop (cm of H2O) in the pouch. The animals were given atropine (5 mg kg-1) and propranolol (1 mg kg-1) intraperitoneally to block adrenergic and cholinergic responses in the pouch. Cervical vagi were isolated and cut craneally. The distal ends were positioned on bipolar electrodes for subsequent stimulation with 5V pulses of 2 ms duration at 15 Hz for a total of 90 s. 3. The reproducibility of NANC responses to two consecutive nerve stimulations at 20 min apart was determined in group 1. 4. In group 2 pouch relaxations to electrical nerve stimulations were determined before and after complete epithelial denudation (determined by histological and pharmacological methods) of the pouch. 5. To determine the influence of relaxant prostaglandins synthesized by the epithelial cells, the effect of indomethacin (given either intravenously or into the pouch) on the pouch relaxation due to NANC stimulation was studied in groups 3 and 4 respectively. 6. In group 5, in order to distinguish between the effects of epithelium removal and prostaglandins, the animals were pretreated with indomethacin (i.v.) 30 min before the experiment. The pouch relaxation to nerve stimulation was then determined before and after the removal of epithelium. 7. The reproducibility of the pouch relaxations to consecutive single doses of VIP 10(-9) M at 20 min apart was determined in group 6. 8. In group 7, the pouch relaxation to a single dose of VIP was determined before and after intravenous indomethacin administration, but with the pouch epithelium left intact. 9. The effect of epithelium removal on VIP-induced pouch relaxation was determined in group 8. VIP-induced response was determined before and after the epithelium removal. 10. The study showed that both epithelium removal and indomethacin administration independently had significant effects on the decrease of the pouch relaxation (NANC inhibitory response). However, epithelium removal significantly diminished pouch relaxation despite indomethacin pretreatment suggesting a second, non-arachidonic dependent, mechanism (possibly via a relaxing factor) whereby epithelium maintains airway homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)