Effects of tachykinin receptor agonists and antagonists on the guinea-pig isolated oesophagus

1. Vagal nerve stimulation of the guinea-pig isolated oesophagus produced a triphasic tetrodotoxin (TTX)-sensitive contractile response. The third pha se, which was resistant to ganglion blocking drugs, was selectively abolish ed by capsaicin, suggesting the involvement of one or more neuropeptides re leased from afferent neurons. Receptors on cholinergic neurons were subsequ ently activated because the response was atropine sensitive. Contractile re sponses resulting from exogenous substance P were abolished by atropine and TTX and enhanced by physostigmine. These findings suggest that the third p hase may be mediated by the action of a substance P-like neuropeptide relea sed from sensory nerve endings that subsequently activated cholinergic neur ons. 2. The tachykinin receptors in the body of the guinea-pig oesophagus were c haracterized by determining the relative agonist potencies of natural tachy kinins as well as tachykinin receptor-selective analogues. Antagonist affin ities were also determined. The results indicated the presence of both NK2 and NK3 receptors. In addition, the effects of a cocktail of peptidase inhi bitors (captopril, thiorphan and amastatin) on responses to various tachyki nins and synthetic analogues were determined. The results indicate that one or more peptidases are present in this preparation. 3. Experiments using various tachykinin receptor antagonists were performed to determine whether the activation of tachykinin receptors played a role in the mediation of the third phase of the response to vagal nerve stimulat ion. While this response was unaffected by NK1 and NK2 receptor-selective a ntagonists, it was only partially inhibited (23%) by the NK3 receptor antag onist SR 142801. Thus, in the guinea-pig oesophagus, it appears that NK3 re ceptors play only a minor role in mediating a contractile response when aff erent neurons are excited by vagal nerve stimulation.