gr-71251 and phosphoramidon

1. Exogenous and endogenous tachykinins facilitate cholinergic nerve-induced bronchoconstriction in guinea-pig. Using a vagally innervated guinea-pig tracheal tube preparation we have investigated the involvement of endogenous capsaicin-sensitive neuropeptides in both pre- and postganglionic cholinergic neurotransmission. The effects of the neutral endopeptidase inhibitor (NEP), phosphoramidon, were investigated in this preparation either alone or in conjunction with sensory neuropeptide depletion by capsaicin pretreatment. The subtype of neurokinin receptor mediating this facilitatory effect of tachykinins has also been examined, by the use of selective tachykinin receptor agonists and a selective NK1 receptor antagonist. 2. Cholinergic contractions of the sealed Krebs filled tracheal tube preparation were recorded as increases in intraluminal pressure and were induced either by (i) pre-ganglionic vagus nerve stimulation (PGS), (ii) stimulation of postganglionic intramural nerves via transmural stimulating electrodes (TMS) in the presence of ganglion-blocking concentrations of hexamethonium and (iii) application of exogenous acetylcholine (ACh). 3. The effect of phosphoramidon, which inhibits the breakdown of tachykinins, was investigated on ACh-, PGS- and TMS-induced contractions. Phosphoramidon (1-10 microM) facilitated contractions of the trachea induced by PGS, in a concentration-dependent manner, but had no effect on contractions of the trachea induced either by TMS or exogenous ACh. 4. The facilitatory effect of phosphoramidon (10 microM) on PGS-induced contractions was abolished by pretreating guinea-pigs with capsaicin 7 +/- 2 days before the in vitro experiments. Capsaicin pretreatment did not significantly alter responses to the spasmogens, ACh or substance P. Depletion of sensory neuropeptides, by capsaicin pretreatment was confirmed by the lack of response to capsaicin (1 microM) in vitro. 5. The facilitatory effect of phosphoramidon (10 microM) on PGS-induced contractions was inhibited by the selective NK1 receptor antagonist, GR71251 (1 microM). When applied to the tissues during nerve stimulation,GR71251 caused a small, but significant, inhibition of PGS-induced contractions during low frequency stimulation. No significant effect of GR71251 on TMS-induced contractions was seen at any frequency. There was no significant effect of the NK1 receptor antagonist on contractions of the trachea induced by exogenous ACh.6. The selective NK1 recepto

Topics: Acetylcholine; Animals; Capsaicin; Electric Stimulation; Ganglia, Parasympathetic; Glycopeptides; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Neuropeptides; Peptide Fragments; Receptors, Neurotransmitter; Receptors, Tachykinin; Substance P; Synaptic Transmission; Tachykinins; Trachea; Vagus Nerve