Endogenous tachykinins facilitate transmission through parasympathetic ganglia in guinea‐pig trachea

Abstract

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 NK, 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 (1-1O JM) 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 JAM) 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 AM) in vitro.5 The facilitatory effect of phosphoramidon (10 AM) on PGS-induced contractions was inhibited by the selective NK, receptor antagonist, GR71251 (1 AM). 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 NK, receptor antagonist on contractions of the trachea induced by exogenous ACh. 6 The selective NK1 receptor agonist, GR73632 facilitated contractions of the trachea induced by stimulation of both pre-and postganglionic cholinergic nerves, in a concentration-dependent manner, at concentrations that had no significant effect on basal tone (0.01-0.3 nM). The facilitatory effect of GR73632 on both PGS-and TMS-induced contractions was antagonized by GR71251 (1 JAM). In contrast, neurokinin A (1 -10 nM), which preferentially stimulates NK2 receptors, facilitated contractions induced by both PGS and TMS, and caused a significant increase in basal tone of the trachea. The selective NK3 receptor ago...

Interleukin-1β-induced airway hyperresponsiveness enhances substance P in intrinsic neurons of ferret airway

“…Thus the logical explanation of the IL-1␤ effect is that SP alters cholinergic responsiveness. Previous studies have shown that SP enhances cholinergic responsiveness either through a direct effect on airway smooth muscle (49) or by enhancing ACh release from parasympathetic nerve terminals (40,44,52). The data in the present study do not discriminate between these two mechanisms because cholinergic responsiveness was enhanced both by cholinergic agonists and by EFS.…”

Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences

“…However, in rabbit trachea the tachykinin receptors mediating this effect were not investigated. Exogenous tachykinins also potentiate cholinergic neurotransmission at pre-and postganglionic nerve terminals in guinea-pig trachea (Hall et al, 1989;Watson et al, 1993). The tachykinin receptor mediating these effects appeared to be of the NK, receptor subtype (Watson et al, 1993).…”

“…Exogenous tachykinins also potentiate cholinergic neurotransmission at pre-and postganglionic nerve terminals in guinea-pig trachea (Hall et al, 1989;Watson et al, 1993). The tachykinin receptor mediating these effects appeared to be of the NK, receptor subtype (Watson et al, 1993). However, in addition, NKA, which preferentially stimulates NK2 receptors facilitated contractions evoked by pre-and postganglionic nerve stimulation (Hall et al, 1989;Watson et al, 1993).…”

“…In addition, SP potentiates cholinergic nerve-induced contractions in rabbit trachea in vitro via a postganglionic, prejunctional mechanism (Armour et al, 1991). Exogenous tachykinins also potentiate cholinergic neurotransmission in guinea-pig trachea (Hall et al, 1989;Watson et al, 1993).…”

“…Capsaicin, at a sub-threshold concentration, acutely releases tachykinins which enhance cholinergic neurotransmission in guinea-pig trachea in vitro (Aizawa et al, 1990). In addition, the inhibitor of neutral endopeptidase (NEP), phosphoramidon, increased the amplitude of contractions produced by preganglionic vagal stimulation in guinea-pig trachea and this effect is blocked by capsaicin pretreatment (Watson et al, 1993). However, Aizawa et al (1990) reported that phosphoramidon also enhanced contractions to electrical field stimulation (EFS) in guinea-pig trachea without changing responses to exogenous ACh.…”