Augmentation of neurally evoked cholinergic bronchoconstrictor responses by prejunctional NK₂ receptors in the guinea‐pig

Abstract

1. We examined the effect of exogenously administered tachykinins, neurokinin A (NKA), substance P (SP) and neurokinin B (NKB) on neurally mediated cholinergic bronchoconstrictor responses in guinea-pigs. 2. Electrical stimulation of regions in the dorsal medulla oblongata produced a cholinergic bronchospasm that was not affected by depletion of endogenous tachykinins with capsaicin pretreatment (50 mg kg-1, s.c., 1 week earlier) or by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon (3 mg kg-1, i.v.). 3. Infusion of NKA (0.03-0.1 microgram kg-1 min-1), SP (1 microgram kg-1 min-1) or NKB (1 microgram kg-1 min-1) potentiated the bronchoconstrictor response to electrical stimulation of the dorsal medulla. The doses of tachykinins tested were subthreshold for direct activation of airway smooth muscle, because they were devoid of direct bronchoconstrictor effects. The relative rank order potency for augmentation of centrally induced bronchospasm was NKA > NKB approximately SP, suggesting activation of the NK2 receptor subtype. 4. Infusion of NKA, SP and NKB had no effect on bronchoconstrictor responses to i.v. methacholine (1 microgram kg-1) indicating that a prejunctional neural mechanism of action was responsible for the effects on CNS stimulation-induced bronchospasm. 5. Potentiation of the bronchoconstrictor response to dorsal medullary stimulation produced by infusion of NKA was blocked by pretreatment with the NK2 antagonist SR 48968 (1 mg kg-1, i.v.) but not by the NK1 antagoinst CP 96,345 (1 mg kg-1, i.v.). 6. The potentiation of CNS-induced bronchospasm produced by infusion of SP was partially inhibited by CP 96,345 (1 mg kg-1, i.v.) but not by SR 48968 (1 mg kg-1, i.v.). Treatment with combined SR 48968 (1 mg kg-1, i.v.) and CP 96,345 (1 mg kg-1, i.v.) completely blocked the SP-induced potentiation of CNS-stimulated bronchospasm. 7. These results identify an important modulatory role for NK2 receptors, located at prejunctional sites on parasympathetic nerves, on cholinergic bronchoconstrictor responses in guinea-pigs. 8. It is proposed that substances that release tachykinins from airway sensory nerves, e.g. inflammatory mediators or irritants, may induce hyperresponsiveness of cholinergic bronchomotor responses by activation of NK2-receptors on parasympathetic airway nerves. Furthermore, these studies indicate that endogenous tachykinins are not involved in the maintenance of basal cholinergic bronchomotor tone in the intact guinea-pig.

Effect of different ozone concentrations on the neurogenic contraction and relaxation of guinea pig airways

“…In addition, this finding raises the possibility of an interaction between e-NANC and cholinergic responses. In fact, it has been already reported that e-NANC neurotransmitters can induce acetylcholine release from postganglionic cholinergic neurons in guinea pig airways (Myers and Undem, 1991;Delaunois et al, 1996;Hey et al, 1996). In our study, this cholinergic component added to the e-NANC response was only manifested after exposure to the highest 0, concentration, since bronchi from non-exposed animals had similar e-NANC responses with or without atropine.…”

“…Thus, we were able to measure the e-NANC component with or without atropine incubation ( fig 1C). In fact, it has been already reported that e-NANC neurotransmitters can induce acetylcholine release from postganglionic cholinergic neurons in guinea pig airways (Myers and Undem, 1991;Delaunois et al, 1996;Hey et al, 1996). These results allow us to conclude that 0, introduced a cholinergic component into the second slow contraction produced by EFS (fig 5A), and that the true e-NANC response was unaffected by 0, (fig 5B), as we also found with the concentration-response curves to SP in bronchial preparations.…”

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

“…Catecholamines may inhibit or facilitate acetylcholine overflow through prejunctional a 2 -and b 2 -adrenoceptors, respectively [153][154][155]. Neurokinins such as substance P may enhance cholinergic transmission through facilitatory neurokinin-1 and/or -2 receptors [156,157]. Interestingly, substance P may also induce MBP release from eosinophils, causing M 2 autoreceptor dysfunction, which could act synergistically to direct facilitation [158].…”

Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor

“…Other guinea pigs were given AbNGF 2 days before ozone exposure (which is 3 days before physiological measurements). Other guinea pigs were treated after ozone exposure with either the neurokinin NK 1 receptor antagonist CP-96,345 [3 mg/kg iv (28)] or the NK2 receptor antagonist SR48968 [0.1 mg/kg iv (18)] 30 min before physiological measurements (Fig. 1).…”