Augmentation of neurally evoked cholinergic bronchoconstrictor responses by prejunctional NK2 receptors in the guinea-pig.
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.
Hey
J A
JA
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
Danko
G
G
del Prado
M
M
Chapman
R W
RW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects*; D016210:Methacholine Chloride / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015287:Neurokinin B / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001713:Biphenyl Compounds; D016085:Bronchoconstrictor Agents; D010880:Piperidines; D016210:Methacholine Chloride; D013373:Substance P; C073839:SR 48968; D015288:Neurokinin A; D015287:Neurokinin B; C066892:CP 96345