Postjunctional inhibitory effect of the NK2 receptor antagonist, SR 48968, on sensory NANC bronchoconstriction in the guinea‐pig

Ya‐Ping ‐P Lou, Lu‐Yuan ‐Y Lee, Hiroyuki Satoh, Jan M. Lundberg

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The effects of a selective NK2 receptor antagonist, SR 48968, on non‐adrenergic non‐cholinergic (NANC) bronchoconstriction in the guinea‐pig were investigated in both in vitro and in vivo studies. In isolated bronchus, the electrical field stimulation (EFS, 1 Hz for 1 min)‐induced NANC bronchoconstriction was inhibited by 83% after preincubation with SR 48968 (10−7 m) for 1 h. The selective NK1 receptor antagonist, CP 96,345 (10−6 m), together with SR 48968 completely abolished the remaining EFS‐evoked NANC bronchial contraction. ST 48968 (10−7 m) totally blocked the bronchial contraction caused by neurokinin A (NKA), but reduced only slightly the bronchoconstriction caused by high concentrations of substance P (SP) and did not influence the response to acetylcholine (ACh). In the guinea‐pig isolated perfused lung, SR 48968 (5 × 10−7 m) perfusion for 30 min markedly reduced, by 95% and 68% respectively, the increase in lung resistance (RL) and the decrease in dynamic compliance (CDyn) evoked by vagal stimulation (1 Hz for 1 min). Capsaicin (10−8 m)‐evoked bronchoconstriction was also significantly inhibited by SR 48968 (5 × 10−7 m). However, the same concentration of SR 48968 did not affect the release of neuropeptide calcitonin gene‐related peptide (CGRP)‐like immunoreactivity (LI) evoked by either vagal stimulation or capsaicin in the isolated perfused lung, suggesting no prejunctional action. SR 48968 (5 × 10−7 m) caused a parallel shift of the concentration‐response curve to the right by a factor of 10 for the bronchoconstriction evoked by NKA (10−9 − 3 × 10−7 m) in the isolated lung, while it abolished the contraction induced by the selective NK2 receptor agonist, Nle10 NKA(4–10) (10−9 − 3 × 10−7 m). In in vivo studies, ST 48968 (0.3 mg kg−1, i.v.) also greatly inhibited the increase in insufflation pressure evoked by either capsaicin (10 μg kg−1, i.v.) or NKA (1 μg kg−1, i.v.), without any measurable effect on the accompanying hypotensive responses. The results suggest: (i) ST 48968 is a selective and potent NK2 postjunctional receptor antagonist both in vitro and in vivo in the guinea‐pig, and (ii) the NANC bronchoconstriction evoked by sensory nerve activation either by antidromic nerve stimulation or by capsaicin is mediated mainly via NK2 receptors and only to a minor extent via NK1 receptors. 1993 British Pharmacological Society

Original languageEnglish
Pages (from-to)765-773
Number of pages9
JournalBritish Journal of Pharmacology
Issue number3
StatePublished - Jul 1993


  • Bronchoconstriction
  • NK receptor antagonist
  • SR 48968
  • calcitonin gene‐related peptide (CGRP)
  • capsaicin
  • neurokinin A
  • substance P
  • vagal stimulation

ASJC Scopus subject areas

  • Pharmacology


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