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

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 (R_L) and the decrease in dynamic compliance (C_Dyn) 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