POSTJUNCTIONAL INHIBITORY EFFECT OF THE NK(2) RECEPTOR ANTAGONIST, SR 48968, ON SENSORY NANC BRONCHOCONSTRICTION IN THE GUINEA-PIG

1 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. 2 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). 3 In the guinea-pig isolated perfused lung, SR 48968 (5 x 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 (I Hz for 1 min). Capsaicin (10(-8) m)-evoked bronchoconstriction was also significantly inhibited by SR 48968 (5 x 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 x 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 x 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 x 10(-7) M). 4 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 mug kg-1, i.v.) or NKA (1 mug kg-1, i.v.), without any measurable effect on the accompanying hypotensive responses. 5 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.