SR 48968, A Novel Non-peptide Tachykinin NK-2-Receptor Antagonist, Selectively Inhibits the Non-Cholinergically Mediated Neurogenic Contraction of Guinea-pig Isolated Bronchial Muscle

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Abstract
We have examined the actions of SR 48968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), a novel non-peptide tachykinin NK-2-receptor antagonist, on the response evoked by electrical field stimulation or by acetylcholine and neurokinin A on guinea-pig isolated airway smooth muscle. Electrical field stimulation (1–32 Hz, 0·3 ms, 30 V for 20 s) evoked a biphasic response in a frequency-dependent manner, consisting of a cholinergically-mediated fast contraction followed by a non-adrenergically-mediated relaxation in tracheal muscle and by a noncholinergically-mediated slow contraction in bronchial muscle. SR 48968 (0·01–1 μm) caused a concentration-dependent inhibition of non-cholinergically mediated contraction of bronchial muscle, without significant influence on cholinergically and non-adrenergically-mediated responses. Submaximal contractions of tracheal and bronchial muscles evoked by exogenous neurokinin A (10–300 Nm) were markedly inhibited by SR 48968 (0·1–1 μm), but those by exogenous acetylcholine (1–3 μm) were slightly inhibited by the antagonist. The results indicate that in guinea-pig isolated bronchial muscle, SR 48968 selectively inhibited non-cholinergically mediated neurogenic contraction via antagonism of NK-2 receptors.
Funding Information
  • Human Science Foundation, Tokyo (SR 48968)