SR-48968, A NOVEL NONPEPTIDE TACHYKININ NK-2-RECEPTOR ANTAGONIST, SELECTIVELY INHIBITS THE NONCHOLINERGICALLY MEDIATED NEUROGENIC CONTRACTION OF GUINEA-PIG ISOLATED BRONCHIAL MUSCLE

We have examined the actions of SR 48968 ((S)-N-methyl-N-[4-(4-acetyla mino-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 neurok inin A on guinea-pig isolated airway smooth muscle. Electrical field s timulation (1-32 Hz, 0.3 ms, 30 V for 20 s) evoked a biphasic response in a frequency-dependent manner, consisting of a cholinergically-medi ated fast contraction followed by a non-adrenergically-mediated relaxa tion in tracheal muscle and by a noncholinergically-mediated slow cont raction in bronchial muscle. SR 48968 (0.01-1 mu M) caused a concentra tion-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 (10-30 0 nM) were markedly inhibited by SR 48968 (0.1-1 mu M), but those by e xogenous acetylcholine (1-3 mu M) were slightly inhibited by the antag onist. The results indicate that in guinea-pig isolated bronchial musc le, SR 48968 selectively inhibited non-cholinergically mediated neurog enic contraction via antagonism of NK-2 receptors.