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.
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 non-cholinergically-mediated slow contraction in bronchial muscle. SR 48968 (0.01-1 microM) 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 microM), but those by exogenous acetylcholine (1-3 microM) 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.
Kamikawa
Y
Y
Department of Pharmacology, Dokkyo University School of Medicine, Tochigi, Japan.
Shimo
Y
Y
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000502:physiology*; D004347:Drug Interactions; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology; D015288:Neurokinin A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects / Q000294:innervation / Q000502:physiology
D001549:Benzamides; D010880:Piperidines; D018039:Receptors, Tachykinin; C073839:SR 48968; D015288:Neurokinin A; D000109:Acetylcholine