SUBSTANCE-P-INDUCED CONTRACTIONS OF THE GUINEA-PIG PROXIMAL COLON THROUGH STIMULATION OF POSTJUNCTIONAL TACHYKININ NK(1) RECEPTORS

The effects of three tachykinin NK1 receptor antagonists and a tachykinin NK2 receptor antagonist against substance P-induced contractions of the guinea-pig proximal colon longitudinal muscle were investigated. Atropine, tetrodotoxin and phosphoramidon did not affect the concentration-response curve for substance P (pEC50 = 7.8). The tachykinin NK1 receptor antagonist, 2S,3S-cis-CP 96345, competitively inhibited the contractions due to substance P (pA2 = 8.5; constrained pA2 = 8.9). but at higher concentrations (greater-than-or-equal-to 3 x 10(-7) M), 2S,3S-cis-CP 96345 also depressed the concentration-response curve for methacholine. The species-selective tachykinin NK1 receptor antagonists, WIN 51708 and WIN 62577 (both 1 x 10(-6) M), and the tachykinin NK2 receptor antagonist, SR 48968 (3 x 10(-7) M), had no effect. It is concluded that substance P induces contractions through the stimulation of tachykinin NK1 receptors on the smooth muscle cells. In this preparation, tachykinin NK2 receptors do not seem to be involved in the contractile action of substance P.