Contractile effect of tachykinins on Suncus murinus (house musk shrew) isolated ileum

Abstract

Recent studies used Suncus murinus to investigate the anti-emetic potential of NK₁ tachykinin receptor antagonists. However, the pharmacology of tachykinin receptors in this species has not been fully characterized. In the present studies, therefore, we examined a range of tachykinin receptor agonists for a capacity to induce contractions of the isolated ileum. The tachykinin NK₁ receptor preferring agonists substance P, septide and [Sar⁹Met(O₂)¹¹] substance P, and the tachykinin NK₂ preferring agonists neurokinin A and GR 64349 (Lys-Asp-Ser-Phe-Val-Gly-R-gamma-lactam-Leu-Met-NH₂) caused concentration dependent contractions with EC₅₀ values in the nanomolar range. However, the tachykinin NK₃ preferring agonists neurokinin B and senktide (1 nM–1 μM) induced only weak contractions. The action of senktide, but not [Sar⁹Met(O₂)¹¹] substance P, septide, or GR 64349, was antagonized significantly by atropine (P < 0.05); tetrodotoxin and hexamethonium were inactive. The tachykinin NK₁ receptor antagonist CP-99,994 ((+)-[(2S,3S)-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine]) (10–100 nM) inhibited substance P- and septide-induced contractions non-competitively. The pA₂ value estimated for CP-99,994 against septide was 7.3 ± 0.1. It also non-competitively antagonized the contractile responses induced by [Sar⁹Met(O₂)¹¹] substance P with a pA₂ of 7.4 ± 0.1. CP-99,994 also had a slight inhibitory action on neurokinin A-induced contractions, but did not modify the action of GR 64349. Conversely, the tachykinin NK₂ receptor antagonist, saredutant, competitively antagonized GR 64349-induced contractions with a pA₂ of 7.34 ± 0.02. On the other hand, the presence of both CP-99,994 and saredutant competitively antagonized substance P-induced contraction. The present studies indicate that tachykininNK₁ and NK₂ receptors exist in the ileum of S. murinus and are involved in mediating contractions directly on smooth muscle, whereas tachykinin NK₃ receptors may play a minor role involving a release of acetylcholine.