Characterization of the 5‐hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle

Abstract

Experiments were carried out to characterize pharmacologically the 5‐hydroxytryptamine (5‐HT) receptor types which mediate inhibition of spontaneous contractions of the intertaenial circular muscle in human isolated colon. 5‐HT caused a reproducible concentration‐dependent inhibition of spontaneous contractions of the circular muscle of human colon in vitro with a mean EC50 value of 0.2 μm and 95% confidence limits of 0.1–0.5 μm. No evidence for a contractile action of 5‐HT was found. Tetrodotoxin (TTX, 1.5 μm) caused a rightward shift of the concentration‐response curve of 5‐HT with a concentration‐ratio of 2.9. The inhibitory response to 5‐HT was mimicked by several indoles with the rank order of potency 5‐HT > 5‐methoxytryptamine = α‐methyl‐5‐HT > 5‐carboxamidotryptamine >> 2‐methyl‐5‐HT. 5‐Hydroxyindalpine was inactive. The substituted benzamides were agonists with the following rank order of potency, 5‐HT > renzapride > zacopride > metoclopramide > cisapride. The inhibitory responses to 5‐HT were not inhibited by methysergide (10 μm) or methiothepin (1 μm), which are antagonists selective for 5‐HT1‐like and 5‐HT2 receptors, nor by ondansetron (10 μ) which is an antagonist at 5‐HT3 receptors. The inhibitory responses induced by 5‐HT and 5‐methoxytryptamine were competitively antagonized by a weak 5‐HT4 receptor antagonist, tropisetron, with pKB values of approximately 6. Tropisetron had no significant effect on the inhibitory response curve produced by isoprenaline (0.01–100 μm). The pharmacological profile of the 5‐HT‐evoked relaxations of human colon circular muscle are consistent with activation of a 5‐HT4‐like receptor. 1994 British Pharmacological Society