CHARACTERIZATION OF THE 5-HYDROXYTRYPTAMINE RECEPTOR-TYPE INVOLVED IN INHIBITION OF SPONTANEOUS ACTIVITY OF HUMAN ISOLATED COLONIC CIRCULAR MUSCLE

1 Experiments were carried out to characterize pharmacologically the 5-hydroxytryptamine (5-HT) receptor types which mediate inhibition of spontaneous contractions of the entertaining circular muscle in human isolated colon. 2 5-HT caused a reproducible concentration-dependent inhibition of spontaneous contractions of the circular muscle of human colon in vitro with a mean EC(50) value of 0.2 mu M and 95% confidence limits of 0.1-0.5 mu M. NO evidence for a contractile action of 5-HT was found. Tetrodotoxin (TTX, 1.5 mu M) caused a rightward shift of the concentration-response curve of 5-HT with a concentration-ratio of 2.9. 3 The inhibitory response to 5-HT was mimicked by several indoles with the rank order of potency 5-HT > 5-methoxytryptamine = alpha-methyl-5-HT > 5-carboxamidotryptamine >> 2-methyl-5-HT. 5-Hydroxyindalpine was inactive. 4 The substituted benzamides were agonists with the following rank order of potency, 5-HT > renzapride > zacopride > metoclopramide > cisapride. 5 The inhibitory responses to 5-HT were not inhibited by methysergide (10 mu M) or methiothepin (1 mu M), which are antagonists selective for 5-HT1-like and 5-HT2 receptors, nor by ondansetron (10 mu M) which is an antagonist at 5-HT3 receptors. 6 The inhibitory responses induced by 5-HT and 5-methoxytryptamine were competitively antagonized by a weak 5-HT4 receptor antagonist, tropisetron, with pK(B) values of approximately 6. Tropisetron had no significant effect on the inhibitory response curve produced by isoprenaline (0.01-100 mu M). 7 The pharmacological profile of the 5-HT-evoked relaxations of human colon circular muscle are consistent with activation of a 5-HT4-like receptor.