CHARACTERIZATION OF THE 5-HYDROXYTRYPTAMINE RECEPTOR-TYPE INVOLVED ININHIBITION OF SPONTANEOUS ACTIVITY OF HUMAN ISOLATED COLONIC CIRCULARMUSCLE

1 Experiments were carried out to characterize pharmacologically the 5 -hydroxytryptamine (5-HT) receptor types which mediate inhibition of s pontaneous contractions of the entertaining circular muscle in human i solated colon. 2 5-HT caused a reproducible concentration-dependent in hibition of spontaneous contractions of the circular muscle of human c olon 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 w as 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 w ith the rank order of potency 5-HT > 5-methoxytryptamine = alpha-methy l-5-HT > 5-carboxamidotryptamine >> 2-methyl-5-HT. 5-Hydroxyindalpine was inactive. 4 The substituted benzamides were agonists with the foll owing rank order of potency, 5-HT > renzapride > zacopride > metoclopr amide > cisapride. 5 The inhibitory responses to 5-HT were not inhibit ed by methysergide (10 mu M) or methiothepin (1 mu M), which are antag onists selective for 5-HT1-like and 5-HT2 receptors, nor by ondansetro n (10 mu M) which is an antagonist at 5-HT3 receptors. 6 The inhibitor y 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 o n the inhibitory response curve produced by isoprenaline (0.01-100 mu M). 7 The pharmacological profile of the 5-HT-evoked relaxations of hu man colon circular muscle are consistent with activation of a 5-HT4-li ke receptor.