Characterisation of 5-hydroxytryptamine (5-HT) receptors in human colonic circular and longitudinal muscle in vitro

5-HT receptor types have been characterised in circular and longitudinal muscle of human colon using functional, radioligand binding and transductional studies in vitro. The mechanical activity of full thickness muscle strips from human colon were recorded isometrically. Longitudinal muscle from taenia coli (LM) had a high basal tension with relatively modest spontaneous activity while intertaenial circular muscle (CM) showed high levels of spontaneous contractions with low basal tone. In CM 5-HT agonists caused concentration-related inhibition of spontaneous contractions while in LM an inhibition of basal tone was seen. These inhibitions caused by 5-HT was mainly non-neuronal as tetrodotoxin had almost no effect on the responses. No evidence for contractile activity of 5-HT was seen in any preparation. Studies in CM identified the receptors present as mainly 5-HT4 type. Evidence for this is based on the study of a range of agonists including 5-HT substituted indoles, substituted benzamides and azabicycloalkyl benzimidazolones showing the following rank orders of potency respectively:5-HT> 5-methoxytryptamine= α-methyl-5-HT> 5-carboxyamidotryptamine > > 2-methyl-5-HT;5-HT> renzapride> zacopride> metoclopramide ≥ cisapride;5-HT> BIMU8> BIMU1> > DAU6285.The 5-HT inhibitory responses were antagonised by 5-HT4 receptor antagonists ICS205-930 and DAU6285 with pK8 values of 5.82-5.93 and 5.90-6.13 respectively. The potent 5-HT4 antagonist, GR113808, also antagonised this response at 0.003μM with a pK_B value of 8.89 but higher concentrations (0.01-0.1μM) produced little or no further shift to the right. It cannot be explained why GR113808 had no effect on the 5-HT-induced response in some patients studied (30% in total) and SDZ205-557, another selective 5-HT4 antagonist, was not effective in antagonising this response. 5-HT receptor type in LM was 5-HT1-like since 5-carboxyamidotryptamine (5-CT), a potent 5-HT1-like agonist, caused relaxation which was antagonised by a 5-HT1/5-HT2 receptor antagonist, methysergide but not 5-HT2 or 5-HT3 receptor antagonist. The effect of 5-HT was variable and relaxation, if induced, was less potent than 5-CT.