Differences in response to 5‐HT4 receptor agonists and antagonists of the 5‐HT4‐like receptor in human colon circular smooth muscle

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Abstract
1 In isolated circular smooth muscle strips of human colon 5-hydroxytryptamine (5-HT) produced a concentration-related inhibition of spontaneous motility. 2 The azabicycloalkyl benzimidazolones, BIMU 8 and BIMU 1, which have 5-HT4 receptor stimulant properties, inhibited motility with EC50 values of 0.76 μM and 3.19 μM respectively and their Emax values were not significantly different from 5-HT (EC50, 0.13 μM). 3 The 5-HT4 receptor antagonist, DAU 6285 (1–10 μM), displaced the 5-HT concentration-response curve to the right in a parallel concentration-dependent manner without depressing the maximum. The Schild plot was linear and the slope did not differ significantly from unity giving a pA2 value of 6.32. 4 The high affinity selective 5-HT4 receptor antagonist, GR 113808, at a concentration of 3 nM displaced the 5-HT concentration-response curve in a parallel manner giving an apparent pKB estimate of 8.9 ±0.24. However, higher concentrations of 10–100 nM GR 113808 did not result in a further significant displacement of the 5-HT concentration-response curve and there was no suppression of Emax. 5 GR 113808 (10 nM) also caused a parallel displacement of the concentration-response curve to the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT) giving apparent pKB values ranging from 8.3–9.3. 6 GR 113808 (3–100 nM) failed to displace 5-HT or 5-MeOT concentration-response curves in tissue strips from 3 patients out of a total of 10 patients studied in whom the response to 5-HT and 5-MeOT was normal. 7 The 5-HT4 receptor antagonist, SDZ 205–557 (0.3–10 μM), had no significant effect on 5-HT-induced inhibition of spontaneous motility. 8 The present results are discussed in the light of variability of response to GR 113808 and SDZ 205–557 in other tissues. 9 Overall, our data indicate that human colon circular smooth muscle can be regarded as a site in which 5-HT4-like receptors are present but it is as yet unclear whether these results are also an indication of receptor variation.