A COMPARATIVE-STUDY OF FUNCTIONAL 5-HT4 RECEPTORS IN HUMAN COLON, RATESOPHAGUS AND RAT ILEUM

1 The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5- HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor an tagonist, GR 113808, were studied in the rat oesophagus, rat ileum and human colon. 2 5-HT relaxed the longitudinal muscle of the rat oesoph agus and rat ileum and the circular muscle of the human colon. Absolut e values of relaxation were measured and showed the order of the maxim um responses, rat oesophagus >> human colon > rat ileum with EC(50) va lues of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with a n EC(50) value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 mu M) or ondansetron (1 mu M). 3 The use of the uptake and metabolism inhibitors, cocaine (30 mu M) and pargyline (100 mu M), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 mu M) p roduced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and red uced the 5-HT maximum effect by 52.0 +/- 0.4%. 4 The compounds, DAU 62 36 and SC 53116, showed a different pattern of potencies and efficacie s in the rat oesophagus, rat ileum and human colon compared to 5-HT. D AU 6236 relaxed the human colonic circular muscle with an EC(50) value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 623 6 (1 mu M) also antagonized the 5-HT-induced relaxation of the human c olon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DA U 6236 was inactive in the majority of tissues. In the minority of oes ophagus tissues that did respond the EC(50) value was 1.2 +/- 0.7 mu M . DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus i n a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC(50) value of 91 +/- 4 nM, with an efficacy less than that obser ved to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat oesophagus. SC 53116 showed no agonist activity in the rat ileum and human colon, but at 1 mu M it did antagonize the effect of 5-HT in the human colon with a dose-ratio of 11.3 +/- 0.3. 5 GR 113808 competitively antagonized the 5-HT4 receptor-mediated rela xation of the rat oesophagus with a pA(2) value of 8.59 (8.18-9.00) ag ainst 5-HT and 9.05 (8.79-9.31) against SC 53116. GR 113808 (0.01 mu M ) also antagonized the 5-HT-induced relaxation of human colonic circul ar muscle with an apparent pA(2) value of 9.02 +/- 0.12. However at 1 mu M the apparent pA(2) value was significantly lower than that measur ed at 0.01 and 0.1 mu M. GR 113808 (0.01 mu M) antagonized the 5-HT4 r eceptor-mediated relaxation of the rat ileum with an apparent pA(2) va lue of 9.30 +/- 0.21. 6 In conclusion, these studies have shown that t he human colon, rat oesophagus and rat ileum contain functional 5-HT4 receptors. However, the 5-HT4 receptor agonists displayed differences in these tissues making it necessary to be cautious when extrapolating from animal to human tissue. This emphasizes the importance of the us e of human tissue in the development of therapeutic drugs.