Pharmacological characterization of 5‐HT 4 receptors mediating relaxation of canine isolated rectum circular smooth muscle

This study aimed to characterize for the first time in vitro 5‐HT 4 receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum. In the presence of methysergide (60 μ M ), 5‐HT induced relaxation of methacholine (1 μ M )‐precontracted muscle strips, yielding a monophasic sigmoidal concentration‐relaxation curve (pEC 50 7.2±0.07). Tetrodotoxin (0.3 μ M ) did not affect the curve to 5‐HT, suggesting the inhibitory 5‐HT receptor is located on the smooth muscle. Granisetron (0.3 μ M ) did also not affect the curve to 5‐HT, which excludes the 5‐HT 3 receptor mediating the relaxation to 5‐HT. The presence of methysergide rules out the involvement of 5‐HT 1 , 5‐HT 2 or 5‐HT 7 receptors. 5‐HT, the selective 5‐HT 4 receptor agonists R076186, prucalopride (R093877) and SDZ HTF‐919 and the 5‐HT 4 receptor agonists cisapride and 5‐MeOT relaxed the muscle strips with a rank order of potency R076186=5‐HT>cisapride>prucaloprideSDZ HTF‐919>5‐MeOT. The selective 5‐HT 4 receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5‐HT, yielding pK B estimates of 9.7, 7.9 and 9.1, respectively. The selective 5‐HT 4 receptor antagonist SB 204070 shifted the curve to 5‐HT rightward and depressed the maximal response (apparent pA 2 10.6). GR 113808 (10 n M ) produced a parallel rightward shift of the curve to the selective 5‐HT 4 receptor agonists R076186 (pA 2 8.8). It is concluded that 5‐HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5‐HT 4 receptors. For the first time, a non‐human species was shown to exhibit relaxant 5‐HT 4 receptors in the large intestine.British Journal of Pharmacology (1999) 127 , 1431–1437; doi: 10.1038/sj.bjp.0702665