5‐HT 4 receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study

We aimed to study 5‐HT 4 receptors in canine stomach contractility both in vivo and in vitro . In anaesthetized Beagle dogs, the selective 5‐HT 4 receptor agonist prucalopride (i.v.) induced dose‐dependent tonic stomach contractions under isobaric conditions, an effect that was antagonized by the selective 5‐HT 4 receptor antagonist GR 125487 (10 μg kg −1 , i.v.). Electrical field stimulation (EFS) of corpus longitudinal muscle strips resulted in atropine‐ and tetrodotoxin‐sensitive contractions ( L ‐NOARG (0.1 m M ) present in all organ bath solutions). Prucalopride increased these contractions (maximal response after single‐dose addition (0.3 μ M ): 165% of initial value, or after cumulative addition: 188%). In the presence of methysergide (3 μ M ), 5‐HT also increased EFS‐contractions (after single‐dose addition (0.3 μ M ): increase to 192%, after cumulative addition: 148%). The selective 5‐HT 4 receptor antagonists GR 113808 (0.1 μ M ) or GR 125487 (10 n M ) antagonized the prucalopride (0.3 μ M )‐induced contraction increments. When EFS‐induced contractions were blocked by atropine or tetrodotoxin, prucalopride was ineffective. In the presence of methysergide (3 μ M ), the contraction increases to 5‐HT (0.3 μ M ) were prevented by GR 113808 (0.1 μ M ). The prucalopride curve (pEC 50 7.9) was shifted in parallel to the right by GR 113808 3 n M (pA 2 9.4). In the presence of methysergide (3 μ M ), the curve to 5‐HT (pEC 50 8.1) was competitively antagonized by GR 113808, yielding a Schild slope of 0.8±0.2 (pK B of 9.1 with unit Schild slope). In corpus circular muscle strips, the prucalopride (0.3 μ M )‐induced augmentation of EFS‐contractions (258%) was also prevented by GR 113808 (0.1 μ M ) (124%). In conclusion, the effects of 5‐HT 4 receptor agonists on proximal stomach motor activity in vivo can be explained by an effect on 5‐HT 4 receptors on cholinergic nerves within the gastric muscle wall.British Journal of Pharmacology (2001) 132 , 1941–1947; doi: 10.1038/sj.bjp.0703985