5‐HT4 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 microg kg(-1), i.v.). Electrical field stimulation (EFS) of corpus longitudinal muscle strips resulted in atropine- and tetrodotoxin-sensitive contractions (L-NOARG (0.1 mM) present in all organ bath solutions). Prucalopride increased these contractions (maximal response after single-dose addition (0.3 microM): 165% of initial value, or after cumulative addition: 188%). In the presence of methysergide (3 microM), 5-HT also increased EFS-contractions (after single-dose addition (0.3 microM): increase to 192%, after cumulative addition: 148%). The selective 5-HT(4) receptor antagonists GR 113808 (0.1 microM) or GR 125487 (10 nM) antagonized the prucalopride (0.3 microM)-induced contraction increments. When EFS-induced contractions were blocked by atropine or tetrodotoxin, prucalopride was ineffective. In the presence of methysergide (3 microM), the contraction increases to 5-HT (0.3 microM) were prevented by GR 113808 (0.1 microM). The prucalopride curve (pEC(50) 7.9) was shifted in parallel to the right by GR 113808 3 nM (pA(2) 9.4). In the presence of methysergide (3 microM), 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 microM)-induced augmentation of EFS-contractions (258%) was also prevented by GR 113808 (0.1 microM) (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.