5‐HT₄ receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study

Abstract

We aimed to study 5‐HT4 receptors in canine stomach contractility both in vivo and in vitro. In anaesthetized Beagle dogs, the selective 5‐HT4 receptor agonist prucalopride (i.v.) induced dose‐dependent tonic stomach contractions under isobaric conditions, an effect that was antagonized by the selective 5‐HT4 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 mM) present in all organ bath solutions). Prucalopride increased these contractions (maximal response after single‐dose addition (0.3 μM): 165% of initial value, or after cumulative addition: 188%). In the presence of methysergide (3 μM), 5‐HT also increased EFS‐contractions (after single‐dose addition (0.3 μM): increase to 192%, after cumulative addition: 148%). The selective 5‐HT4 receptor antagonists GR 113808 (0.1 μM) or GR 125487 (10 nM) antagonized the prucalopride (0.3 μM)‐induced contraction increments. When EFS‐induced contractions were blocked by atropine or tetrodotoxin, prucalopride was ineffective. In the presence of methysergide (3 μM), the contraction increases to 5‐HT (0.3 μM) were prevented by GR 113808 (0.1 μM). The prucalopride curve (pEC50 7.9) was shifted in parallel to the right by GR 113808 3 nM (pA2 9.4). In the presence of methysergide (3 μM), the curve to 5‐HT (pEC50 8.1) was competitively antagonized by GR 113808, yielding a Schild slope of 0.8±0.2 (pKB of 9.1 with unit Schild slope). In corpus circular muscle strips, the prucalopride (0.3 μM)‐induced augmentation of EFS‐contractions (258%) was also prevented by GR 113808 (0.1 μM) (124%). In conclusion, the effects of 5‐HT4 receptor agonists on proximal stomach motor activity in vivo can be explained by an effect on 5‐HT4 receptors on cholinergic nerves within the gastric muscle wall. British Journal of Pharmacology (2001) 132, 1941–1947; doi:10.1038/sj.bjp.0703985

Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation

“…Consistent with our results, the literature would also support the presence of 5-HT 4 receptors on cholinergic nerves and 5-HT 2 receptors on the smooth muscle (14,17,29). Several studies have reported presynaptic 5-HT 4 receptors on cholinergic neurons innervating the circular muscle in the canine human proximal stomach, whose activation leads to release of ACh from the cholinergic neurons (29). Recent studies (38) have shown that serotonin affects fundic murine muscle by acting through prejunctional 5-HT 3 and 5-HT 4 receptors and postjunctional excitatory 5-HT 1D and inhibitory 5-HT 1A receptors.…”

“…We were able to show that the 5-HT 4 receptor agonist tegaserod was able to increase the EFS-induced contractions in the antrum without an effect on ACh contractions, suggesting that 5-HT 4 receptors may facilitate release of ACh from activated cholinergic nerves. Consistent with our results, the literature would also support the presence of 5-HT 4 receptors on cholinergic nerves and 5-HT 2 receptors on the smooth muscle (14,17,29). Several studies have reported presynaptic 5-HT 4 receptors on cholinergic neurons innervating the circular muscle in the canine human proximal stomach, whose activation leads to release of ACh from the cholinergic neurons (29).…”

YH12852, a potent and highly selective 5‐HT4 receptor agonist, significantly improves both upper and lower gastrointestinal motility in a guinea pig model of postoperative ileus

“…We employed the 5‐HT 4 receptor antagonist GR113808 to show that pretreatment with GR113808 leads to antagonism of the restorative effect of YH12852 on upper GI transit. Our findings are in line with earlier studies suggesting that GR113808 blocks 5‐HT 4 receptor‐mediated GI stimulation . The results also support the conclusion that YH12852 is a highly selective 5‐HT 4 receptor agonist that exerts an enterokinetic effect by binding with 5‐HT 4 receptors.…”

Effects of gastric electrical field stimulation with long pulses on gastric emptying in dogs

“…Although electrical field stimulation has been widely used in vitro to assess the excitability of muscle strips, 26–28 effects of gastric electrical field stimulation, with two electrodes far apart, on gastric motility or emptying have never been investigated. While the concept of this current study is similar to previous studies of gastric electrical stimulation, there is a major difference in the arrangement of stimulation electrode, that is, the two stimulation electrodes were far apart: one in the corpus and the other in the antrum.…”