5-HT4 receptor mediated stimulation of gastric emptying in rats

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 351; no. 6; p. 589
• Main Authors: Hegde, S S, Wong, A G, Perry, M R, Ku, P, Moy, T M, Loeb, M, Eglen, R M
• Format: Journal Article
• Language: English
• Published: Germany 01.06.1995
• Subjects: Analysis of Variance; Animals; Benzamides - pharmacology; Drug Interactions; Gastric Emptying - physiology; Male; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - physiology; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists - pharmacology
• ISSN: 0028-1298
• DOI: 10.1007/bf00170157

It is well documented that certain substituted benzamides, such as cisapride, and benzimidazolones, such as BIMU 8, enhance gastric emptying in rats. As these compounds possess 5-HT3 antagonistic and 5-HT4 agonistic properties, the precise mechanisms (5-HT3 or 5-HT4) underlying their gastroprokinetic effects is still unclear. In the present study, we used SC 49518 (a benzamide and selective 5-HT4 receptor agonist) and two selective 5-HT4 receptor antagonists (RS 23597-190 and SB 204070) to elucidate the role of 5-HT4 receptors in gastroprokinesis. SC 49518 (1-316 micrograms/kg; ip) produced significant and dose-dependent stimulation of gastric emptying in rats (ED50 = 2.3 micrograms/kg; ip). SC 49518 also produced dose-dependent inhibition of bradycardia induced by 2-methyl 5-HT (von Bezold-Jarisch reflex) but with a 156 fold lower potency (ID50 = 0.36 mg/kg; ip). The gastroprokinetic effects of SC 49518 (3-316 micrograms/kg; ip) were significantly antagonized by the selective 5-HT4 receptor antagonist RS 23597-190 (0.1 mg/kg/min; iv). SB 204070 (0.003-1 mg/kg; ip), another selective 5-HT4 receptor antagonist, produced dose-dependent inhibition of the gastroprokinetic effects of SC 49518 (10 micrograms/kg; ip), the inhibition attaining statistical significance at the dose of 0.1 mg/kg; ip. RS 23597-190 had no effects on gastric emptying per se whereas SB 204070 significantly increased gastric emptying by itself at 1 mg/kg; ip but not at 0.1 mg/kg; ip. These findings show, for the first time, that SC 49518, a selective 5-HT4 receptor agonist, produces potent stimulation of gastric emptying in rats via a mechanism involving activation of 5-HT4 receptors.