5-HT4 receptor mediated stimulation of gastric emptying in rats

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 gastroprokinesic 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 g/kg; ip) produced significant and dose-dependent stimulation of gastric emptying in rats (ED₅₀ = 2.3 g/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 g/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 gastroprokinesic effects of SC 49518 (10 g/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. It is suggested that a similar mechanism may account for the gastroprokinetic effects of other non-selective benzamides and benzimidazolones.