title: 5-HT4 receptor mediated stimulation of gastric emptying in rats.
abstract: 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA 94304, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Hegde
authors.forename: A G
authors.initials: AG
authors.lastname: Wong
authors.forename: M R
authors.initials: MR
authors.lastname: Perry
authors.forename: P
authors.initials: P
authors.lastname: Ku
authors.forename: T M
authors.initials: TM
authors.lastname: Moy
authors.forename: M
authors.initials: M
authors.lastname: Loeb
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004347:Drug Interactions; D005746:Gastric Emptying / Q000502:physiology*; D008297:Male; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D001549:Benzamides; D011758:Pyrroles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C074211:SC 53116; C079311:N-(exo-(hexahydro-1H-pyrrolizine-1-yl)methyl)-2-methoxy-4-amino-5-chlorobenzamide; D044422:Receptors, Serotonin, 5-HT4