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5-HT4 receptor mediated stimulation of gastric emptying in rats

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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 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 μg/kg; ip) produced significant and dose-dependent stimulation of gastric emptying in rats (ED50 = 2.3 μg/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 μg/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 μg/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.

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Authors and Affiliations

  1. Institute of Pharmacology, Syntex Discovery Research, 3401 Hillview Avenue, 94304, Palo Alto, CA, USA

    S. S. Hegde, A. G. Wong, M. R. Perry, P. Ku, T. M. Moy, M. Loeb & R. M. Eglen

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  1. S. S. Hegde
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  2. A. G. Wong
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  3. M. R. Perry
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  4. P. Ku
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  5. T. M. Moy
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  6. M. Loeb
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  7. R. M. Eglen
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Hegde, S.S., Wong, A.G., Perry, M.R. et al. 5-HT4 receptor mediated stimulation of gastric emptying in rats. Naunyn-Schmiedeberg's Arch Pharmacol 351, 589–595 (1995). https://doi.org/10.1007/BF00170157

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  • DOI: https://doi.org/10.1007/BF00170157

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