| 5-Hydroxytryptamine(5-HT),or serotonin,is an important neurotransmitter and paracrine hormone with key physiological roles in both brain and peripheral tissues. Serotonin is heterogeneously distributed throughout the central nervous system(CNS) and has been implicated in numerous CNS regulatory processes.In peripheral systems,5-HT regulates the contraction and relaxation of smooth muscle fibers,as well as autonomic function,with major effects on the gastrointestinal tract and vasculature.5-HT has proven to be an important mediator of gastrointestinal motility.To date,14 members of the 5-HT receptor family have been identified.The stimulation of 5-HT1B/1D receptors induces gastric accommodation in humans and dogs,and delays gastric emptying in humans.The blockade of 5-HT3 receptors inhibits gastrointestinal motility in humans. In addition,the stimulation of 5-HT4 receptors elicits gastrointestinal contractile activity and increases the rate of gastric emptying in humans and dogs.With regard to gastric smooth muscle activity,it is generally accepted that the 5-HT1B/1D and 5-HT7 receptors are relaxant whereas the 5-HT2,5-HT3 and 5-HT4 receptors are contractile.In the intestine,5-HT has long been known to increase intestinal propulsive motility and the secretion of water and electrolytes,which lead to the induction of defecation and, in some cases,diarrhea in animal models and humans.The colonic motor and secretory changes associated with increased levels of gut 5-HT are largely mediated through 5-HT4 as well as 5-HT3 receptors.Stimulation of 5-HT4 receptors in the gut has striking effects on gastrointestinal smooth muscle tone.As activation of abdominal vagal afferents can stimulate the "vomiting center" in the CNS,it has been suggested that 5-HT4 receptors may play a role in the emetic response.In guinea pig intestinal longitudinal muscle strips with adherent myenteric plexus, 5-HT4 receptor agonists induce contraction by stimulating release of acetylcholine, whereas in esophageal muscle strips,the effect of 5-HT4 agonists is exerted directly on smooth muscle receptors to induce cAMP dependent relaxation.The benzamide derivatives that possess 5-HT4 agonistic activity have been prescribed as prokinetics drugs for treatment of gastrointestinal dysfunctions.A benzamide derivative of cisapride has been withdrawn from the pharmaceutical market by its manufacturer due to its risk of inducing fatal cardiac arrhythmia.Another 5-HT4 agonist mosapride,also a benzamide derivative,currently serves as an effective prokinetics drug in clinical application. A domestic pharmaceuticals enterprise has researched and developed a new drug of a 5-HT4 agonist SHR116958,an analogue to mosapride.We attempt to identify the prokinetic role of SHR116958 in gut and its counteraction to drugs inhibiting enterokinesia through various experimental models both in vivo and in vitro,as well as the underlying mechanisms of this new drug,in order to provide experimental supporting evidences for its registration.Objective:To investigate the pharmacodynamics and the mechanisms of action of SHR116958 on its prokinetic activity with in vivo and in vitro animal models.Methods and results:1.Pharmacodynamics:The dose groups from 0.02 to 0.20 mg/kg strikingly increased the rate of intestinal carbo medicinalis facilitation in one-month-old mice.The doses of 0.06 and 0.20 mg/kg were statistically significant or highly significant compared with the control group.The dose groups from 0.02 to 0.20 mg/kg strikingly increased the rate of intestinal carbo medicinalis facilitation in three-month-old mice.All dose groups were statistically significant or highly significant compared with the control group.The dose group of 0.20 mg/kg strikingly increased the gastric emptying rate of phenol red,and statistically significant compared with control group.The 0.06 mg/kg dose group also somewhat increase the rate gastric emptying,however it was not statistically significant compared with control group.Compared with control group,only SHR116958 2.0mg/kg dose group increased the output of fecal pellets and demonstrated that it promoted enterocinesia.2.The analysis of mechanisms:The 1.80mg/kg dose of SHR116958 strikingly decreased kaolin intake after rotation, and it was statistically highly significant compared with rotation group.The 1.80 mg/kg dose of SHR116958 reversed the inhibition of piboserod in the rate of intestinal carbo medicinalis facilitation.The 1.80 mg/kg dose of SHR116958 significantly counteracted the inhibition of atropine,morphine,erythromycin,and cisplatin in the rate of intestinal carbo medicinalis facilitation.Parameters after spontaneous activities from SHR116958 dose groups of 0.6 mg/kg, 1.8 mg/kg,and 6.0 mg/kg were significant or highly significant compared with rotation group in dose-dependent manner.Parameters from the groups of mosapride and ondansetron were significant or highly significant compared with rotation group. Parameters from the groups that were pretreated with drugs inhibiting enterokinesia,such as piboserod,morphine,cisplatin,erythromycin,tamoxifen and atropine were significant or highly significant compared with rotation group.In twitch inhibition in guinea pig ileum,groups which were only treated with SHR116958 and pretreated with drug inhibiting enterokinesia like piboserod,morphine, and atropine before with SHR116958 decreased tention rates relative to those from pretreatment in dose-dependent manner.Conclusion:Results from intestinal carbo medicinalis propulsion in mice,gastric emptying of phenol red in mice,fecal pellet output in mice,counteraction to drugs affecting enterokinesia in mice,spontaneous activity after rotation,and pica after rotation in mice heterogeneously demonstrated that different doses of SHR116958 promoted gastrointestinal propulsion in dose-dependent manner,with no obvious toxical reactions, which coincided with the pseudo-indications such as functional dyspepsia with heartburn, belch,early satiety and epigastric distention.From the results of the twitch inhibition mediated by 5-HT4 receptor in electrically stimulated ileum of guinea pig,it turned out that the mechanism of SHR116958,similar to which of mosapride,would be to facilitate the release of acetylcholine by stimulating 5-HT4 receptors from cholinergic interneurons and myenteric nerve plexus in gut,to increase gastrointestinal activity,and eventually to improve the conditions of the patients suffered from functional dyspepsia.SHR116958 was safe to apply within the pharmacodynamic dose limits,and it was likely to be reported to a higher authority as a new drug with prokinetic effects on gastrointestine. |
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