Effects Of Three 5-HT₄ Receptor Agonists On Gut Motility And Cardiac Proarrhythmia In Vitro

Functional gastrointestinal disorders (FGD) are the common diseases in digestional system. It is estimated that the morbility is 20-40 percent in common population.The primary reason of FGD is disfunction of digestinal tract. Hence, the key to treat these sorts of disorders is to modulate or improve the motility of digestinal tract.The general gastrointestinal prokinetic agents include Dopamine-receptor antagonist and 5-hydroxytryptamine4 (5-HT4) receptor agonist.Domperidone and metodopramide are Dopamine-receptor antagonist, they act mainly on upper gastrointestinal tract and have no effect on lower gastrointestinal tract. Cisapride, as a 5-HT4 receptor agonist,is widely used to treat gastrointestinal motility disorders for many years. But it was withdrawn from the market in the United States in July 2000 because of its propensity to induce torsade de pointes (TdP) arrhythmias. 1Afterwards,mosapride, the substituted benzamide prokinetics, being another 5-HT4 receptor agonist,was used to treat the functional gastrointestinal disorders.but the research from animal and clinic showed that it only had effects on upper gastrointestinal tract, and did not produce any effects on lower gastrointestinal tract.For this reason, it will play an important role in the treatment of functional gastrointestinal disorders to search and select an 5-HT agent that has full gastrointestinal prokinetic but has no or little latent side effects on heart. Zacopride, as a benzamide derivatives, acts on 5-HT4 receptor and induces the release of acetylcholine from digestional tract, accordingly it has prokinetic effects on experimental animals.RS67506, a selective 5-HT4 receptor partial agonist developed for the treatment of gastrointestinal disorders. It was reported that RS-67506 induced a significant increase in spontaneous contractility of smooth muscle preparations from the bovine abomasal antrum. In mice, RS67506 shortened the whole gut transit time, and may be useful in treating gastrointestinal disorders associated with impaired lower intestinal propulsion such as constipation. In pilot experiment, we found that RS-67506 and Zacopride had little side effects on heart rhythm and cardiac function. Therefore, the present study was designed to compare the proarrhythmic action of RS67506 and Zacopride with cisapride in their equal validity of prokinetic actions of gut and expect the clinic prospect of RS67506 and Zacopride. Our present study will provide experimental base for their application to clinic as a safe and effective prokinetic agent.