An Experimental Study To Observe The Effects Of Gastrokinetic Agents On Human Sphincter Of Oddi

IntroductionDomperidone, mosapride and tegaserod are most widely used gastrokinetic agents in clinic. They own different chemical structures and mechanisms, expressing various effects on different parts of gastrointestinal tract. The sphincter of Oddi (SO) who modulates the flowing of bile and pancreatic juice is a structure that surrounds the end of common bile duct and main pancreatic duct. SO is a key component of digestive system. The effect of gastrokinetic agents on SO need to be assessed when they work on gastrointestinal tract. The aim of this study was to observe the effects of domperidone, mosapride and tegaserod on the motility of human sphincter of Oddi and analyze the mechanisms of action.Materials and methods32 patients with T tube after choledochotomy were included and divided into three groups randomly: domperidone group, 10 cases;mosapride group, 12 cases;tegaserod group, 10 cases. The pressure of SO were manometried via chole-dochofiberscope through T tube fistula. The main equipments included PC polygraph HR, triple - lumen manometry catheter and cholechofiberscope. All patients were not given any medicine and kept fasting over eight hours. After the manometry system was set, T tube was removed and the choledochofiberscope was used to observe SO via T tube fisula. The catheter was placed in duodenum via the side hole of choledochofiberscope under direct vision, the duodenal pres-sure curve was recorded. The catheter was drawn to SO to record the pressure cure of SO. Then, the catheter was dragged to the common bile duct and pressure curve was recorded. All drugs were given subligually and manometric processes were repeated at 10 min and 20 min after drugs intake respectly. Dates to be recorded and analyzed included basic pressure of the sphincter of Oddi ( SOBP) , amplitude of the sphincter of Oddi ( SOCA) , duration of phasic contractions ( SOD) , duodenal pressure ( DP) and common bile duct pressure ( CBDP) . All results were expressed as mean (M) ± standard deviation ( SD). A paired - samples t test was used and a single - tailed P value <0. 05 was considered statistically significant.Results1. Domperidone group: SOBP decreased by 37. 81% at 20 min after administration and it decreased markedly ( p = 0. 031);SOCA decreased by 37. 86% at 20 min after administration and it decreased markedly ( p = 0. 021);SOF,SOD and CBDP did not change after domperidone intake.2. Mosapride group: SOBP decreased by 52. 22% at 20 min after administration and it was decreased markedly! p =0. 044);SOCA decreased by 46.0% at lOmin after adminiatration and it decreased markedly(p =0.037);SOF,SOD and CBDP did not change.3. Tegaserod group: SOBP,SOCA,SOF,SOD and CBDP did not change after tegaserod intake.DiscussionCompared with endoscopic retrograde manometry, choledochofiberscope manometry is more safe, little pain and less complicate. We have successfully used this technique for years to observe the effects of different drugs on SO mo-tility. It is a reliable way to evaluate SO motility.During this experiment, we conclude that domperidone in clinical dose decreases SOBP and SOCA, SO motility is inhibited;mosapride in clinical dosedecreases SOBP and SOCA, SO motility is inhibited;tegaserod in clinical dose may not affect the motility of SO.Domperidone is a peripheral dopamine antagonist without cholinergic action and has powerful affinity with dopamine 2 receptor on gastrointestinal tract. It increases the amplitude and frequency of gastric sinus and duodenum. Domperidone completely prevents the dopamine effect and plasma motilin increases significantly during dopamine intake, while somatostatin blood levels do not change in human. Domperidone induced a decrease of SOBP and SOCA. We think that the mechanism may be noncholinergic and nonadrenergic effects.Mosapride is a 5 - HT4 agonist and has no action on dopamine receptor. Mo-sapride enhances gastroduodenal motility. Although the chemical structure of mosapride is similar with cisapride, torsades de pointes ventricular tachycardia has not been found in patients who took mosapride. We have not found any reports a-bout the effect of mosapride on SO motility. As the familiar structures of cisapride and mosapride, they may own the same or similar mechanisms. Cisapride given intravenously increased the amplitude of SO contractions and decreased the tone of the sphincter in dog. Cisapride administration in the Australian Possum resulted in a decrease of the amplitude and frequency of SO. In human, cisapride in a clinical dose given sublingually reduced SOBP and SOCA via choledo-chofiberscope manometry and SO motility was inhibited. The mechanism that mosapride affects the SO motility may be noncholinergic —nonadrenergic and is related with the releasing of several hormanes. After all, it is double sides that mosapride works on SO: inhibiting and enhancing.Tegaserod is a potent 5 - hydroxytryptamine 4 (5 HT4) receptor agonist and has significant binding ability for human 5 - HT4. Tegaserod activates 5 - HT4 receptor and stimulates the releasing of neurotransmitters. Fisher RS et al evaluated the effect of tegaserod on SO in volunteer and patients who were diagonsed as irritable bowel syndrome with constipation (IBS - C). As a result , there were no significant changes in the luminal diameters of the common bile duct or the common hepatic duct after tegaserod administration compared with placebo. It means no significant pharmacodynamic effect of tegaserod on gallbladder contractility or on CBD and CHD diameters as a surrogate marker of SO functionduring both the interdigestive and the digestive periods in healthy female subjects and female patients with IBS - C. In our study, SO motility was unchanged after tegaserod intake.SO motility appears to be completely dependent on the strong duodenal contraction during interdigestive period. The migrating motor complex ( MMC) of duodenum is disturbed and motility is strengthened to get strong propagation as food intake. At the same time, SO motility is inhibited and relaxed to cause an increase in bile flow to duodenum. In our opinions, domperidone and mosapride induce an increase of gastroduodenal motility and it is a model of food intake. The strengthen of duodenal motility induced by gastrokinetic agents causes the relax of SO and increases the plasma hormones such as CCK, P substance and so on. The selective character of cisapride, mosapride and tegaserod to receptors is increased, as a result ,the pharmalogical effects on the same target site may be decreased or even disappeared. Tegaserod is a high selective 5 - HT4 agonist and may lost its effect on SO.Conclusion1. Domperidone in clinical dose decreases SOBP and SOCA and inhibits SO motility.2. Mosapride in clinical dose decreases SOBP and SOCA and inhibits SO motility.3. Tegaserod in clinical dose does not affect SO motility.