| Objective: Gastroparesis is characterized by a delay in the emptying ofstomach contents in the absence of mechanical obstructions in the stomach.The most common known underlying cause of gastroparesis is diabetesmellitus. Previous reports had showed that delayed gastric emptying occurs inup to90%of patients with chronic diabetes. Diabetic gastroparesis (DG), firstproposed by Kassmander in1958, is well-established one of complications indiabetes mellitus. To date, the pathogenesis of diabetic gastroparesis (DG) isconsidered to be closely related to diabetic autonomic neuropathy,hyperglycemia, expression loss of intestines nerve cell, gastrointestinalhormonal abnormalities, gastrointestinal ischemia, and so on. The researcheson gastric microangiopathy in pathogenesis of DG are limited, however,gastric microcirculation is basis on normal function of stomachic smoothmuscle cells, nerve cells and other cells which participate in contraction of thestomach. Therefore, we consider that well-balanced gastric microcirculation isthe foundation of gastric motility. Microangiopathy is a risk factor for diabeticcomplications and is visible in DN, retinopathy, and neuropathy, resulting inpathological changes in the alimentary tract. ET and NO are important indicesof the blood vessel endothelium status. These compounds have contrastingeffects on blood vessels. The former causes vessels to contract, which may beharmful to health, whereas the latter causes vessels to relax, thereby providinga protective effect. Thus, a dynamic balance between ET and NO is importantto maintain a normal blood vessel endothelium. Under thepathology conditions, angiotensin-Ⅱcan stimulate endothelium to synthesizeand secrete ET, decrease activation of endotheliocyte nitric oxide synthase,(NOS), eliminate NO in endotheliocyte, and then suppress the endothelialcells activity. ATII has biological functions when it binds to AT1R. Thus, the expression of AT1R can be used to determine the biological activity of ATII.Irbesartan is a non-peptide chronic ATII receptor antagonist, studies hadindicated that angiotensin receptor inhibitors could improve vascularendothelial function, which contribute to reduce microvascular complication.Leptin, coded by Ob gene, is polypeptide hormone that is from secretion of fatcells and the gastric mucosa epithelial cells. The combined action of thegastrointestinal hormone leptin and its receptors may cause delayed gastricemptying through central and peripheral pathways. ATII stimulates adipocytesto synthesize and secrete leptin. However, ATII may induce hypertrophy inglomerular cells, the proliferation of mesangial cells, and the increased levelsof extracellular base proteins. Consequently, a metabolic decrease of leptinoccurs in the kidney. ATII receptor blockers reduce or mitigate the synthesisand effect of ATII, which restrains the synthesis and secretion of leptin. Thisstudy aimed to investigate the mechanism by which irbesartan improves theimpaired gastric emptying of DG rats. Changes in the serum leptin levels aswell as the expression levels of ET, NO synthase (NOS), and AT1R mRNAwere observed.Methods: Thirty male Sprague-Dawley rats were randomly divided intoeither a normal control group (NC group, n=10) or a diabetes mellitus group(DM group, n=20). Diabetes mellitus was induced with streptozotocin (50mg/kg i.p.). The DM group was further divided into a diabetic control group(DM group, n=10) and an irbesartan group (DI group, n=10). The DI groupwas given irbesartan0.012g/(kg.d) through stomach feeding, while the NCand DM groups were given equal volume of saline by gavage. Six weeks later,all the rats were administered with phenol red solution to measure the rate ofgastric emptying. All experimental rats were weighed at the end of drugintervention to compare the changes in their weight after the intervention. Theblood glucose (BG), serum creatinine (Scr), serum total cholesterol (TC), andserum triglyceride (TG) levels were determined using an automatic analyzer.The blood serum leptin level and the ET content in the stomach tissue sampleswere determined using radioimmunoassay kits. Chemical colorimetry was used to measure the activity of nitric oxide synthase(NOS) in the stomachtissue. The expression level of angiotensin receptor (AT1R) mRNA wasdetermined by RT-PCR.Result：1Compared with the general condition of ratsIn normal control group, all the rats were in good spirits, fur luster,sensitive reaction, ease, food intake, water intake and urine volume of normal,no significant change during the whole experiment; after injection of STZ, therats appeared gradually polyphagia, polydipsia, polyuria, significantly reduced,unresponsive, color dull dull. Before the experiment finished, diabetic ratsshowed muscle loss, highlighting bones, slow in reacting. Being failedto tolerate hyperglycemi, two rats died in DM group and one in DI group.2Comparison of rat characteristicsBG, TG, and TC were all higher in diabetic rats than in the non-diabeticcontrols (P <0.05). No significant differences were observed between thediabetes control group and the irbesartan-treated group for theabove-mentioned parameters (P>0.05).The weight of all diabetic rats were reduced compared with normalcontrols (P <0.05), whereas the irbesartan-treated rats weighed more than thediabetes controls (P <0.05).Scr was significantly affected in diabetic rats after treatment withirbesartan. Compared with the diabetes control group, the Scr level of theirbesartan-treated group was reduced (P <0.05).3Comparison of rat gastric emptying rateSix weeks after STZ treatment, gastric emptying was significantlyreduced in the diabetes control group compared with the normal control group(P <0.05). The GER was significantly accelerated in the irbesartan-treatedgroup compared with that of the diabetes control group (P <0.05), whereastheir GERs were still lower than those of normal controls were (P <0.05).4The results of HE stainingRat gastric mucosa in normal control group rat is complete, mucosa hierarchical structure is clear, gland is neatly arranged, and blood vessels arein rich; compared with the normal control group, diabetes control group of ratgastric mucosa is not complete, mucosal hierarchy is not clear, gland arrangedin disorder, vascular quantity declines in the number; there is more completegastric mucosa in irbesartan-treated group than in diabetes control group.5ET content, NOS activity and AT1R mRNA expressionResults showed that the ET levels of the two diabetic groups werenotably increased compared with that of the normal control group (P <0.05).After irbesartan intervention, the ET level was significantly lower in theirbesartan-treated group than in the diabetes control group (P <0.05).The iNOS activity significantly increased, whereas the cNOS activitywas markedly decreased, compared with those of normal controls (P <0.05).However, in the irbesartan-treated group, iNOS activity significantly declined(P <0.05). There were no significant changes in the cNOS activity betweenthe irbesartan-treated group and the diabetes control group (P>0.05).The expression of AT1R mRNA in the stomachs of all diabetic rats wassignificantly upregulated compared to that of the normal control group(P <0.05). When treatment with irbesartan was complete, the AT1R mRNAexpression level was notably decreased (P <0.05).6Comparison of serum leptin concentrationsIn all diabetic rats, the serum leptin level was higher than that in normalcontrols (P <0.05). However, the serum leptin levels of diabetic rats weremarkedly decreased after treatment with irbesartan (P <0.05).Conclusions:1There is delayed gastric emptying in the diabetic gastroparesis rats,irbesartan can significantly increase the gastric emptying rate of diabeticgastroparesis rats, which indicates that it is a treatment for diabeticgastroparesis.2Irbesartan can obviously decrease levels of ET, iNOS, AT1R mRNA ingastric tissue of diabetic gastroparesis rats, which may improve function ofmicrovascular endothelial cell, so that it may maintain gastric dynamics. 3Irbesartan can reduce synthesis and secretion of leptin by restrainingeffect of ATⅡ and increase metabolism of leptin by improving renal function,these lead to reducing of leptin, and then lessen the delay action of leptin forgastric emptying. That may be the mechanism of irbesartan improving gastricemptying. |
