【摘要】：一、文獻及理論研究糖尿病膀胱功能障礙(DBD)是糖尿病慢性高血糖的一個并發(fā)癥。在糖尿病發(fā)展的過程中,部分患者逐漸出現(xiàn)排尿間隔延長、排尿感覺遲緩、排尿乏力、點滴而下與排尿不凈。尿動力學檢測提示有膀胱感覺受損、膀胱容量增加、逼尿肌收縮能力下降、殘余尿量增多等特點。由于膀胱的生理活動受周圍神經(jīng)所支配,因此多年來研究糖尿病膀胱病的發(fā)病機制主要針對于神經(jīng)源性病變。可是,在臨床上也能觀察到患病不久的糖尿病患者出現(xiàn)下泌尿系的癥狀,表現(xiàn)卻為尿急、尿頻、夜尿與急迫性尿失禁,而且尿動力學檢測也提示不同程度的逼尿肌不穩(wěn)定或逼尿肌反射亢進。這兩種系列相反的癥狀體征被認為與疾病的時間推演有聯(lián)系,是糖尿病高血糖引起膀胱經(jīng)歷兩個階段、兩種病理變化的具體體現(xiàn),即從早期膀胱過度活躍(OAB)的代償期階段到晚期膀胱失張力(UAB)的失代償期階段。而且,研究也發(fā)現(xiàn)膀胱的上皮細胞、神經(jīng)元、逼尿肌與尿道任何一方面出現(xiàn)異常都可以引起膀胱發(fā)生儲尿或排尿的功能障礙。非腎上腺素能非膽堿能(NANC)通道對膀胱的生理病理有重要的作用。既往認為,膀胱的收縮主要是因為副交感神經(jīng)釋放的ACh與M受體結(jié)合而成。其后發(fā)現(xiàn),嘌呤受體P2X與ATP結(jié)合后也能達到相似的作用。而且,P2X受體的表達異常往往與膀胱病變有密切關(guān)系,因此在膀胱病變中探索不同P2X亞型的角色也變得重要起來。P2X1受體主要分布于逼尿平滑肌細胞邊緣,而P2X3受體主要分布在膀胱上皮細胞下的神經(jīng)束。在病理狀態(tài)下,兩者的表達量變化可能提示膀胱在感覺或收縮活動上出現(xiàn)異常。中醫(yī)方面,以往把糖尿病膀胱病(DC)或糖尿病神經(jīng)源性膀胱(DNB)歸屬于中醫(yī)“癃閉”的范疇。這只是按糖尿病后期常見的局部下泌尿道癥狀來命名,并不能體現(xiàn)與糖尿病有整體相關(guān)性,而且也未能體現(xiàn)膀胱從功能活躍到功能低下狀態(tài)的一個演變過程。糖尿病以多飲、多食、多尿與體重下降為癥狀特點,屬于中醫(yī)“消渴病”的范疇。所以,本文提出DBD早期出現(xiàn)OAB狀態(tài)仍然屬于中醫(yī)“消渴病”的范疇,而后期出現(xiàn)DAB狀態(tài)則應(yīng)該稱為“消渴—癃閉”,以明確區(qū)分單純的“癃閉”。糖尿病患者自身的陽氣虧虛是消渴病的一個重要發(fā)病因素,并發(fā)的膀胱功能障礙的病機也因此離不開陽虛的一面。從六經(jīng)辨證來說,糖尿病涉及六經(jīng),而糖尿病膀胱功能障礙的基本病位主要在太陽。太陽走體表屬陽。陽氣虛弱,邪犯太陽,從經(jīng)入腑,可以導致太陽腑病。太陽腑屬膀胱,膀胱的正常氣化功能可以調(diào)節(jié)津液的輸布與尿液、汗液的排泄。膀胱氣化失常,失于固攝或失于開合是直接導致膀胱發(fā)生儲尿或排尿功能障礙的兩個重要病機。五苓散是中醫(yī)經(jīng)典《傷寒論》的處方,對調(diào)節(jié)膀胱功能具有重要的影響。從藥物組成來看,茯苓、豬苓、·澤瀉、白術(shù)四味藥物都有利尿作用,因此五苓散常常被視為利尿劑,多用于膀胱排尿障礙出現(xiàn)少尿的時候。然而,桂枝的溫陽通陽作用可能對膀胱的氣化起了決定性的影響,因此有學者認為五苓散不僅僅是利尿劑,也是發(fā)汗劑。它的溫陽化氣作用,有助于水液代謝得到正常調(diào)節(jié)。這可能也適用于尿頻、尿急、尿量增多的膀胱儲尿障礙階段。本病的病程發(fā)展與癥狀變化往往涉及太陰與少陰。溫補太陰、少陰陽氣不僅是要顧護先后天之本,也意在加強五苓散對膀胱的溫陽化氣作用。因此,加味五苓散是在五苓散的基礎(chǔ)上加用黃芪、熟附子與烏藥,以黃芪補太陽、太陰,熟附子補少陰,并佐以烏藥溫腎理氣。由于文獻報道糖尿病膀胱功能障礙的發(fā)病率高,并且嚴重影響患者的生活質(zhì)量,中醫(yī)藥的干預(yù)可能為患者提供一種治療途徑。已知本病的代償期與失代償期會有不同的下泌尿系表現(xiàn),而且五苓散被認為有雙向調(diào)節(jié)作用。然而,加味五苓散的作用靶點與機制仍然存疑。本研究假設(shè)加味五苓散是透過調(diào)節(jié)嘌呤受體的表達來發(fā)揮藥效,從而達到與癥狀相反的治療目的。以加味五苓散作為中藥干預(yù)措施,預(yù)期嘌呤受體P2X1與P2X3的表達會降低,并且出現(xiàn)膀胱儲尿功能改善的相關(guān)指征。研究結(jié)果可能有助于理解嘌呤受體在加味五苓散雙向調(diào)節(jié)作用的角色。二、實驗研究目的：以DBD大鼠模型探討加味五苓散對大鼠膀胱P2X1與P2X3受體表達的作用機制。方法：110只SPF級雄性SD大鼠經(jīng)普通飼料適應(yīng)性喂養(yǎng)1周后,進行隨機分組。正常組10只,其余納入造模組,包括模型組、托特羅定組、中藥高劑量組、中藥中劑量組、中藥低劑量組。其后,造模組大鼠改以高脂飼料喂養(yǎng)1個月后,按45mg/kg劑量腹腔內(nèi)注射1%STZ。72hr后消毒剪尾取尾靜脈血,檢測血糖≥16.67mmol/L,并且伴見多飲、多食、多尿等情況,即考慮為糖尿病大鼠模型。每2周觀察體重與血糖的變化,并且每4周以代謝籠收集大鼠的飲水量與排尿量。造模后第9周開始,對托特羅定組大鼠灌服2m1托特羅定,對中藥高、中、低劑量組分別灌服加味五苓散水煎劑6ml、3ml、1.5ml。第12周所有大鼠腹腔注射25%烏拉坦以麻醉,剖腹暴露膀胱并且在膀胱頂部造瘺,以30ml/h速率灌注生理鹽水,以檢測糖尿病大鼠的尿動力學變化。其后,分離膀胱測量濕重。經(jīng)常規(guī)脫水、石蠟包埋和切片,膀胱組織在HE染色后用光鏡觀察組織病理情況。最后,以免疫印跡、免疫細胞組化技術(shù)對嘌呤受體P2X1、 P2X3的表達進行檢測。結(jié)果：造模組大鼠出現(xiàn)高血糖的成模率為94.74%。在實驗結(jié)束時共有44只大鼠完成實驗,占總體的40%。其中正常組10只,造模組34只(包括模型組7只,托特羅定組6只,中藥高劑量組6只,中藥中劑量組7只,中藥高劑量組8只)。實驗期間,正常組大鼠的整體情況良好,而造模組大鼠表現(xiàn)精神緊張,毛發(fā)稀疏枯黃。其余各項指標的結(jié)果如下：①體重：組間對比發(fā)現(xiàn)中藥低劑量組大鼠比托特羅定組大鼠要重,但與其它組沒有統(tǒng)計學差異。組內(nèi)比較則發(fā)現(xiàn)只有模型組大鼠體重下降(p=0.009),其它組則沒有統(tǒng)計學變化。②血糖：組間對比發(fā)現(xiàn)中藥低劑量組大鼠血糖較模型組大鼠的低。但是,組內(nèi)比較則沒有發(fā)現(xiàn)藥物干預(yù)后各組的血糖有統(tǒng)計學變化。③飲水量：組間比較發(fā)現(xiàn)托特羅定組、中藥中劑量組、中藥低劑量組的飲水量較模型組為低。組內(nèi)比較則只有托特羅定組大鼠的飲水量下降(p=0.018)。④排尿量：組間比較并沒有發(fā)現(xiàn)造模組大鼠的排尿量有差異,但是組內(nèi)比較則發(fā)現(xiàn)只有模型組與托特羅定組大鼠的排尿量有減少(p=0.006與p=0.002)。⑤尿動力學：除中藥高劑量組外,其余造模組大鼠的排尿時間較正常組大鼠為延長。模型組與托特羅定組大鼠的最大膀胱排尿壓均較正常組大鼠的為低,以托特羅定組的差異較為顯著(p0.005),但中藥組各組大鼠與正常組和模型組大鼠并沒有差異。除中藥高劑量組外,其余造模組大鼠的膀胱順應(yīng)性較正常組大鼠的為高,以托特羅定組大鼠的差異最為顯著(p0.005)。造模組大鼠之間并沒有統(tǒng)計學差異。⑥膀胱濕重與膀胱濕重指數(shù)：造模組各組大鼠的膀胱濕重較正常組為重,其中以模型組、中藥高劑量組與中藥中劑量組的差異較為顯著(p0.005)；中藥中劑量組的膀胱濕重最重,而托特羅定組最輕,兩者有統(tǒng)計學差異。而膀胱濕重指數(shù)方面,造模組大鼠均比正常組大鼠為高。⑦病理檢測：光鏡觀察HE染色切片,發(fā)現(xiàn)造模組大鼠的膀胱逼尿肌層有增厚現(xiàn)象,肌細胞肥大,形態(tài)多樣,肌束排列紊亂有斷裂,結(jié)構(gòu)松散,肌束間間隙明顯增寬,膠原纖維減少。⑧免疫印跡：各組的P2X1、P2X3受體表達未見明顯異常,但是發(fā)現(xiàn)模型組的P2X3比值下降,托特羅定組與中藥低劑量組又下調(diào),而中藥中劑量組與高劑量組則上調(diào)。⑨免疫組化：P2X1受體主要表達在逼尿肌、上皮細胞和血管壁；P2X3受體表達在逼尿肌。結(jié)論：本研究有以下幾點結(jié)果：1)本研究成功建立DBD大鼠模型。2)未發(fā)現(xiàn)加味五苓散能降低DBD大鼠的體重、血糖、飲水量與排尿量。3)未發(fā)現(xiàn)加味五苓散能改善第12周DBD大鼠的尿動力學排尿時間、最大膀胱排尿壓與膀胱順應(yīng)性。4)未發(fā)現(xiàn)加味五苓散能減輕膀胱重量與修復膀胱組織結(jié)構(gòu)。5)發(fā)現(xiàn)DBD大鼠的P2X1受體主要表達在逼尿肌、上皮細胞和血管壁；P2X3受體的表達也見于逼尿肌。6)發(fā)現(xiàn)加味五苓散未能影響膀胱P2X1受體的表達,但是對P2X3受體的表達有調(diào)控作用,惟暫未發(fā)現(xiàn)有明顯差異。此外,本研究有幾點發(fā)現(xiàn)值得注意：1)雖然加味五苓散并不能降低高血糖狀態(tài),但它可能避免體重病態(tài)性下降。它的利尿作用可能延緩膀胱從OAB階段向UAB階段發(fā)展的趨勢。中、低劑量的加味五苓散可能有助于改善糖尿病口渴多飲的癥狀。對癥而言,未發(fā)現(xiàn)加味五苓散具有抗利尿的作用。2)加味五苓散的利尿效果可能有助于延緩逼尿肌向UAB發(fā)展的進程。3)糖尿病使P2X3受體表達下調(diào)。加味五苓散低劑量與中高劑量對P2X3受體表達分別為下調(diào)與上調(diào),提示可能對P2X3受體有雙向調(diào)節(jié)作用。
[Abstract]:1. Literature and theoretical studies have shown that diabetic bladder dysfunction (DBD) is a complication of chronic hyperglycemia in diabetes mellitus. During the development of diabetes mellitus, some patients gradually appear to have prolonged voiding interval, slow voiding feeling, weak voiding, dripping down and unclean voiding. Because the physiological activity of the bladder is dominated by peripheral nerves, the pathogenesis of diabetic cystopathy has been studied for many years mainly for neurogenic lesions. However, symptoms of the lower urinary system can also be observed in patients with diabetes mellitus who have been ill for a short time. Urinary urgency, frequent urination, nocturia, and urgent urinary incontinence, and urodynamic tests also suggest varying degrees of detrusor instability or detrusor hyperreflexia. These two series of opposite symptoms and signs are thought to be associated with the timing of the disease, diabetic hyperglycemia causes the bladder to undergo two stages, two specific pathological changes. In addition, abnormalities in bladder epithelial cells, neurons, detrusors and urethra in any aspect of the bladder can cause dysfunction of urine storage or micturition. Non-adrenergic non-cholinergic NANC channels play an important role in the physiology and pathology of the bladder. It was previously believed that the contraction of the bladder was mainly due to the binding of ACh released by the parasympathetic nerve to M receptor. It was found that the binding of purine receptor P2X to ATP could also achieve a similar effect. It is also important to explore different P2X subtypes in cystic lesions. P2X1 receptors are mainly located at the edge of detrusor smooth muscle cells, while P2X3 receptors are mainly located in the nerve tracts under the bladder epithelial cells. In pathological conditions, the changes in the expression of the two may indicate abnormal sensory or contractile activities in the bladder. Diabetic cystopathy (DC) or diabetic neurogenic bladder (DNB) is classified as "amenorrhea" in traditional Chinese medicine. It is only named according to the common local lower urinary tract symptoms in the late stage of diabetes mellitus. It does not reflect the overall correlation with diabetes mellitus, nor does it reflect the evolution of bladder from active to dysfunctional state. Diabetes mellitus is characterized by polydipsia, polyphagia, polyuria and weight loss, which belongs to the category of "diabetes" in traditional Chinese medicine. Therefore, this paper suggests that the early onset of OAB in DBD still belongs to the category of "diabetes" in traditional Chinese medicine, while the late onset of DAB should be called "diabetes-amenorrhea" to clearly distinguish between simple "amenorrhea". Deficiency of Yang Qi is an important pathogenic factor of diabetes, and the pathogenesis of bladder dysfunction can not be separated from Yang deficiency. Diabetes mellitus is related to the Six Meridians, while the basic location of diabetic bladder dysfunction is mainly in the sun. The normal vaporization of the bladder can regulate the delivery of fluid and urine, sweat excretion. Bladder vaporization disorders, loss of solid uptake or loss of opening and closing are two important pathogenesis that directly lead to urinary storage or urinary dysfunction in the bladder. Poria cocos, Poria cocos, Alisma orientalis and Atractylodes macrocephala have diuretic effects. Wuling powder is often considered as a diuretic and is used in the treatment of oliguria due to bladder dysuria. However, the warming yang and clearing Yang effects of Guizhi may play a decisive role in the gasification of bladder. Some scholars believe that Wuling Powder is not only a diuretic, but also a sweating agent. Its function of warming Yang and removing Qi helps to regulate the metabolism of water. This may also be applicable to the stage of bladder dysuria with frequent, urgent and increased urine volume. Therefore, Jiawei Wuling powder is based on Wuling powder plus astragalus, aconite and Wuyao, Astragalus to fill the sun, Taiyin, aconite to fill the shaoyin, and aconite to warm the kidney and regulate qi. It is known that the compensatory phase and decompensated phase of the disease have different lower urinary tract manifestations, and Wuling Powder is considered to have two-way regulatory effect. However, the target and mechanism of Jiawei Wuling Powder are still questionable. Wuling Powder exerts its effect by regulating the expression of purine receptor to achieve the opposite therapeutic purpose. Taking Weiwuling Powder as an intervention measure of traditional Chinese medicine, it is expected that the expression of purine receptor P2X1 and P2X3 will be decreased, and the related indications of improving bladder urinary storage function will appear. Objective: To explore the mechanism of Jiawei Wuling Powder on the expression of P2X1 and P2X3 receptors in bladder of rats with DBD. Methods: 110 SPF male SD rats were randomly divided into normal group (10 rats) and model group (10 rats). The rats in the model group were fed with high-fat diet for one month, then were injected with 45 mg/kg of 1% STZ.72 HR intraperitoneally. The tail vein blood was sterilized and cut off to detect blood glucose (> 16.67 mmol/L) and accompanied with excessive drinking, eating and urine, which was considered as diabetes mellitus. Rat models were established by observing the changes of body weight and blood glucose every 2 weeks, and collecting water intake and urination volume every 4 weeks with metabolic cage. Rats in the Tolterodine group were given 2 M1 tolterodine at the 9th week after modeling. Rats in the high, middle and low dosage groups were given 6 ml, 3 ml, 1.5 ml modified Wuling Powder Decoction respectively. After anesthesia, bladder was exposed by laparotomy and fistula was made at the top of the bladder. Urodynamic changes in diabetic rats were detected by infusion of saline at a rate of 30 ml/h. Wet weight was measured by separating the bladder and routine dehydration, paraffin embedding and biopsy were performed. The expression of purine receptor P2X1 and P2X3 was detected by cytochemistry. Results: The model rate of hyperglycemia was 94.74%. At the end of the experiment, 44 rats completed the experiment, accounting for 40% of the total. During the experiment, the rats in the normal group were in good condition, while the rats in the model group were nervous and their hair was thin and yellow. The results of other indexes were as follows: 1. Body weight: The rats in the low dose group were heavier than those in the tolterodine group, but there was no statistical difference between the two groups. Blood glucose: The blood glucose of rats in the low dose group was lower than that in the model group. However, there was no statistical change in blood glucose among the groups after drug intervention. It was found that the water intake of tolterodine group, middle-dose group and low-dose group was lower than that of model group (p=0.018). Urodynamics: Except for the high dose group of Chinese medicine, the urination time of the other model group was longer than that of the normal group. The maximum urinary pressure of the model group and the tolterodine group was lower than that of the normal group, and the difference between the tolterodine group and the tolterodine group was more significant (p0.005). There was no significant difference in bladder compliance between the two groups. Except for the high dose group, the bladder compliance of the other model groups was higher than that of the normal group, and the difference was most significant in the Tolterodine group (p0.005). There was no significant difference between the two groups. The wet weight of bladder in each group was heavier than that in the normal group, and the difference between the model group, the high dose group and the middle dose group was more significant (p0.005); the wet weight of bladder in the middle dose group was the heaviest, while that in the tolterodine group was the lightest, and the wet weight index of bladder in the model group was higher than that in the normal group. _Pathological examination: HE staining slices showed that the detrusor layer of bladder in the model group was thickened, the myocytes were hypertrophic, the shape was diverse, the muscle bundles were disorderly arranged, the structure was loose, the space between muscle bundles was significantly widened, and the collagen fibers were reduced. At present, the P2X3 ratio of model group was decreased, while that of tolterodine group and low-dose group was down-regulated, while that of middle-dose group and high-dose group was up-regulated. _Immunohistochemistry: P2X1 receptor was mainly expressed in detrusor, epithelial cells and vascular wall; P2X3 receptor was expressed in detrusor. BD rat model. 2) No modified Wuling powder was found to reduce the body weight, blood sugar, water intake and urination in DBD rats. 3) No modified Wuling powder was found to improve the urodynamic urination time, maximal bladder pressure and bladder compliance in 12-week DBD rats. 4) No modified Wuling powder was found to reduce bladder weight and repair bladder tissue structure. The expression of P2X1 receptor in detrusor, epithelial cells and vessel wall was found in DBD rats, and the expression of P2X3 receptor was also found in detrusor. Although Jiawei Wuling Powder does not reduce hyperglycemia, it may avoid morbid weight loss. Its diuretic effect may delay the development of bladder from OAB stage to UAB stage. 2) The diuretic effect of Jiawei Wuling Powder may be helpful to delay the development of detrusor to UAB. 3) The expression of P2X3 receptor is down-regulated by diabetes mellitus. The expression of P2X3 receptor is down-regulated and up-regulated by low dose and medium and high dose of Jiawei Wuling Powder respectively, suggesting that it may have two-way regulation on P2X3 receptor.
【學位授予單位】：廣州中醫(yī)藥大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R285.5

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