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研究生:吳威毅
研究生(外文):Wu, Wei-Yi
論文名稱:膀胱泌尿上皮鈣離子感知接受器於排尿功能之調節角色以及其對於膀胱功能障礙之治療潛力
論文名稱(外文):The Modulatory Role of Bladder Urothelial Calcium-sensing Receptor in Micturition Function and Its Therapeutic Potential in Bladder Dysfunction
指導教授:鄭劍廷
指導教授(外文):Chien, Chiang-Ting
口試委員:吳忠信黃國晉鍾旭東徐世平鄭劍廷
口試委員(外文):Wu, Chung-HsinHuang, Kuo-ChinChung, Shiu-DongHsu, Shih-PingChien, Chiang-Ting
口試日期:2021-12-28
學位類別:博士
校院名稱:國立臺灣師範大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:英文
論文頁數:82
中文關鍵詞:鈣離子感知接受器化學感知逼尿肌排尿泌尿上皮
外文關鍵詞:calcium-sensing receptorchemosensorydetrusormicturitionurothelium
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鈣離子感知接受器能調節許多除了調鈣作用以外的生理功能。然而鈣離子感知接受器於下泌尿道功能中所扮演之角色仍尚未明瞭。本研究之目的為檢測大鼠的膀胱泌尿上皮細胞的鈣離子感知接受器是否能影響膀胱平滑肌的活性、排尿反射、骨盆神經活性、膀胱血液微循環以及膀胱炎引起的膀胱過度活躍。在此研究中,我們使用西方墨點法以與免疫組織化學染色來確認大鼠膀胱鈣離子感知接受器的表現以及表現位置。並使用離體肌肉張力儀來測定藉由專一促進劑(AC-265347)所活化的鈣離子感知接受器以及專一拮抗劑(NPS-2143)所抑制的鈣離子感知接受器如何分別去影響膀胱逼尿肌的自發性活性與收縮力。再使用膀胱壓力檢測、骨盆神經活性記錄、膀胱表面血液微循環檢測來評估膀胱內灌注鈣離子感知接受器促進劑、鈣離子感知接受器拮抗劑、氯化鈣、以及含有鈣離子感知接受器拮抗劑之氯化鈣分別所產生的作用。除此之外我們還應用多種膀胱過度活躍或功能障礙之動物模式來評估鈣離子感知接受器促進劑對於膀胱過度活躍或功能障礙的治療潛力。在研究結果中我們藉由鈣離子感知接受器與泌尿上皮特異蛋白之共定位確認鈣離子感知接受器表現在膀胱泌尿上皮。在離體實驗中,泌尿上皮鈣離子感知接受器之活化會減低乙醯膽鹼所引發的膀胱平滑肌收縮,然而泌尿上皮鈣離子感知接受器之抑制會增加膀胱平滑肌的自發性收縮振幅與自發性收縮頻率。膀胱內灌注鈣離子感知接受器促進劑會抑制排尿頻率、非排尿收縮時期的骨盆感覺神經活性、以及排尿時期的骨盆運動神經活性。膀胱內同時灌注鈣離子感知接受器拮抗劑與氯化鈣會增加排尿頻率以及骨盆感覺神經活性,然而單獨灌注氯化鈣或鈣離子感知接受器拮抗劑則無影響。除此之外,上述這些膀胱內灌注實驗處理皆不影響膀胱血液微循環。泌尿上皮鈣離子感知接受器之活化能改善膀胱過度活躍相關的尿路動力參數。我們確認泌尿上皮鈣離子感知接受器展現出化學感知功能,且是透過平滑肌與神經相關機制來調節排尿功能、而非透過膀胱血液動力之干擾來調節排尿功能,並能改善膀胱過度活躍。此研究提供了尿液中物質能透過泌尿上皮鈣離子感知接受器來調節排尿功能之有力證據,並指出泌尿上皮鈣離子感知接受器能於膀胱疾病的醫療介入中作為一個具有潛在臨床應用價值的治療標的。
Calcium-sensing receptor regulates several physiological functions other than calcitropic actions. However, the role of calcium-sensing receptor in lower urinary tract function has remained unknown. In this research, we determined whether urothelial calcium-sensing receptor in rat bladders influence detrusor activity, micturition reflex, pelvic nerve activities, bladder microcirculation, and cystitis-induced bladder hyperactivity. Western blot and immunohistochemistry were utilized to confirm the expression and the location of calcium-sensing receptor in rat bladders. In vitro myography was used to determine the spontaneous activity and contractility of bladder strips affected by activation and inhibition of calcium-sensing receptor via specific agonist, AC‐265347, and antagonist, NPS-2143 hydrochloride, respectively. Cystometry, pelvic nerve activities recording, bladder surface microcirculation detection were executed to assess the influences of intravesical infusion with AC‐265347, NPS-2143 hydrochloride, CaCl2, and CaCl2 containing NPS-2143 hydrochloride. Several bladder hyperactivity or dysfunction animal models was applied to assess the therapeutic potential of calcium-sensing receptor agonist on bladder hyperactivity or dysfunction. Calcium-sensing receptor was confirmed for its expression in bladder urothelium via the colocalization with uroplakin III A. The activation of urothelial calcium-sensing receptor via AC-265347 decreased acetylcholine-induced contraction, whereas its inhibition via NPS-2143 hydrochloride increased the amplitude and frequency of detrusor spontaneous contractions in in vitro experiments. Intravesical infusion of AC-265347 inhibited voiding frequency, pelvic afferent and efferent nerve activities during non-micturition contractions and voiding phase, respectively. Intravesical infusion of CaCl2 combined with NPS-2143 hydrochloride increased voiding frequency and pelvic afferent nerve activities, whereas CaCl2 or NPS-2143 hydrochloride alone demonstrated no effects. Moreover, these intravesical treatments didn’t affect bladder microcirculation. Activation of urothelial calcium-sensing receptor ameliorated bladder hyperactivity-related urodynamic parameters. Urothelial calcium-sensing receptor demonstrated chemosensory function, modulated micturition function via detrusor-related and neuron-related mechanisms, rather than bladder hemodynamic disturbance, and alleviated bladder hyperactivity. This study provided concrete evidence of how substances in urine mediate micturition function via urothelial calcium-sensing receptor, and implicated it as a clinical potential therapeutic target in the intervention of bladder disorders.
摘要 II
Abstract IV
Abbreviation X
Chapter 1. Introduction 1
1-1 Influence of Urine on Micturition Function 2
1-2 Neural Control of Micturition 2
1-3 Role of Urothelium in Micturition 3
1-4 Physiological Role of Calcium-Sensing Receptor 6
1-5 Research Aims 8
Chapter 2. Material and Methods 9
2-1 Animals 10
2-2 Western blot 10
2-3 Immunohistochemistry 12
2-4 Immunofluorescence 12
2-5 Measurement of in vitro bladder strip contractility 13
2-6 Measurement of cystometric parameters 15
2-7 Pelvic nerve activities recording 17
2-8 Measurement of bladder surface microcirculation 18
2-9 Intravesical acetic acid-induced bladder hyperactivity 19
2-10 Intravesical adenosine triphosphate-induced bladder hyperactivity 20
2-11 Cyclophosphamide-induced bladder hyperactivity 20
2-12 Bladder function altered by dietary-induced hypercalciuria 21
2-13 Data and statistical analysis 21
Chapter 3. Results 23
3-1 Qualitative analysis of CaSR in bladder 24
3-2 Distribution of CaSR in bladder 24
3-3 The influence of CaSR on in vitro myogenic spontaneous activity 25
3-4 CaSR affected in vitro acetylcholine-induced contraction 26
3-5 The effect of elevated calcium concentration on in vitro myogenic spontaneous activity and acetylcholine-induced contraction 27
3-6 Effect of CaSR on micturition in the anaesthetized rat 29
3-7 Influence of CaSR on pelvic nerve activities 31
3-8 Assessment of bladder surface microcirculation before and after intravesical administrations of different solution 32
3-9 Influence of CaSR agonist on bladder hyperactivity or dysfunction 33
3-10 Quantitative analysis of CaSR in bladder from different groups 36
Chapter 4. Discussion and Conclusion 37
4-1 The functional role of urothelial CaSR in micturition 38
4-2 Urothelial CaSR regulates detrusor smooth muscle 41
4-3 Urothelial CaSR affects the neural control of urinary bladder 44
4-4 Urothelial CaSR participates in urine substance-mediated micturition 45
4-5 Urothelial CaSR is irrelevant to bladder hemodynamics 47
4-6 Therapeutic potential of urothelial CaSR in bladder hyperactivity and dysfunction 48
4-7 Current treatments of bladder hyperactivity and the potential of intravesical drug administration 50
4-8 Conclusion 52
4-9 Future works 53
References 54
Figures 60
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