Elucidation on mechanisms of vanilloid and cannabinoid functions in the urogenital afferent neurotransmissions

阐明香草酸和大麻素在泌尿生殖传入神经传递中的功能机制

• 批准号: 14370508
• 负责人: TAKEDA Masayuki
• 金额: $ 8.96万
• 依托单位: University of Yamanashi (2003-2004)山梨医科大学 (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370508/
• 关键词: Vanilloid; Cannabinoid; VR1 and CB1; Epithelial sodium channel (ENaC); Afferent neurotransmission in urinary bladder; Amiloride; バニロイド; カンナビノイド; Valilloid receptor; Cannabinois receptor; CB1; VR1; Prostatic cell; Benign prostatic hyperplasia

Backaround of the study on the significance of epithelial sodium channel (ENaC) in the mechanism inducing overactive bladder :Overactive bladder (OAB) is the symptom-based syndrome which was newly defined by the International Continence Society in 2002, and is a storage dysfunction exhibiting urinary urgency as an essential symptom. The mechanism inducing urinary urgency has not been revealed, although it has been speculated that it is involved in the abnormality in the afferent transmission. One has noted the significance on the role of unmyelinated C-fibers in which vanilloid receptors (VR1, VRL1) are largely expressed under pathologic conditions such as spinal cord injury, while the essence of mechanoceptors which convey urinary sensations is unknown. The recent studies demonstrated that the urothelium produced transmitters including ATP, influencing the transmission in the bladder sensory (Fry, C.H. : Urology, 2004). Thus, we examined the epithelial sodium channel (ENaC), one of th … More e candidates involved in the mechanosensory transduction in the bladder.Materials and Methods :1)Study in the human : Urothelia from patients without bladder outlet obstruction and with benign prostatic hyperplasia presenting OAB symptoms, were used. The expression of ENaC proteins was examined by immunohistofluorescent staining using anti-ENaC subunit polyclonal antibodies, and the ENaC genes expression was assessed by a quantitative RT-PCR.2)Study in the rat (in vitro) : Urothelia from female rats without bladder outlet obstruction and with partial urethral obstruction, were used. The expression of ENaC proteins was examined by immunohistofluorescent staining using anti-ENaC subunit polyclonal antibodies, and the ENaC genes expression was assessed by a quantitative RT-PCR.3)Study in the rat (in vivo) : Detrusor contractility and intermicturition interval were evaluated during cystometry. The effects of amiloride, an ENaC inhibitor, on these parameters were also examined.Results :1)Study in the human : The expression of proteins for ENaC subunits (α, β, γ) was detected in the human urinary bladder. The expression levels of each ENaC subunit mRNA in obstructed bladders were significantly greater than those in controls (Urology, 64 : 1255-1260, 2004).2)Study in the rat (in vitro) : The expression of proteins for ENaC subunits (α, β, γ) was detected in the rat urinary bladder, although the expression levels of each subunit mRNA were not quantitatively different between bladders with and without bladder outlet obstruction3)Amiloride, an ENaC inhibitor, did not change the detrusor contractility, whereas it markedly increased the intermicturition interval.Conclusions and Discussion :The studies revealed a remarkable species difference between the human and rat bladders with obstructed urethra in the expression levels of ENaC subunits (α, β, γ) mRNA, while these suggested the possibility that ENaC was involved in the induction of overactive bladder. Less

膀胱过度活动症（Overactive bladder，OAB）是2002年国际尿失禁学会（International Continence Society）最新定义的一种以排尿为基础的综合征，是以尿急为主要症状的储尿功能障碍。引起尿急的机制尚未被揭示，尽管已经推测其参与传入传递的异常。人们已经注意到无髓鞘C纤维的作用的重要性，其中香草酸受体（VR 1，VRL 1）在病理条件下如脊髓损伤时大量表达，而传递泌尿感觉的机械感受器的本质尚不清楚。最近的研究表明，尿道分泌物产生包括ATP的递质，影响膀胱感觉中的传递（Fry，C.H.：Urology，2004）。因此，我们检测了上皮钠通道（ENaC）， ...更多信息 材料和方法：1）人体研究：采用无膀胱出口梗阻和良性前列腺增生患者的尿路上皮，表现为OAB症状。采用荧光染色法检测ENaC蛋白的表达，RT-PCR法检测ENaC基因的表达。2）体外实验：取无膀胱出口梗阻和部分尿道梗阻的雌性大鼠的尿道上皮细胞。采用荧光染色法检测ENaC蛋白的表达，RT-PCR法检测ENaC基因的表达。3）大鼠体内研究：膀胱测压法检测逼尿肌收缩力和排尿间期。结果：1）人体研究：在人膀胱中检测到ENaC亚基（α、β、γ）蛋白的表达。梗阻组ENaC各亚基mRNA表达水平均显著高于对照组（Urology，64：1255-1260，2004）。（体外）：膀胱组织中ENaC亚单位（α、β、γ）蛋白表达，虽然在有和没有膀胱出口梗阻的膀胱中，每个亚单位mRNA的表达水平在数量上没有差异。3）Amiloride，一种ENaC抑制剂，不改变逼尿肌收缩性，结论：ENaC亚单位（α，β，γ）mRNA在尿道梗阻的人和大鼠膀胱中的表达存在明显的种属差异，提示ENaC可能参与了膀胱过度活动症的发生。少

项目成果

Takeda M, Araki I, Kamiyama M, Takihana Y, Komuro M, Furuya Y: "Diagnosis and treatment of voiding symptoms"Urology. 62, suppl 2. 11-19 (2003)

Takeda M、Araki I、Kamiyama M、Takihana Y、Komuro M、Furuya Y：“排尿症状的诊断和治疗”泌尿外科。

Lower urinary tract symptoms in men and women without lower urinary tract diseases: natural history of bladder function.

无下尿路疾病的男性和女性的下尿路症状：膀胱功能的自然史。

• 发表时间: 2003
• 期刊: Journal of Urology 170
• 作者: Araki I;Takeda M
• 通讯作者: Takeda M

過活動膀胱症候群治療薬をスクリーニングするために用いる標的物質、及び過活動膀胱症候群治療薬

用于筛选膀胱过度活动症候群疗法的目标物质及膀胱过度活动症候群疗法

• 发表时间: 2004

Incontinence

• DOI: 10.1016/j.mcna.2011.02.006
• 发表时间: 2011-05-01
• 期刊: MEDICAL CLINICS OF NORTH AMERICA
• 影响因子: 5.9
• 作者: Markland, Alayne D.;Vaughan, Camille P.;Goode, Patricia S.
• 通讯作者: Goode, Patricia S.

Hiramatsu N, Kasai A, Yao J, Meng Y, Takeda M, Maeda S, Kitamura M: "AP-1-independent Sensitization of Oxidative Stress-induced Apoptosis by Proteasome Inhibitors"Biochem Biophys Res Com. 316. 545-552 (2001)

Hiramatsu N、Kasai A、Yao J、Meng Y、Takeda M、Maeda S、Kitamura M：“蛋白酶体抑制剂对氧化应激诱导的细胞凋亡的 AP-1 独立敏感性”Biochem Biophys Res Com。