Merrill Liana, Vizzard Margaret A
Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont.
Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont
Am J Physiol Regul Integr Comp Physiol. 2014 Aug 15;307(4):R471-80. doi: 10.1152/ajpregu.00008.2014. Epub 2014 Jun 25.
Individuals with functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) often report symptom (e.g., urinary frequency) worsening due to stress. One member of the transient receptor potential ion channel vanilloid family, TRPV4, has recently been implicated in urinary bladder dysfunction disorders including OAB and IC/BPS. These studies address the role of TRPV4 in stress-induced bladder dysfunction using an animal model of stress in male rats. To induce stress, rats were exposed to 7 days of repeated variate stress (RVS). Quantitative PCR data demonstrated significant (P ≤ 0.01) increases in TRPV4 transcript levels in urothelium but not detrusor smooth muscle. Western blot analyses of split urinary bladders (i.e., urothelium and detrusor) showed significant (P ≤ 0.01) increases in TRPV4 protein expression levels in urothelial tissues but not detrusor smooth muscle. We previously showed that RVS produces bladder dysfunction characterized by decreased bladder capacity and increased voiding frequency. The functional role of TRPV4 in RVS-induced bladder dysfunction was evaluated using continuous, open outlet intravesical infusion of saline in conjunction with administration of a TRPV4 agonist, GSK1016790A (3 μM), a TRPV4 antagonist, HC067047 (1 μM), or vehicle (0.1% DMSO in saline) in control and RVS-treated rats. Bladder capacity, void volume, and intercontraction interval significantly decreased following intravesical instillation of GSK1016790A in control rats and significantly (P ≤ 0.01) increased following administration of HC067047 in RVS-treated rats. These results demonstrate increased TRPV4 expression in the urothelium following RVS and that TRPV4 blockade ameliorates RVS-induced bladder dysfunction consistent with the role of TRPV4 as a promising target for bladder function disorders.
患有功能性下尿路疾病（包括间质性膀胱炎（IC）/膀胱疼痛综合征（BPS）和膀胱过度活动症（OAB））的个体常报告症状（如尿频）因压力而加重。瞬时受体电位离子通道香草酸受体家族的成员之一TRPV4，最近被认为与包括OAB和IC/BPS在内的膀胱功能障碍性疾病有关。这些研究使用雄性大鼠应激动物模型，探讨TRPV4在应激诱导的膀胱功能障碍中的作用。为了诱导应激，将大鼠暴露于7天的重复可变应激（RVS）中。定量PCR数据显示，尿路上皮中TRPV4转录水平显著（P≤0.01）升高，但逼尿肌平滑肌中未升高。对分离的膀胱（即尿路上皮和逼尿肌）进行的蛋白质免疫印迹分析显示，尿路上皮组织中TRPV4蛋白表达水平显著（P≤0.01）升高，但逼尿肌平滑肌中未升高。我们之前表明，RVS会导致膀胱功能障碍，其特征为膀胱容量减少和排尿频率增加。使用连续、开放出口膀胱内输注生理盐水，并联合给予TRPV4激动剂GSK1016790A（3μM）、TRPV4拮抗剂HC067047（1μM）或赋形剂（0.1%二甲基亚砜溶于生理盐水中），在对照大鼠和接受RVS处理的大鼠中评估TRPV4在RVS诱导的膀胱功能障碍中的功能作用。在对照大鼠膀胱内滴注GSK1016790A后，膀胱容量、排尿量和收缩间期显著降低，而在接受RVS处理的大鼠中给予HC067047后，这些指标显著（P≤0.01）升高。这些结果表明，RVS后尿路上皮中TRPV4表达增加，并且TRPV4阻断可改善RVS诱导的膀胱功能障碍，这与TRPV4作为膀胱功能障碍的一个有前景的靶点的作用一致。
