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首页> 外文期刊>BMC Urology >Altered detrusor contractility and voiding patterns in mice lacking the mechanosensitive TREK-1 channel
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Altered detrusor contractility and voiding patterns in mice lacking the mechanosensitive TREK-1 channel

机译：缺乏机械敏感性TREK-1通道的小鼠逼尿肌收缩力和排尿模式改变

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Previously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice. Adult C57BL/6?J wild-type (WT, N?=?32) and TREK-1 KO (N?=?33) mice were used in this study. The overall phenotype and bladder function were evaluated by gene and protein expression of TREK-1 channel, in vitro contractile experiments using detrusor strips in response to stretch and pharmacological stimuli, and cystometry in unanesthetized animals. TREK-1 KO animals had an elevated basal muscle tone and enhanced spontaneous activity in the detrusor without detectable changes in bladder morphology/histology. Stretch applied to isolated detrusor strips increased the amplitude of spontaneous contractions by 109% in the TREK-1 KO group in contrast to a 61% increase in WT mice (p?≤?0.05 to respective baseline for each group). The detrusor strips from TREK-1 KO mice also generated more contractile force in response to electric field stimulation and high potassium concentration in comparison to WT group (p?≤?0.05 for both tests). However, cystometric recordings from TREK-1 KO mice revealed a significant increase in the duration of the intermicturition interval, enhanced bladder capacity and increased number of non-voiding contractions in comparison to WT mice. Our results provide evidence that global down-regulation of TREK-1 channels has dual effects on detrusor contractility and micturition patterns in vivo. The observed differences are likely due to expression of TREK-1 channel not only in detrusor myocytes but also in afferent and efferent neural pathways involved in regulation of micturition which may underly the “mixed” voiding phenotype in TREK-1 KO mice.
机译：我们实验室先前发布的结果确定了机械门控的两孔结构域钾通道TREK-1，它是人膀胱平滑肌中的主要机械传感器。在离体人体逼尿肌上进行的体外实验的局限性之一是无法评估TREK-1对排尿功能的体内作用，因为该通道也在神经系统中表达，并可能通过神经途径调节排尿。因此，在本研究中，我们旨在通过使用TREK-1敲除（KO）小鼠评估TREK-1通道在体内膀胱功能和排尿模式中的作用。在该研究中使用成年C57BL /6αJ野生型（WT，Nα＝β32）和TREK-1 KO（Nα＝β33）小鼠。通过TREK-1通道的基因和蛋白表达，在未麻醉动物中使用逼尿肌条响应拉伸和药理刺激的体外收缩实验以及膀胱测压术，评估总体表型和膀胱功能。 TREK-1 KO动物的逼尿肌基底肌张力增高，自发活动增强，膀胱形态/组织学无变化。 TREK-1 KO组中施加于孤立的逼尿肌条上的拉伸使自发性收缩幅度增加了109％，而WT小鼠则增加了61％（每组相对于基线的p≤0.05）。与WT组相比，TREK-1 KO小鼠的逼尿肌条对电场刺激和高钾浓度也产生了更大的收缩力（两个试验的p≤≤0.05）。然而，TREK-1 KO小鼠的膀胱测压记录显示，与WT小鼠相比，排尿间隔的持续时间显着增加，膀胱容量增加，无空收缩次数增加。我们的结果提供证据表明，TREK-1通道的整体下调对体内逼尿肌的收缩性和排尿方式有双重影响。观察到的差异很可能是由于TREK-1通道不仅在逼尿肌细胞中表达，而且还与参与排尿调节的传入和传出神经通路有关，这可能是TREK-1 KO小鼠的“混合”排尿表型的潜在原因。

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