Therapeutic receptor targets for lower urinary tract dysfunction
Therapeutic receptor targets for lower urinary tract dysfunction
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DOI：
10.1007/s00210-007-0209-z
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Tyagi, Pradeep
中科院分区：
文献类型：
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作者：
Yoshimura, Naoki;Kaiho, Yasuhiro;Tyagi, Pradeep
下尿路储存和定期释放尿液的功能取决于膀胱、尿道和尿道外括约肌中平滑肌和横纹肌的活动。在尿液储存期间，出口关闭，膀胱平滑肌处于静止状态。当膀胱容量达到排尿阈值时，脑桥背外侧排尿中心（脑桥排尿中心）的激活会引起膀胱收缩和尿道相互松弛，导致膀胱排空。排尿期间，骶副交感神经（骨盆）神经向膀胱提供兴奋性输入（胆碱能和嘌呤能），向尿道提供抑制性输入（氮能）。这些外周系统通过脊髓和大脑水平的兴奋性和抑制性调节进行整合。神经系统的损伤或疾病，以及药物和周围器官的疾病，都可能导致下尿路功能障碍。在膀胱过度活动症 (OAB) 情况下，促进尿液储存的治疗靶点可以在尿路上皮、逼尿肌、自主神经和传入通路、脊髓和大脑的水平上找到。越来越多的证据表明，尿路上皮具有特殊的感觉和信号传导特性，包括：（1）表达烟碱、毒蕈碱、速激肽、肾上腺素、缓激肽和瞬时受体电位（TRP）受体，（2）与传入神经有密切的物理联系，以及（3）释放化学分子的能力，例如三磷酸腺苷（ATP）、乙酰胆碱和 一氧化氮。这些导致传入敏化的尿路上皮感觉分子的表达和/或敏感性增加已被证明是 OAB 的可能发病机制。通过调节配体受体（例如神经激肽、ATP 或 β(3)-肾上腺素受体）和离子通道（例如 TRPV1 或 K）的活性来靶向传入通路和/或膀胱平滑肌可有效抑制 OAB。在压力性尿失禁的情况下，针对压力条件（例如打喷嚏或咳嗽）期间神经介导的尿道失禁反射的药物疗法可能有效增加出口阻力。治疗靶点包括脊髓中的肾上腺素能受体和血清素能受体以及尿道括约肌中的肾上腺素能受体，它们分别可以增强应激条件下的尿道反射活动并增加基线尿道压力。
The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed, and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunction. In the overactive bladder (OAB) condition, therapeutic targets for facilitation of urine storage can be found at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain. There is increasing evidence showing that the urothelium has specialized sensory and signaling properties including: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors, (2) close physical association with afferent nerves, and (3) ability to release chemical molecules such as adenosine triphosphate (ATP), acetylcholine, and nitric oxide. Increased expression and/or sensitivity of these urothelial-sensory molecules that lead to afferent sensitization have been documented as possible pathogenesis of OAB. Targeting afferent pathways and/or bladder smooth muscles by modulating activity of ligand receptors (e.g., neurokinin, ATP, or beta(3)-adrenergic receptors) and ion channels (e.g., TRPV1 or K) could be effective to suppress OAB. In the stress urinary incontinence condition, pharmacotherapies targeting the neurally mediated urethral continence reflex during stress conditions such as sneezing or coughing could be effective for increasing the outlet resistance. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord as well as adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively.