Serviço de Urologia. Hospital Santo Antonio, Porto, Portugal.
Servicio de Histología. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Eur J Pharmacol. 2014 Jul 15;735:68-76. doi: 10.1016/j.ejphar.2014.03.060. Epub 2014 Apr 18.
We have analysed the effects of large-conductance calcium-activated potassium channel (BK) stimulation on neurogenic and myogenic contraction of human bladder from healthy subjects and patients with urinary symptoms and evaluated the efficacy of activating BK to relief bladder hyperactivity in rats. Bladder specimens were obtained from organ donors and from men with benign prostatic hyperplasia (BPH). Contractions elicited by electrical field stimulation (EFS) and carbachol (CCh) were evaluated in isolated bladder strips. in vivo cystometric recordings were obtained in anesthetized rats under control and acetic acid-induced hyperactive conditions. Neurogenic contractions of human bladder were potentiated by blockade of BK and small-conductance calcium-activated potassium channels (SK) but were unaffected by the blockade of intermediate calcium-activated potassium channels (IK). EFS-induced contractions were inhibited by BK stimulation with NS-8 or NS1619 or by SK/IK stimulation with NS309 (3µM). CCh-induced contractions were not modified by blockade or stimulation of BK, IK or SK. The anti-cholinergic agent, oxybutynin (0.3µM) inhibited either neurogenic or CCh-induced contractions. Neurogenic contractions of bladders from BPH patients were less sensitive to BK inhibition and more sensitive to BK activation than healthy bladders. The BK activator, NS-8 (5mg/kg; i.v.), reversed bladder hyperactivity induced by acetic acid in rats, while oxybutynin was ineffective. NS-8 did not significantly impact blood pressure or heart rate. BK stimulation specifically inhibits neurogenic contractions in patients with urinary symptoms and relieves bladder hyperactivity in vivo without compromising bladder contractile capacity or cardiovascular safety, supporting its potential therapeutic use for relieving bladder overactivity.
我们分析了大电导钙激活钾通道（BK）刺激对来自健康受试者和有尿路症状的患者的人膀胱的神经源性和肌源性收缩的影响，并评估了激活 BK 以缓解大鼠膀胱过度活动的疗效。膀胱标本取自器官捐献者和良性前列腺增生（BPH）男性患者。通过电刺激（EFS）和卡巴胆碱（CCh）诱发的离体膀胱条的收缩。在麻醉大鼠中获得了在对照和乙酸诱导的过度活跃条件下的体内尿动力学记录。人膀胱的神经源性收缩被 BK 和小电导钙激活钾通道（SK）的阻断增强，但不受中间钙激活钾通道（IK）的阻断影响。EFS 诱导的收缩被 NS-8 或 NS1619 对 BK 的刺激或 NS309（3µM）对 SK/IK 的刺激抑制。CCh 诱导的收缩不受 BK、IK 或 SK 的阻断或刺激的影响。抗胆碱能药物奥昔布宁（0.3µM）抑制神经源性或 CCh 诱导的收缩。与健康膀胱相比，BPH 患者的膀胱神经源性收缩对 BK 抑制的敏感性降低，对 BK 激活的敏感性增加。BK 激活剂 NS-8（5mg/kg；静脉内）逆转了乙酸诱导的大鼠膀胱过度活动，而奥昔布宁无效。NS-8 对血压或心率没有显著影响。BK 刺激特异性抑制有尿路症状的患者的神经源性收缩，并在体内缓解膀胱过度活动，而不会损害膀胱收缩能力或心血管安全性，支持其用于缓解膀胱过度活动的潜在治疗用途。
