Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder
Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder
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DOI：
10.1152/ajprenal.00060.2005
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发表时间：
2005-09-01
影响因子：
4.2
通讯作者：
Nelson, MT
中科院分区：
文献类型：
--
作者：
Thorneloe, KS;Meredith, AL;Nelson, MT
膀胱过度活动症和尿失禁是主要的医学问题，缺乏有效的治疗方法。此前，我们表明（Meredith AL、Thornloe KS、Werner ME、Nelson MT 和 Aldrich RW. J Biol Chem 279: 36746-36752, 2004）基因 mSlo1 编码膀胱平滑肌 (UBSM) 的大电导 Ca2+ 激活 K+ (BK) 通道，并且 mSlo1 的消融会导致肌源性和肌源性增强。神经介导的收缩力和排尿频率增加。在这里，我们检查了 BK 通道缺失情况下的体内尿动力学后果和神经递质依赖性。 Slo(-/-) 小鼠的 UBSM 条带对神经刺激的收缩敏感性大大增强。在Slo(-/-)和Slo(-/-)小鼠中获得50%最大收缩所需的刺激频率分别为8.3+/-0.9和19.1+/-1.8Hz。这种增强至少部分是由于 UBSM 兴奋性的改变，因为毒蕈碱诱导的 Slo(-/-) 收缩性在没有神经元活动的情况下升高。通过用伊比利亚毒素(IBTX)阻断Slo(-/-)条中的BK通道来模拟毒蕈碱诱导的Slo(-/-)收缩性，而IBTX对Slo(-/-)条没有影响。 IBTX还增强Slo(-/-) UBSM的嘌呤能收缩，但对Slo(-/-)条带的嘌呤能收缩没有影响。对清醒、自由活动的小鼠进行体内膀胱压力和尿量测量（膀胱测量）。 Slo(-/-)小鼠表现出膀胱压力增加、明显的压力波动和尿液滴落。我们的结果表明，UBSM 中的 BK 通道在泌尿功能和功能障碍中具有非常重要的作用，因此可能代表一个重要的治疗靶点。
Overactive bladder and incontinence are major medical issues, which lack effective therapy. Previously, we showed (Meredith AL, Thornloe KS, Werner ME, Nelson MT, and Aldrich RW. J Biol Chem 279: 36746-36752, 2004) that the gene mSlo1 encodes large-conductance Ca2+-activated K+ ( BK) channels of urinary bladder smooth muscle (UBSM) and that ablation of mSlo1 leads to enhanced myogenic and nerve-mediated contractility and increased urination frequency. Here, we examine the in vivo urodynamic consequences and neurotransmitter dependence in the absence of the BK channel. The sensitivity of contractility to nerve stimulation was greatly enhanced in UBSM strips from Slo(-/-) mice. The stimulation frequency required to obtain a 50% maximal contraction was 8.3 +/- 0.9 and 19.1 +/- 1.8 Hz in Slo(-/-) and Slo(-/-) mice, respectively. This enhancement is at least partially due to alterations in UBSM excitability, as muscarinic-induced Slo(-/-) contractility is elevated in the absence of neuronal activity. Muscarinic-induced Slo(-/-) contractility was mimicked by blocking BK channels with iberiotoxin (IBTX) in Slo(-/-) strips, whereas IBTX had no effect on Slo(-/-) strips. IBTX also enhanced purinergic contractions of Slo(-/-) UBSM but was without effect on purinergic contractions of Slo(-/-) strips. In vivo bladder pressure and urine output measurements (cystometry) were performed on conscious, freely moving mice. Slo(-/-) mice exhibited increased bladder pressures, pronounced pressure oscillations, and urine dripping. Our results indicate that the BK channel in UBSM has a very significant role in urinary function and dysfunction and as such likely represents an important therapeutic target.