Excitatory Cholinergic and Purinergic Signaling in Bladder Are Equally Susceptible to Botulinum Neurotoxin A Consistent with Co-Release of Transmitters from Efferent Fibers
Excitatory Cholinergic and Purinergic Signaling in Bladder Are Equally Susceptible to Botulinum Neurotoxin A Consistent with Co-Release of Transmitters from Efferent Fibers
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DOI：
10.1124/jpet.110.169342
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发表时间：
2010-09-01
影响因子：
3.5
通讯作者：
Dolly, J. Oliver
中科院分区：
文献类型：
--
作者：
Lawrence, Gary W.;Aoki, K. Roger;Dolly, J. Oliver
本研究解剖了大鼠膀胱肌条中神经肌肉传递的介质，以检查它们对肉毒杆菌神经毒素（BoNT）抑制的敏感性，并阐明了BoNT/A在缓解与膀胱过度活动症相关的平滑肌痉挛中的临床有效性的基础。BoNT/A、BoNT/C1或BoNT/E通过仅作用于神经源性河豚毒素敏感性反应，以剂量依赖性方式降低由电场刺激（EFS）诱导的肌肉收缩的峰值和平均力。切割囊泡相关膜蛋白的BoNTs被证明效率要低得多。乙酰胆碱（ACh）和ATP被发现提供了几乎所有的兴奋性输入，因为毒蕈碱受体拮抗剂阿托品与P2 X（1）和P2 X（3）的脱敏激动剂或非选择性ATP受体拮抗剂联合使用可以消除EFS诱发的收缩。这两个发射器被释放在神经支配的肌肉层，因此，持续去除尿路刺激后。阿托品或P2 X（1）或P2 X（3）受体的脱敏剂不会改变BoNT/A减弱肌肉收缩的速率。此外，尽管胆碱能和嘌呤能信号可以通过使用高频EFS（其增强了在P2 X受体脱敏后减少的肌肉收缩中的短暂的、主要是阿托品抗性的尖峰）来部分描绘，但它们被证明对BoNT/A同样敏感。因此，从肌肉传出神经中释放的ATP与ACh的等效阻断可能有助于BoNT/A治疗膀胱过度活动的有效性，包括对抗胆碱能药物的无应答者。因为嘌呤能受体是已知的感觉传入兴奋的介质，通过BoNT/A抑制传出ATP释放也可以帮助改善一些接受者报告的急性疼痛和紧迫感。
Mediators of neuromuscular transmission in rat bladder strips were dissected pharmacologically to examine their susceptibilities to inhibition by botulinum neurotoxins (BoNTs) and elucidate a basis for the clinical effectiveness of BoNT/A in alleviating smooth muscle spasms associated with overactive bladder. BoNT/A, BoNT/C1, or BoNT/E reduced peak and average force of muscle contractions induced by electric field stimulation (EFS) in dose-dependent manners by acting only on neurogenic, tetrodotoxin-sensitive responses. BoNTs that cleaved vesicle-associated membrane protein proved to be much less effective. Acetylcholine (ACh) and ATP were found to provide virtually all excitatory input, because EFS-evoked contractions were abolished by the muscarinic receptor antagonist, atropine, combined with either a desensitizing agonist of P2X(1) and P2X(3) or a nonselective ATP receptor antagonist. Both transmitters were released in the innervated muscle layer and, thus, persisted after removal of urothelium. Atropine or a desensitizer of the P2X(1) or P2X(3) receptors did not alter the rate at which muscle contractions were weakened by BoNT/A. Moreover, although cholinergic and purinergic signaling could be partially delineated by using high-frequency EFS (which intensified a transient, largely atropine-resistant spike in muscle contractions that was reduced after P2X receptor desensitization), they proved equally susceptible to BoNT/A. Thus, equi-potent blockade of ATP co-released with ACh from muscle efferents probably contributes to the effectiveness of BoNT/A in treating bladder overactivity, including nonresponders to anticholinergic drugs. Because purinergic receptors are known mediators of sensory afferent excitation, inhibition of efferent ATP release by BoNT/A could also help to ameliorate acute pain and urgency sensation reported by some recipients.