Department of Urology, The Second Hospital of Shandong University, Jinan, China.
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China.
Free Radic Biol Med. 2023 Nov 20;209(Pt 1):1-8. doi: 10.1016/j.freeradbiomed.2023.10.001. Epub 2023 Oct 5.
Several studies have indicated that reactive oxygen species (ROS) can lead to detrusor overactivity (DO), but the underlying mechanisms are not known. Hydrogen dioxide (HO) is used commonly to investigate the effects of ROS. In present study, we investigated the effects of HO on phasic spontaneous bladder contractions (SBCs) of isolated human-bladder strips (iHBSs) and the underlying mechanisms. Samples of bladder tissue were obtained from 26 patients undergoing cystectomy owing to bladder cancer. SBCs of iHBSs were recorded in organ-bath experiments. HO (1μM-10mM) concentration-dependently increased the SBCs of iHBSs. These enhancing effects could be mimicked by an agonist of transient receptor potential (TRP)A1 channels (allyl isothiocyanate) and blocked with an antagonist of TRPA1 channels (HC030031; 10 μM). HO induced enhancing effects also could be attenuated by desensitizing sensory afferents with capsaicin (10 μM), blocking nerve firing with TTX (1 μM), blocking neurokinin effects with NK2 receptor antagonist (SR48968, 10 μM), and blocking PGE2 synthesis with indomethacin (10 μM), respectively. Our study: (i) suggests activation of TRPA1 channels on bladder sensory afferents, and then release of substance P or PGE2 from sensory nerve terminals, contribute to the HO-induced enhancing effects on SBCs of iHBSs; (ii) provides insights for the mechanisms underlying ROS leading to DO; (iii) indicates that targeting TRPA1 channels might be the promising strategy against overactive bladder in conditions associated with excessive production of ROS.
已有多项研究表明活性氧（ROS）可导致逼尿肌过度活动（DO），但其潜在机制尚不清楚。过氧化氢（HO）常用于研究 ROS 的影响。在本研究中，我们研究了 HO 对分离人膀胱条（iHBS）的相位自发性膀胱收缩（SBC）的影响及其潜在机制。膀胱组织样本取自 26 例因膀胱癌而行膀胱切除术的患者。在器官浴实验中记录 iHBS 的 SBC。HO（1μM-10mM）浓度依赖性地增加 iHBS 的 SBC。TRP 通道（TRPA1 通道）激动剂（丙烯基异硫氰酸酯）可模拟这些增强作用，而 TRPA1 通道拮抗剂（HC030031；10μM）可阻断这些作用。HO 诱导的增强作用也可通过用辣椒素（10μM）敏化感觉传入、用 TTX（1μM）阻断神经放电、用 NK2 受体拮抗剂（SR48968，10μM）阻断神经激肽效应、用吲哚美辛（10μM）阻断 PGE2 合成分别减弱。我们的研究：（i）表明膀胱感觉传入上的 TRPA1 通道的激活，随后感觉神经末梢释放 P 物质或 PGE2，导致 HO 对 iHBS 的 SBC 增强作用；（ii）为 ROS 导致 DO 的潜在机制提供了见解；（iii）表明靶向 TRPA1 通道可能是针对与 ROS 过度产生相关的过度活动膀胱的有前途的策略。
