{"title":"通过从粘膜释放乙酰胆碱,激活 Piezo1 通道可增强离体人膀胱条带的自发收缩。","authors":"","doi":"10.1016/j.ejphar.2024.176954","DOIUrl":null,"url":null,"abstract":"<div><p>Enhanced spontaneous bladder contractions (SBCs) have been thought one of the important underlying mechanisms for detrusor overactivity (DO). Piezo1 channel has been demonstrated involved in bladder function and dysfunction in rodents. We aimed to investigate the modulating role of Piezo1 in SBCs activity of human bladder. Human bladder tissues were obtained from 24 organ donors. SBCs of isolated bladder strips were recorded in organ bath. Piezo1 expression was examined with reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining. ATP and acetylcholine release in cultured human urothelial cells was measured. Piezo1 is abundantly expressed in the bladder mucosa. Activation of Piezo1 with its specific agonist Yoda1 (100 nM–100 μM) enhanced the SBCs activity in isolated human bladder strips in a concentration-dependent manner. The effect of Yoda1 mimicked the effect of a low concentration (30 nM) of carbachol, which can be attenuated by removing the mucosa, blocking muscarinic receptors with atropine (1 μM), and blocking purinergic receptors with pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS, 30 μM), but not by tetrodotoxin (1 μM). Activation of urothelial Piezo1 with Yoda1 (30 μM) or hypotonic solution induced the release of ATP and acetylcholine in cultured human urothelial cells. In patients with benign prostatic hyperplasia, greater Piezo1 expression was observed in bladder mucosa from patients with DO than patients without DO. We conclude that upregulation and activation of Piezo1 may contribute to DO generation in patients with bladder outlet obstruction by promoting the urothelial release of ATP and acetylcholine. Inhibition of Piezo1 may be a novel therapeutic approach in the treatment of overactive bladder.</p></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014299924006435/pdfft?md5=6098c10406f63f8cc0fbd097755f2d9b&pid=1-s2.0-S0014299924006435-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Activation of Piezo1 channels enhances spontaneous contractions of isolated human bladder strips via acetylcholine release from the mucosa\",\"authors\":\"\",\"doi\":\"10.1016/j.ejphar.2024.176954\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Enhanced spontaneous bladder contractions (SBCs) have been thought one of the important underlying mechanisms for detrusor overactivity (DO). Piezo1 channel has been demonstrated involved in bladder function and dysfunction in rodents. We aimed to investigate the modulating role of Piezo1 in SBCs activity of human bladder. Human bladder tissues were obtained from 24 organ donors. SBCs of isolated bladder strips were recorded in organ bath. Piezo1 expression was examined with reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining. ATP and acetylcholine release in cultured human urothelial cells was measured. Piezo1 is abundantly expressed in the bladder mucosa. Activation of Piezo1 with its specific agonist Yoda1 (100 nM–100 μM) enhanced the SBCs activity in isolated human bladder strips in a concentration-dependent manner. The effect of Yoda1 mimicked the effect of a low concentration (30 nM) of carbachol, which can be attenuated by removing the mucosa, blocking muscarinic receptors with atropine (1 μM), and blocking purinergic receptors with pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS, 30 μM), but not by tetrodotoxin (1 μM). Activation of urothelial Piezo1 with Yoda1 (30 μM) or hypotonic solution induced the release of ATP and acetylcholine in cultured human urothelial cells. In patients with benign prostatic hyperplasia, greater Piezo1 expression was observed in bladder mucosa from patients with DO than patients without DO. We conclude that upregulation and activation of Piezo1 may contribute to DO generation in patients with bladder outlet obstruction by promoting the urothelial release of ATP and acetylcholine. Inhibition of Piezo1 may be a novel therapeutic approach in the treatment of overactive bladder.</p></div>\",\"PeriodicalId\":12004,\"journal\":{\"name\":\"European journal of pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0014299924006435/pdfft?md5=6098c10406f63f8cc0fbd097755f2d9b&pid=1-s2.0-S0014299924006435-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European journal of pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014299924006435\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014299924006435","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
自发性膀胱收缩(SBC)增强被认为是导致逼尿肌过度活动(DO)的重要潜在机制之一。啮齿类动物的 Piezo1 通道已被证实参与了膀胱功能和功能障碍。我们旨在研究 Piezo1 在人类膀胱 SBCs 活动中的调节作用。人体膀胱组织取自 24 位器官捐献者。在器官浴中记录离体膀胱条带的 SBCs。通过逆转录-定量聚合酶链反应和免疫荧光染色检测 Piezo1 的表达。测量了培养的人尿道细胞中 ATP 和乙酰胆碱的释放。Piezo1 在膀胱粘膜中大量表达。用特异性激动剂 Yoda1(100nM 至 100μM)激活 Piezo1 可增强离体人膀胱条带中 SBCs 的活性,且呈浓度依赖性。Yoda1 的作用模拟了低浓度(30nM)卡巴胆碱的作用,而移除粘膜、用阿托品(1μM)阻断毒蕈碱受体和用吡哆醛-磷酸-6-氮苯基-2',4'-二磺酸盐(10μM)阻断嘌呤能受体可减轻卡巴胆碱的作用,但河豚毒素(1μM)则不能。用 Yoda1(30μM)或低渗溶液激活尿道 Piezo1 可诱导培养的人尿道细胞释放 ATP 和乙酰胆碱。在良性前列腺增生患者中,观察到有 DO 患者的膀胱粘膜中 Piezo1 的表达高于无 DO 患者。我们的结论是,Piezo1 的上调和激活可能会促进尿道释放 ATP 和乙酰胆碱,从而促使膀胱出口梗阻患者产生 DO。抑制 Piezo1 可能是治疗膀胱过度活动症的一种新的治疗方法。
Activation of Piezo1 channels enhances spontaneous contractions of isolated human bladder strips via acetylcholine release from the mucosa
Enhanced spontaneous bladder contractions (SBCs) have been thought one of the important underlying mechanisms for detrusor overactivity (DO). Piezo1 channel has been demonstrated involved in bladder function and dysfunction in rodents. We aimed to investigate the modulating role of Piezo1 in SBCs activity of human bladder. Human bladder tissues were obtained from 24 organ donors. SBCs of isolated bladder strips were recorded in organ bath. Piezo1 expression was examined with reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining. ATP and acetylcholine release in cultured human urothelial cells was measured. Piezo1 is abundantly expressed in the bladder mucosa. Activation of Piezo1 with its specific agonist Yoda1 (100 nM–100 μM) enhanced the SBCs activity in isolated human bladder strips in a concentration-dependent manner. The effect of Yoda1 mimicked the effect of a low concentration (30 nM) of carbachol, which can be attenuated by removing the mucosa, blocking muscarinic receptors with atropine (1 μM), and blocking purinergic receptors with pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS, 30 μM), but not by tetrodotoxin (1 μM). Activation of urothelial Piezo1 with Yoda1 (30 μM) or hypotonic solution induced the release of ATP and acetylcholine in cultured human urothelial cells. In patients with benign prostatic hyperplasia, greater Piezo1 expression was observed in bladder mucosa from patients with DO than patients without DO. We conclude that upregulation and activation of Piezo1 may contribute to DO generation in patients with bladder outlet obstruction by promoting the urothelial release of ATP and acetylcholine. Inhibition of Piezo1 may be a novel therapeutic approach in the treatment of overactive bladder.
期刊介绍:
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.