Kang Sung-Hyun, McDermott Catherine, Farr Stefanie, Chess-Williams Russ
Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Queensland, 4229, Australia.
Naunyn Schmiedebergs Arch Pharmacol. 2015 Jul;388(7):773-80. doi: 10.1007/s00210-015-1097-2. Epub 2015 Feb 17.
Intravesical administration of the cytotoxic drug doxorubicin is a common treatment for superficial carcinoma of the bladder, but it is associated with significant urological adverse effects. The aim of this study was to identify doxorubicin-induced changes in the local mechanisms involved in regulating bladder function. As a model of intravesical doxorubicin administration in patients, doxorubicin (1 mg/mL) was applied to the luminal surface of porcine bladders for 60 min. Following treatment, the release of urothelial/lamina propria mediators (acetylcholine (Ach), ATP and prostaglandin E2 (PGE2) and contractile responses of isolated tissue strips was investigated. Doxorubicin pretreatment did not affect contractile responses of detrusor muscle to carbachol, but did enhance neurogenic detrusor responses to electrical field stimulation (219 % at 5 Hz). Contractions of isolated strips of urothelium/lamina propria to carbachol were also enhanced (30 %) in tissues from doxorubicin pretreated bladders. Isolated strips of urothelium/lamina propria from control bladders demonstrated a basal release of all three mediators (Ach > ATP > PGE2), with increased release of ATP when tissues were stretched. In tissues from doxorubicin-pretreated bladders, the basal release of ATP was significantly enhanced (sevenfold), while the release of acetylcholine and PGE2 was not affected. The application of luminal doxorubicin, under conditions that mimic intravesical administration to patients, affects urothelial/lamina propria function (increased contractile activity and ATP release) and enhances efferent neurotransmission without affecting detrusor smooth muscle. These actions would enhance bladder contractile activity and sensory nerve activity and may explain the adverse urological effects observed in patients following intravesical doxorubicin treatment.
膀胱内灌注细胞毒性药物阿霉素是浅表性膀胱癌的常用治疗方法，但它会带来显著的泌尿系统不良反应。本研究的目的是确定阿霉素诱导的膀胱功能调节局部机制的变化。作为患者膀胱内灌注阿霉素的模型，将阿霉素（1毫克/毫升）应用于猪膀胱腔面60分钟。处理后，研究尿路上皮/固有层介质（乙酰胆碱（Ach）、ATP和前列腺素E2（PGE2））的释放以及离体组织条的收缩反应。阿霉素预处理不影响逼尿肌对卡巴胆碱的收缩反应，但增强了神经源性逼尿肌对电场刺激的反应（5赫兹时为219%）。在阿霉素预处理膀胱的组织中，尿路上皮/固有层离体条对卡巴胆碱的收缩也增强了（30%）。对照膀胱的尿路上皮/固有层离体条显示所有三种介质均有基础释放（Ach＞ATP＞PGE2），组织拉伸时ATP释放增加。在阿霉素预处理膀胱的组织中，ATP的基础释放显著增强（七倍），而乙酰胆碱和PGE2的释放未受影响。在模拟患者膀胱内灌注的条件下应用腔内阿霉素，会影响尿路上皮/固有层功能（增加收缩活性和ATP释放）并增强传出神经传递，而不影响逼尿肌平滑肌。这些作用会增强膀胱收缩活性和感觉神经活性，可能解释了膀胱内灌注阿霉素治疗后患者出现的泌尿系统不良反应。
