Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

中文翻译：

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慢性内皮多巴胺受体刺激可改善常染色体显性遗传性多囊肾病的内皮功能和血流动力学


改变的多囊蛋白介导的内皮血流机械敏感性导致常染色体显性遗传性多囊肾病 （ADPKD） 患者发生高血压和心血管并发症。刺激内皮 5 型多巴胺受体 （DR5） 可以急性代偿多囊蛋白缺乏症的内皮后果，但必须在 ADPKD 中评估这种方法的慢性影响。19 例接受标准护理治疗的 ADPKD 患者被随机分配接受 DR 激动剂罗替高汀使用透皮贴剂治疗 2 个月，9 例在 2 mg/24 小时，10 例在 4 mg/24 小时或 10 例未治疗。4 mg/24 小时剂量的罗替高汀显着增加一氧化氮释放 （亚硝酸盐水平从 10±30 到 46±34 nmol/L） 和桡动脉内皮依赖性血流介导的扩张 （从 16.4±6.3 到 22.5±7.3%）响应手部皮肤加热。全身血流动力学没有显着改变，但肺单管眼压计显示，4 mg/24 小时的罗替高汀降低了主动脉增强指数和脉压，而不影响颈动脉到股动脉脉搏波速度。血浆肌酐和尿素、尿环状 AMP（导致 ADPKD 囊肿生长）和copeptin（加压素的替代标志物）不受罗替高汀的影响。在内皮细胞中多囊蛋白-1 特异性缺失的小鼠中，长期输注外周 DR5 激动剂非诺多泮也改善了肠系膜动脉血流介导的扩张并降低了血压。 因此，我们的研究表明，在 ADPKD 患者中，长期服用罗替高汀通过恢复血流诱导的一氧化氮释放和血流动力学来改善导管动脉内皮功能，这表明内皮 DR5 激活可能代表一种有前途的药理学方法来预防 ADPKD 的心血管并发症。