Audrey Dumont , Mouad Hamzaoui , Déborah Groussard , Michèle Iacob , Dominique Bertrand , Isabelle Remy-Jouet , Mélanie Hanoy , Frank Le Roy , Laurence Chevalier , Christoph Enzensperger , Hans-Dieter Arndt , Sylvanie Renet , Anaïs Dumesnil , Emilie Lévêque , Thomas Duflot , Valéry Brunel , Aurore Michel-Després , Marie-Pierre Audrézet , Vincent Richard , Robinson Joannidès , Jérémy Bellien
{"title":"慢性内皮多巴胺受体刺激可改善常染色体显性多囊肾的内皮功能和血液动力学。","authors":"Audrey Dumont , Mouad Hamzaoui , Déborah Groussard , Michèle Iacob , Dominique Bertrand , Isabelle Remy-Jouet , Mélanie Hanoy , Frank Le Roy , Laurence Chevalier , Christoph Enzensperger , Hans-Dieter Arndt , Sylvanie Renet , Anaïs Dumesnil , Emilie Lévêque , Thomas Duflot , Valéry Brunel , Aurore Michel-Després , Marie-Pierre Audrézet , Vincent Richard , Robinson Joannidès , Jérémy Bellien","doi":"10.1016/j.kint.2024.08.020","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"106 6","pages":"Pages 1158-1169"},"PeriodicalIF":14.8000,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease\",\"authors\":\"Audrey Dumont , Mouad Hamzaoui , Déborah Groussard , Michèle Iacob , Dominique Bertrand , Isabelle Remy-Jouet , Mélanie Hanoy , Frank Le Roy , Laurence Chevalier , Christoph Enzensperger , Hans-Dieter Arndt , Sylvanie Renet , Anaïs Dumesnil , Emilie Lévêque , Thomas Duflot , Valéry Brunel , Aurore Michel-Després , Marie-Pierre Audrézet , Vincent Richard , Robinson Joannidès , Jérémy Bellien\",\"doi\":\"10.1016/j.kint.2024.08.020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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.</div></div>\",\"PeriodicalId\":17801,\"journal\":{\"name\":\"Kidney international\",\"volume\":\"106 6\",\"pages\":\"Pages 1158-1169\"},\"PeriodicalIF\":14.8000,\"publicationDate\":\"2024-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Kidney international\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0085253824006264\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney international","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0085253824006264","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease
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.
期刊介绍:
Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide.
KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics.
The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.