title: Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.
authors.affiliation: 1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Department of Nephrology, Rouen University Hospital, Rouen, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lorthioir
authors.affiliation: 1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France [4] Centre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, Rouen, France.
authors.forename: Robinson
authors.initials: R
authors.lastname: Joannidès
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [2] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rémy-Jouet
authors.affiliation: 1] Department of Nephrology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fréguin-Bouilland
authors.affiliation: Department of Pharmacology, Rouen University Hospital, Rouen, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Iacob
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [2] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Clothilde
authors.initials: C
authors.lastname: Roche
authors.affiliation: 1] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France [2] Equipe d'Accueil (EA) 4651, Rouen, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Monteil
authors.affiliation: INSERM U1078, Université de Bretagne Occidentale and European University of Brittany, Brest, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Lucas
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [2] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Sylvanie
authors.initials: S
authors.lastname: Renet
authors.affiliation: INSERM U1078, Université de Bretagne Occidentale and European University of Brittany, Brest, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Audrézet
authors.affiliation: 1] Department of Nephrology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Godin
authors.affiliation: 1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.affiliation: 1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.affiliation: 1] Department of Nephrology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guerrot
authors.affiliation: 1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France [4] Centre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, Rouen, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Bellien
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology; D016022:Case-Control Studies; D004298:Dopamine / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D008297:Male; D009154:Mutation; D009569:Nitric Oxide / Q000502:physiology; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D017534:Radial Artery / Q000503:physiopathology; D050396:TRPP Cation Channels / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D055815:Young Adult
chemical_list: D004298:Dopamine; D009569:Nitric Oxide; D050396:TRPP Cation Channels