title: Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway.
abstract: BACKGROUND
  Hyperphosphataemia is an independent risk factor for accelerated cardiovascular disease in chronic kidney disease (CKD), although the mechanism for this is poorly understood. We investigated the effects of sustained exposure to a high-phosphate environment on endothelial function in cellular and preclinical models, as well as in human subjects.
  
  
  METHODS
  Resistance vessels from rats and humans (± CKD) were incubated in a normal (1.18 mM) or high (2.5 mM) phosphate concentration solution and cells were cultured in normal- (0.5 mM) or high-phosphate (3 mM) concentration media. A single-blind crossover study was performed in healthy volunteers, receiving phosphate supplements or a phosphate binder (lanthanum), and endothelial function measured was by flow-mediated dilatation.
  
  
  RESULTS
  Endothelium-dependent vasodilatation was impaired when resistance vessels were exposed to high phosphate; this could be reversed in the presence of a phosphodiesterase-5-inhibitor. Vessels from patients with CKD relaxed normally when incubated in normal-phosphate conditions, suggesting that the detrimental effects of phosphate may be reversible. Exposure to high-phosphate disrupted the whole nitric oxide pathway with reduced nitric oxide and cyclic guanosine monophosphate production and total and phospho endothelial nitric oxide synthase expression. In humans, endothelial function was reduced by chronic phosphate loading independent of serum phosphate, but was associated with higher urinary phosphate excretion and serum fibroblast growth factor 23.
  
  
  CONCLUSIONS
  These directly detrimental effects of phosphate, independent of other factors in the uraemic environment, may explain the increased cardiovascular risk associated with phosphate in CKD.
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.|The Renal Transplant Unit, Western Infirmary, (Now based at The Queen Elizabeth University Hospital) Glasgow, UK.
authors.forename: Kathryn K
authors.initials: KK
authors.lastname: Stevens
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Denby
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.|The Renal Transplant Unit, Western Infirmary, (Now based at The Queen Elizabeth University Hospital) Glasgow, UK.
authors.forename: Rajan K
authors.initials: RK
authors.lastname: Patel
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.|The Renal Transplant Unit, Western Infirmary, (Now based at The Queen Elizabeth University Hospital) Glasgow, UK.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Mark
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kettlewell
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: The Renal Transplant Unit, Western Infirmary, (Now based at The Queen Elizabeth University Hospital) Glasgow, UK.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Clancy
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.|The Renal Transplant Unit, Western Infirmary, (Now based at The Queen Elizabeth University Hospital) Glasgow, UK.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Jardine
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology; D004730:Endothelium, Vascular / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D006801:Humans; D054559:Hyperphosphatemia / Q000097:blood / Q000150:complications* / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010710:Phosphates / Q000502:physiology / Q000633:toxicity; D051381:Rats; D011921:Rats, Inbred WKY; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications* / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction; D016037:Single-Blind Method; D014664:Vasodilation / Q000187:drug effects
chemical_list: D010710:Phosphates; D009569:Nitric Oxide; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP
keywords: cardiovascular risk; chronic kidney disease; endothelial function; nitric oxide; phosphate