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Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.

Abstract：

BACKGROUND:Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). METHODS:Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. FINDINGS:Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. INTERPRETATION:Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. FUND: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.

journal_name

EBioMedicine

journal_title

EBioMedicine

authors

Chen X,Umeh CC,Tainsh RE,Feng DD,Maguire M,Zuo F,Rahimian M,Logan R,Wang X,Ascherio A,Macklin EA,Buys ES,Schwarzschild MA,Parkinson Study Group (PSG) The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) investigators.

doi

10.1016/j.ebiom.2018.10.039

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

259-268

issn

2352-3964

pii

S2352-3964(18)30457-2

journal_volume

37

pub_type

杂志文章,随机对照试验

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