Severe Hypouricemia Impairs Endothelium‐Dependent Vasodilatation and Reduces Blood Pressure in Healthy Young Men: A Randomized, Placebo‐Controlled, and Crossover Study

BACKGROUND: Uric acid (UA) is a plasmatic antioxidant that has possible effects on blood pressure. The effects of UA on endothelial function are unclear. We hypothesize that endothelial function is not impaired unless significant UA depletion is achieved through selective xanthine oxidase inhibition with febuxostat and recombinant uricase (rasburicase). METHODS AND RESULTS: Microvascular hyperemia, induced by iontophoresis of acetylcholine and sodium nitroprusside, and heating‐induced local hyperemia after iontophoresis of saline and a specific nitric oxide synthase inhibitor were assessed by laser Doppler imaging. Blood pressure and renin‐angiotensin system markers were measured, and arterial stiffness was assessed. CRP (C‐reactive protein), allantoin, chlorotyrosine/tyrosine ratio, homocitrulline/lysine ratio, myeloperoxidase activity, malondialdehyde, and interleukin‐8 were used to characterize inflammation and oxidative stress. Seventeen young healthy men were enrolled in a randomized, double‐blind, placebo‐controlled, 3‐way crossover study. The 3 compared conditions were placebo, febuxostat alone, and febuxostat together with rasburicase. The allantoin (μmol/L)/UA (μmol/L) ratio differed between sessions (P<0.0001). During the febuxostat‐rasburicase session, heating‐induced hyperemia became altered in the presence of nitric oxide synthase inhibition; and systolic blood pressure, angiotensin II, and myeloperoxidase activity decreased (P≤0.03 versus febuxostat). The aldosterone concentration decreased in the febuxostat‐rasburicase group (P=0.01). Malondialdehyde increased when UA concentration decreased (both P<0.01 for febuxostat and febuxostat‐rasburicase versus placebo). Other parameters remained unchanged. CONCLUSIONS: A large and short‐term decrease in UA in humans alters heat‐induced endothelium‐dependent microvascular vasodilation, slightly reduces systolic blood pressure through renin‐angiotensin system activity reduction, and markedly reduces myeloperoxidase activity when compared with moderate UA reduction. A moderate or severe hypouricemia leads to an increase in lipid peroxidation through loss of antioxidant capacity of plasma. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03395977.