Lowering serum urate does not improve endothelial function in patients with type 2 diabetes.
OBJECTIVE
Endothelial dysfunction contributes to excess cardiovascular risk in patients with type 2 diabetes. There is strong evidence of an association between high serum uric acid concentrations and endothelial dysfunction, and uric acid has been proposed as an independent cardiovascular risk factor in type 2 diabetes. We hypothesised that lowering of uric acid concentrations might allow restoration of endothelial function in this high-risk group.


METHODS
Intravenous urate oxidase (1.5 mg) was administered to ten patients with type 2 diabetes and ten healthy participants in a two-way, randomised, placebo-controlled, crossover study. Forearm blood flow responses to intra-brachial acetylcholine, sodium nitroprusside and N(G)-monomethyl-L-arginine (L-NMMA) were measured using venous occlusion plethysmography. The augmentation index (AIx) was determined by pulse wave analysis as a measure of large arterial stiffness.


RESULTS
Acetylcholine and L-NMMA evoked lesser responses in patients with type 2 diabetes than in healthy participants. Baseline AIx was higher in patients with type 2 diabetes (mean +/- SD: 13.1 +/- 6.9%) than in healthy participants (2.0 +/- 5.1%; p = 0.006). Urate oxidase lowered serum uric acid concentrations by 64 +/- 11% (p < 0.001), but this had no effect on forearm blood flow responses or AIx in either group.


CONCLUSIONS
Substantial short-term lowering of uric acid did not have a direct vascular effect, suggesting that, on its own, this might not be an effective strategy for restoring endothelial function in patients with type 2 diabetes.
Waring
W S
WS
Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, UK. s.waring@ed.ac.uk
McKnight
J A
JA
Webb
D J
DJ
Maxwell
S R J
SR
D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000008:administration & dosage; D010919:Placebos; D014503:Urate Oxidase / Q000008:administration & dosage / Q000627:therapeutic use*; D014527:Uric Acid / Q000097:blood*; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D010919:Placebos; D009599:Nitroprusside; D014527:Uric Acid; D019323:omega-N-Methylarginine; D014503:Urate Oxidase; D000109:Acetylcholine