Lowering Serum Urate Does Not Improve Endothelial Function in Patients with Type 2 Diabetes

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2007 Oct 12

PMID 17928991

Citations 20

Authors

W S Waring

J A McKnight

D J Webb

S R J Maxwell

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: 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/interpretation: 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.

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References

Rathmann W, Hauner H, Dannehl K, Gries F . Association of elevated serum uric acid with coronary heart disease in diabetes mellitus. Diabete Metab. 1993; 19(1 Pt 2):159-66. View

Radi R, Tan S, PRODANOV E, Evans R, Parks D . Inhibition of xanthine oxidase by uric acid and its influence on superoxide radical production. Biochim Biophys Acta. 1992; 1122(2):178-82. DOI: 10.1016/0167-4838(92)90321-4. View

Guerci B, Kearney-Schwartz A, Bohme P, Zannad F, Drouin P . Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function. Diabetes Metab. 2001; 27(4 Pt 1):425-34. View

Waring W, Maxwell S, Webb D . Uric acid concentrations and the mechanisms of cardiovascular disease. Eur Heart J. 2002; 23(23):1888-9. DOI: 10.1053/euhj.2002.3343. View

Makimattila S, Yki-Jarvinen H . Endothelial dysfunction in human diabetes. Curr Diab Rep. 2003; 2(1):26-36. DOI: 10.1007/s11892-002-0054-x. View

Kato M, Hisatome I, Tomikura Y, Kotani K, Kinugawa T, Ogino K . Status of endothelial dependent vasodilation in patients with hyperuricemia. Am J Cardiol. 2005; 96(11):1576-8. DOI: 10.1016/j.amjcard.2005.07.068. View

Tan S, Radi R, Gaudier F, Evans R, Rivera A, Kirk K . Physiologic levels of uric acid inhibit xanthine oxidase in human plasma. Pediatr Res. 1993; 34(3):303-7. DOI: 10.1203/00006450-199309000-00013. View

Lehto S, Niskanen L, Ronnemaa T, Laakso M . Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke. 1998; 29(3):635-9. DOI: 10.1161/01.str.29.3.635. View

Khosla U, Zharikov S, Finch J, Nakagawa T, Roncal C, Mu W . Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005; 67(5):1739-42. DOI: 10.1111/j.1523-1755.2005.00273.x. View

10.

Kon Koh K, Quon M, Han S, Chung W, Ahn J, Seo Y . Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation. 2004; 110(24):3687-92. DOI: 10.1161/01.CIR.0000143085.86697.13. View

11.

Takazawa K, ORourke M, Fujita M, Tanaka N, Takeda K, Kurosu F . Estimation of ascending aortic pressure from radial arterial pressure using a generalised transfer function. Z Kardiol. 1996; 85 Suppl 3:137-9. View

12.

Zhao G, Zhang X, Smith C, Xu X, Ochoa M, Greenhouse D . Reduced coronary NO production in conscious dogs after the development of alloxan-induced diabetes. Am J Physiol. 1999; 277(1):H268-78. DOI: 10.1152/ajpheart.1999.277.1.H268. View

13.

George J, Carr E, Davies J, Belch J, Struthers A . High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006; 114(23):2508-16. DOI: 10.1161/CIRCULATIONAHA.106.651117. View

14.

Feig D, Mazzali M, Kang D, Nakagawa T, Price K, Kannelis J . Serum uric acid: a risk factor and a target for treatment?. J Am Soc Nephrol. 2006; 17(4 Suppl 2):S69-73. DOI: 10.1681/ASN.2005121331. View

15.

Leyva F, Anker S, Godsland I, Teixeira M, Hellewell P, Kox W . Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J. 1999; 19(12):1814-22. DOI: 10.1053/euhj.1998.1188. View

16.

Nitenberg A, Pham I, Antony I, Valensi P, Attali J, Chemla D . Cardiovascular outcome of patients with abnormal coronary vasomotion and normal coronary arteriography is worse in type 2 diabetes mellitus than in arterial hypertension: a 10 year follow-up study. Atherosclerosis. 2005; 183(1):113-20. DOI: 10.1016/j.atherosclerosis.2005.02.030. View

17.

Kuppusamy U, Indran M, Rokiah P . Glycaemic control in relation to xanthine oxidase and antioxidant indices in Malaysian Type 2 diabetes patients. Diabet Med. 2005; 22(10):1343-6. DOI: 10.1111/j.1464-5491.2005.01630.x. View

18.

Corry D, Tuck M . Uric acid and the vasculature. Curr Hypertens Rep. 2006; 8(2):116-9. DOI: 10.1007/s11906-006-0006-y. View

19.

Kim S, Park K, Kim Y, Oh S, Chae I, Kim H . Effects of acute hyperglycemia on endothelium-dependent vasodilation in patients with diabetes mellitus or impaired glucose metabolism. Endothelium. 2003; 10(2):65-70. DOI: 10.1080/10623320303362. View

20.

Kang D, Park S, Lee I, Johnson R . Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005; 16(12):3553-62. DOI: 10.1681/ASN.2005050572. View