Q J Med 2000; 93: 707-713
© 2000 Association of Physicians
Review |
Uric acid as a risk factor for cardiovascular disease
From the Clinical Pharmacology Unit and Research Centre, Department of Medical Sciences, University of Edinburgh, Edinburgh, UK
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Introduction |
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 Top Introduction Uric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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Over recent years there has been renewed debate about the nature of the association between raised serum uric acid concentration and cardiovascular disease.1 Several large studies have identified the value, in populations, of serum uric acid concentration in predicting the risk of cardiovascular events, such as myocardial infarction. This has directed research towards the potential mechanisms by which uric acid might have direct or indirect effects on the cardiovascular system. It has been difficult to identify the specific role of elevated serum uric acid because of its association with established cardiovascular risk factors such as hypertension, diabetes mellitus, hyperlipidaemia and obesity.2,3 Indeed, it is not even clear at this stage whether uric acid has a damaging or protective effect in these circumstances. Increased understanding of the mechanisms underlying these associations may allow a clearer interpretation of the importance of elevated serum uric acid concentrations, and the potential value of specific urate-lowering treatment on cardiovascular disease.
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Uric acid synthesis |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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Purines arise from metabolism of dietary and endogenous nucleic acids, and are degraded ultimately to uric acid in man, through the action of the enzyme xanthine oxidase (Figure 1
). Uric acid is a weak acid (pKa 5.8), distributed throughout the extracellular fluid compartment as sodium urate, and cleared from the plasma by glomerular filtration.4 Around 90% of filtered uric acid is reabsorbed from the proximal renal tubule, while active secretion into the distal tubule by an ATPase-dependent mechanism contributes to overall clearance.5 Serum uric acid concentration within the population has a Gaussian distribution, with a typical reference range (95% CI) of 120–420 µmol/l. For an individual, urate concentration is determined by a combination of the rate of purine metabolism (both endogenous and exogenous) and the efficiency of renal clearance. Purine metabolism is influenced by dietary, as well as genetic factors regulating cell turnover. Uric acid is sparingly soluble in aqueous media, and persistent exposure to high serum levels predisposes to urate crystal deposition within soft tissues.4 All species apart from man and higher apes express urate oxidase, an enzyme responsible for further metabolism of uric acid to allantoin (a more soluble waste product) prior to excretion.6 In man, the urate oxidase gene located on chromosome 1 is not expressed due to two non-sense mutations.7 Loss of uric oxidase activity appears to have developed under evolutionary pressure,7 suggesting that higher serum uric acid concentrations, or reduced urate oxidase may confer important advantages in man.
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Uric acid as a risk factor for cardiovascular disease |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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An epidemiological link between elevated serum uric acid and an increased cardiovascular risk has been recognized for many years.8,9 Observational studies show that serum uric acid concentrations are higher in patients with established coronary heart disease compared with healthy controls.10 Elevated serum uric acid concentrations are also found in healthy offspring of parents with coronary artery disease, indicating a possible causal relationship.2 However, hyperuricaemia is also associated with possible confounding factors including elevated serum triglyceride and cholesterol concentrations, blood glucose, fasting and post-carbohydrate plasma insulin concentrations, waist-hip ratio and body mass index.3,8,11,12 About one quarter of hypertensive patients have co-existent hyperuricaemia13 and, interestingly, asymptomatic hyperuricaemia predicts future development of hypertension, irrespective of renal function.14
Among patients with established hypertension, elevated serum uric acid concentration has been associated with a significantly increased cardiovascular risk during a mean 6.6-year follow-up period.15 The proportional hazard ratio for one SD elevation of uric acid (29.2 µmol/l) was 1.22 (95%CI 1.11–1.35), which was higher than for one S.D. elevation of blood glucose (1.10, 95%CI 1.02–1.19), cholesterol (1.18, 95%CI 1.09–1.29) or systolic blood pressure (1.09, 95%CI 1.00–1.19). Thiazide diuretics confer unequivocal benefits in treatment of hypertensive patients, and cause a significant reduction in cardiovascular and all-cause mortality.16 Persistence of the relationship between elevated serum uric acid concentration and increased cardiovascular risk among thiazide-treated patients has prompted speculation that uric acid elevation may attenuate some of their potential benefits.17 Indeed, the US National Health and Nutrition Survey (NHANES) III showed that age-adjusted rates of myocardial infarction and stroke are higher across increasing serum uric acid quartiles among male and female hypertensive patients.18
Some studies have suggested that the importance of uric acid may be independent of confounding risk factors. Multivariate analysis of data from the MONICA cohort of 1044 males showed a significant association between raised serum uric acid and cardiovascular mortality, independent of body mass index, serum cholesterol concentration, hypertension, diuretic use, alcohol intake and smoking habits.19 Comparison of those individuals within the highest serum uric acid quartile (
373 µmol/l) versus those in the lowest quartile (
319 µmol/l) gave an adjusted risk of myocardial infarction of 1.7 (95%CI 0.8–3.3) and cardiovascular death of 2.2 (95%CI 1.0–4.8). The Gothenburg prospective study of 1462 women aged 38 to 60 years also found a significant relationship between serum uric acid concentration and total mortality during 12-year follow-up, which was independent of body mass index, serum lipid concentrations, smoking habit, blood pressure and age.20 Uric acid also has a predictive role in high-risk patient groups. For instance, diabetes mellitus is a very powerful risk factor for cardiovascular disease, and a prospective study of 1017 non-insulin-dependent patients showed that serum uric acid concentration >295 µmol/l conferred a hazard ratio of 1.91 (95%CI 1.24–2.94) of fatal or non-fatal stroke during 7-year follow-up.21
In contrast to these findings, several studies have suggested that the relationship between elevated serum uric acid and cardiovascular risk does not persist after correcting for other risk factors. The British Regional Heart Study of 7688 men aged 40 to 59 years showed a significant association between elevated serum uric acid and fatal and non-fatal coronary disease over a mean 16.8 years.22 However, this relationship disappeared after correcting for other risk factors, particularly serum cholesterol concentration. The Coronary Drug Project Research Group studied 2789 men, aged 30 to 64 years, and found that the association between increased cardiovascular risk and elevated serum uric acid concentration was not significant after consideration of other risk factors, and when thiazide diuretic use was considered.23 Similar findings have been reported from the Social Insurance Institution of Finland Study24 and Framingham Heart Study.25
The Atherosclerosis Risk in Communities study of 11 488 healthy men and women showed an apparent association between serum uric acid concentration and early carotid artery atherosclerosis, which was dependent of other coronary risk factors.26 Similarly, the Honolulu Heart Program found that elevated serum uric acid was not an independent risk factor for the presence at autopsy of aortic or coronary atherosclerosis in Japanese men.27
In summary, although there is overwhelming evidence that elevated serum uric acid concentrations are strongly associated with increased cardiovascular risk and poor outcome, prospective population studies are often confounded by co-existent risk factors. It remains unclear whether uric acid is an independent predictor of poor cardiovascular outcome. To unravel this association, it is important to understand the mechanisms by which hyperuricaemia relates to other risk factors, vascular dysfunction and cardiovascular disease. We shall now consider these relationships in more detail.
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Uric acid as a marker of subclinical ischaemia |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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Adenosine is synthesized and released by cardiac and vascular myocytes. Binding to specific adenosine receptors causes relaxation of vascular smooth muscle and arteriolar vasodilatation.28 Adenosine makes a small contribution to normal resting vascular tone, since competitive antagonism at the adenosine receptor by methylxanthines, such as theophylline, reduce blood flow response to ischaemia in the forearm vascular bed.29 Under conditions of hypoxia and tissue ischaemia, vascular adenosine synthesis and release are upregulated, causing significantly increased circulating concentrations.30 Cardiac and visceral ischaemia promote generation of adenosine, which may serve as an important regulatory mechanism for restoring blood flow and limiting the ischaemia31 (Figure 1). Adenosine synthesized locally by vascular smooth muscle in cardiac tissue is rapidly degraded by the endothelium to uric acid, which undergoes rapid efflux to the vascular lumen due to low intracellular pH and negative membrane potential.32 Xanthine oxidase activity33 and uric acid synthesis34 are increased in vivo under ischaemic conditions, and therefore elevated serum uric acid may act as a marker of underlying tissue ischaemia. In the human coronary circulation, hypoxia, caused by transient coronary artery occlusion, leads to an increase in the local circulating concentration of uric acid.35 Study of tourniquet-induced lower limb exsanguination in patients undergoing surgery shows a five-fold increase in systemic vascular xanthine oxidase activity during reperfusion, and a significant elevation of serum uric acid, which persists for at least 2 h.36 These findings are also consistent with the inverse relation between baseline serum uric acid concentration and maximal lower limb blood flow in patients with cardiac failure, where higher concentrations could predict subclinical ischaemia.37 In conclusion therefore, elevated serum uric acid may be a marker of local or systemic tissue ischaemia and provides one possible explanation for a non-causal associative link between hyperuricaemia and cardiovascular disease.
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Uric acid as a marker of insulin resistance |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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Insulin resistance syndromes result in attenuation of insulin-mediated glucose utilization and confer a substantial increase in cardiovascular risk,38 through activation of several pathways including the sympathetic nervous system.39 Elevated serum uric acid is a consistent feature of the insulin resistance syndromes, which are also characterized by elevated plasma insulin level (fasting and post-carbohydrate), blood glucose concentration, and serum triglyceride concentration, and raised body mass index and waist-hip ratio.2,3 Insulin has a physiological action on renal tubules, causing reduced sodium and uric acid clearance.40 Despite blunting of the action of insulin on glucose metabolism, sensitivity to the renal effects persists.40,41 Because plasma insulin concentration is characteristically elevated, hyperuricaemia may arise as a consequence of enhanced renal insulin activity. Elevated serum uric acid concentrations predict subsequent development of diabetes mellitus42 and hypertension,14 even in the presence of normal creatinine clearance and plasma glucose concentrations, and therefore may be a subtle, early marker of peripheral insulin resistance syndromes. Thus a link between elevated serum uric acid concentration and cardiovascular disease may arise through its non-causal relationship with insulin resistance syndromes, where cardiovascular risk is mediated by other factors.
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Direct impact of uric acid on vascular function |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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The endothelium plays a central role in maintaining vascular tone through synthesis and release of nitric oxide, a potent vasodilator.43 Reduction of nitric oxide bioavailability is an important early step in the development of atherosclerosis.44 So-called endothelial dysfunction, associated with impaired endothelium-dependent vasodilatation may arise from excessive free radical activity, which disrupts synthesis and accelerates degradation of nitric oxide.45 Thus increased oxidative stress appears to have an important role in development and progression of atherosclerosis and is a characteristic finding associated with its major risk factors, such as diabetes mellitus, hypertension, hypercholesterolaemia and smoking.44,46 Serum uric acid possesses antioxidant properties, and contributes about 60% of free radical scavenging activity in human serum.47,48 Uric acid interacts with peroxynitrite to form a stable nitric oxide donor, thus promoting vasodilatation and reducing the potential for peroxynitrite-induced oxidative damage.49 Thus, uric acid could be expected to protect against oxidative stresses.
However, uric acid has been found to promote low-density lipoprotein (LDL) oxidation in vitro, a key step in the progression of atherosclerosis,50,51 and these effects are inhibited by vitamin C52 indicating an important interaction between aqueous anti-oxidants. Uric acid can also stimulate granulocyte adherence to the endothelium,53 and peroxide and superoxide free radical liberation.53,54 Therefore uric acid may have a deleterious effect on the endothelium through leukocyte activation and, interestingly, a consistent relationship has been noted between elevated serum uric acid concentration and circulating inflammatory markers.55–57 Uric acid traverses dysfunctional endothelial cells and accumulates as crystal within atherosclerotic plaques.32,58 These crystals may contribute to local inflammation and plaque progression, and we speculate that crystal accumulation may be greater in patients with elevated serum uric acid concentration.
Thus, while uric acid appears to make a significant contribution to serum anti-oxidant capacity, it could also lead directly or indirectly to vascular injury. It is interesting to note that treatment of chronic cardiac failure patients with allopurinol (a xanthine oxidase inhibitor) restored endothelial function.59 This effect may have been due to an increase in recorded serum antioxidant capacity,59 although the effect of uric acid was not considered. Study of the direct effects of uric acid on vascular function has been hampered by its poor solubility, although this has been overcome recently.60 Direct study of the actions of uric acid on endothelial function, platelet aggregation, vessel wall elasticity and autonomic cardiovascular regulation is required so that its effects on the cardiovascular system and in cardiovascular disease can be determined.
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Conclusions |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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Raised serum uric acid concentrations are a powerful predictor of cardiovascular risk and poor outcome, although the underlying mechanisms remain unclear. Several potential explanations have been put forward to explain the apparent association between hyperuricaemia and cardiovascular risk. Studies have demonstrated mechanisms by which uric acid could be directly injurious to the endothelium and to cardiovascular function. Paradoxically, uric acid elevation could be expected to confer protective anti-oxidant effects in the cardiovascular system, but these potential benefits may be obscured by detrimental effects elsewhere. The effects of raising or lowering serum uric acid on endothelial function, autonomic regulation and progression of atherosclerosis require direct investigation, in order to understand a possible dual action in the cardiovascular system. Identifying the mechanisms by which uric acid interacts with cardiovascular regulation will give us greater understanding of the role of hyperuricaemia for individual patients and allow a more rational approach to treatments that modify serum uric acid concentration.
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Acknowledgments |
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This work has been supported by an endowment grant from the Faculty of Medicine of The University of Edinburgh (E80870). Dr W.S. Waring is in receipt of a Bristol Myer-Squibb Cardiovascular Research Fellowship. Professor D.J. Webb is currently supported by a Research Leave Fellowship from the Wellcome Trust (WT 0526330).
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Notes |
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Address correspondence to Dr W.S. Waring, Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2LH. e-mail: s.waring{at}ed.ac.uk
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References |
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TopIntroductionUric acid synthesisUric acid as a...Uric acid as a...Uric acid as a...Direct impact of uric...ConclusionsReferences |
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1. Dobson A. Is raised serum uric acid a cause of cardiovascular disease or death? Lancet1999; 354:1578.[ISI][Medline]
2. Bonora E, Targher G, Zenere MB, Saggiani F, Cacciatori V, Tosi F, Travia D, Zenti MG, Branzi P, Santi L, Muggeo M. Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord1996; 20:975–80.[ISI][Medline]
3. Agamah ES, Srinivasan SR, Webber LS, Berenson GS. Serum uric acid and its relation to cardiovascular disease risk factors in children and young adults from a biracial community: the Bogalusa Heart Study. J Lab Clin Med1991; 118:241–9.[ISI][Medline]
4.
Emmerson BT. The management of gout. N Engl J Med1996; 334:445–51.
5. Steele TH. Hyperuricemic nephropathies. Nephron1999; 81 (Suppl. 1):45–9.
6. Yeldandi AV, Patel YD, Liao M, Kao FT, Rao MS, Reddy JK, Le Beau MM. Localization of the human urate oxidase gene (UOX) to 1p22. Cytogenet Cell Genet1992; 61:121–2.[ISI][Medline]
7. Wu X, Muzny DM, Lee CC, Casker CT. Two independent mutational events in the loss of urate oxidase. J Mol Evol1992; 34:78–84.[ISI][Medline]
8. Kohn PM, Prozan GB. Hyperuricemia: relationship to hypercholesterolemia and acute myocardial infarction. JAMA1959; 170:1909–15.
9. Beard JT. Serum uric acid and coronary heart disease. Am Heart J1983; 106:397–400.[ISI][Medline]
10. Torun M, Yardim S, Simsek B, Burgaz S. Serum uric acid levels in cardiovascular diseases. J Clin Pharm Ther1998; 23:25–9.[ISI][Medline]
11.
Lee J, Sparrow D, Vokonas PS, Landsberg L, Weiss ST. Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol1995; 142:288–94.
12. Patten RL, Hewitt D, Waldman GT, Jones G, Little JA. Associations of plasma high-density lipoprotein cholesterol with clinical chemistry data. Circulation1980; 62:IV31–IV41.
13. Tykarski A. Evaluation of renal handling of uric acid in essential hypertension: hyperuricemia related to decreased urate secretion. Nephron1991; 59:364–8.[ISI][Medline]
14.
Selby JV, Friedman GD, Quesenberry CPJ. Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol1990; 131:1017–27.
15.
Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertens1999; 34:144–50.
16. SHEP Cooperative Research Group. Prevention of stroke by anti-hypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). Lancet1991; 265:3255–64.
17. Alderman MH, Cohen H, Kinlign S, Madhavan S. Does treatment-mediated increase in serum uric acid reduce the cardioprotective effect of diuretics in hypertensive patients? Am J Hypertens1998; 2:16A.
18. Ward H. Uric acid as an independent risk factor in the treatment of hypertension. Lancet1998, 352:670–1.[ISI][Medline]
19. Liese AD, Hense HW, Lowel H, Doring A, Tietze M, Keil U. Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases. Epidemiology1999; 10:391–7.[ISI][Medline]
20. Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J. Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand1988; 224:549–55.[ISI][Medline]
21.
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. Stroke1998; 29:635–9.
22.
Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart1997; 78:147–53.
23. The Coronary Drug Project Research Group. Serum uric acid: its association with other risk factors and with mortality in coronary heart disease. J Chron Dis1976; 29:557–69.[ISI][Medline]
24. Reunanen A, Takkunen H, Knekt P, Aromaa A. Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand Suppl1982; 668:49–59.[Medline]
25.
Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med1999; 131:7–13.
26. Iribarren C, Folsom AR, Eckfeldt JH, McGovern PG, Nieto FJ. Correlates of uric acid and its association with asymptomatic carotid atherosclerosis: the ARIC Study. Atherosclerosis Risk in Communities. Ann Epidemiol1996; 6:331–40.[ISI][Medline]
27.
Reed DM, MacLean CJ, Hayashi T. Predictors of atherosclerosis in the Honolulu Heart Program I. Biologic, dietary and lifestyle characteristics. Am J Epidemiol1987; 126:214–25.
28.
Berne M. The role of adenosine in the regulation of coronary blood flow. Circulation Res1980; 47:807–13.
29.
Costa F, Sulur P, Angel M, Cavalcante J, Haile V, Christman B, Biaggioni I. Intravascular source of adenosine during forearm ischemia in humans. Implications for reactive hyperemia. Hypertens1999; 33:1453–7.
30. Raatikainen MJ, Peuhkurinen KJ, Hassinen IE. Contribution of endothelium and cardiomyocytes to hypoxia-induced adenosine release. J Mol Cell Cardiol1994; 26:1069–80.[ISI][Medline]
31. Fredholm BB, Sollevi A. Cardiovascular effects of adenosine. Clin Physiol1986; 6:1–21.[ISI][Medline]
32.
Kroll K, Bukowski TR, Schwartz LM, Knoepfler D, Bassingthwaighte JB. Capillary endothelial transport of uric acid in guinea pig heart. Am J Physiol1992, 262:H420-H431.
33. Castelli P, Condemi AM, Brambillasca C, Fundaro P, Botta M, Lemma M, Vanelli P, Santoli C, Gatti S, Riva E. Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery. J Cardiovasc Pharmacol1995; 25:119–25.[ISI][Medline]
34. Kogure K, Ishizaki M, Nemoto M, Kuwano H, Tatemoto K, Maruyama Y, Ikarashi Y, Makuuchi M. Evaluation of serum uric acid changes in different forms of hepatic vascular inflow occlusion in human liver surgeries. Life Sci1999; 64:305–13.[ISI][Medline]
35. De Scheerder I, van de Kraay AM, Lamers JM, Koster JF, de Jong JW, Serruys PW. Myocardial malondialdehyde and uric acid release after short-lasting coronary occlusions during coronary angioplasty: potential mechanisms for free radical generation. Am J Cardiol1991; 68:392–5.[ISI][Medline]
36. Mathru M, Dries DJ, Barnes L, Tonino P, Sukhani R, Rooney MW. Tourniquet-induced exsanguination in patients requiring lower limb surgery. An ischemia-reperfusion model of oxidant and antioxidant metabolism. Anesthesiology1996; 84:14–22.[ISI][Medline]
37.
Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart1997; 78:39–43.
38. Cleland SJ, Petrie JR, Ueda S, Elliott HL, Connell JM. Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease. Clin Exp Pharmacol Physiol1998; 25:175–84.[ISI][Medline]
39. Modan M, Halkin H. Hyperinsulinemia or increased sympathetic drive as links for obesity and hypertension. Diabetes Care1991; 14:470–87.[Abstract]
40. Muscelli E, Natali A, Bianchi S, Bigazzi R, Galvan AQ, Sironi AM, Frascerra S, Ciociaro D, Ferrannini E. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens1996; 9:746–52.[ISI][Medline]
41. DeFronzo RA. The effect of insulin on renal sodium metabolism. A review with clinical implications. Diabetologia1981; 21:165–71.[ISI][Medline]
42.
Perry IJ, Wannamethee SG, Walker MK, Thomson AG, Whincup PH, Shaper AG. Prospective study of risk factors for development of non-insulin dependent diabetes in middle aged British men. BMJ1995; 310:560–4.
43. Webb DJ. The pharmacology of human blood vessels in vivo. J Vasc Res1995; 32:2–15.[ISI][Medline]
44. Vallance P. Nitric oxide in the human cardiovascular system- SKB lecture 1997. Br J Clin Pharmacol1998; 45:433–9.[ISI][Medline]
45. Hoeschen RJ. Oxidative stress and cardiovascular disease. Can J Cardiol1997; 13:1021–5.[ISI][Medline]
46. Ferro CJ, Webb DJ. Endothelial dysfunction and hypertension. Drugs1997, 53(Suppl. 1): 30–41.
47.
Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA1981; 78:6858–62.
48. Maxwell SR, Thomason H, Sandler D, LeGuen C, Baxter MA, Thorpe GH, Jones AF, Barnett AH. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest1997; 27:484–90.[ISI][Medline]
49.
Skinner KA, White CR, Patel R, Tan S, Barnes S, Kirk M, Darley-Usmar V, Parks DA. Nitrosation of uric acid by peroxynitrite. Formation of a vasoactive nitric oxide donor. J Biol Chem1998; 273:24491–7.
50. Bagnati M, Perugini C, Cau C, Bordone R, Albano E, Bellomo G. When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid. Biochem J1999; 340:143–52.
51. Schlotte V, Sevanian A, Hochstein P, Weithmann KU. Effect of uric acid and chemical analogues on oxidation of human low density lipoprotein in vitro. Free Rad Biol Med1998; 25:839–47.[ISI][Medline]
52. Abuja PM. Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein. FEBS Lett1999; 446:305–8.[ISI][Medline]
53. Boogaerts MA, Hammerschmidt DE, Roelant C, Verwilghen RL, Jacob HS. Mechanisms of vascular damage in gout and oxalosis: crystal induced, granulocyte mediated, endothelial injury. Thromb Haemost1983; 50:576–80.[ISI][Medline]
54. Falasca GF, Ramachandrula A, Kelley KA, O'Connor CR, Reginato AJ. Superoxide anion production and phagocytosis of crystals by cultured endothelial cells. Arthritis Rheum1993; 36:105–16.[ISI][Medline]
55. Duff GW, Atkins E, Malawista SE. The fever of gout: urate crystals activate endogenous pyrogen production from human and rabbit mononuclear phagocytes. Trans Assoc Am Physicians1983; 96:234–45.[Medline]
56.
Hutton CW, Collins AJ, Chambers RE, Whicher J, Dieppe PA. Systemic response to local urate crystal induced inflammation in man: a possible model to study the acute phase response. Ann Rheum Dis1985; 44:533–6.
57.
Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, Poole-Wilson PA, Coats AJ. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J1998; 19:1814–22.
58. Patetsios P, Rodino W, Wisselink W, Bryan D, Kirwin JD, Panetta TF. Identification of uric acid in aortic aneurysms and atherosclerotic artery. Ann N Y Acad Sci1996; 800:243–5.[ISI][Medline]
59. Farquharson CAJ, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in patients with chronic heart failure. Scott Med J1999; 44:24.
60. Waring WS, Webb DJ, Maxwell SRJ. Effect of local hyperuricaemia on endothelial function in the human forearm vascular bed. Br J Clin Pharmacol2000; 49:511.
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