European Journal of Heart Failure

European Journal of Heart Failure 2005 7(4):461-467; doi:10.1016/j.ejheart.2004.03.020

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© 2005 European Society of Cardiology

The increase in serum uric acid concentration caused by diuretics might be beneficial in heart failure

Ariel J. Reyes^*

Institute of Cardiovascular Theory Sotelo 3908, 11700 Montevideo, Uruguay

^* Tel.: +598 2 3362263; Fax: +598 2 3362341. E-mail address: ajreyes{at}internet.com.uy

	Abstract

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
Patients with mild-moderate chronic heart failure (CHF) often have raised levels of serum uric acid (UA). This is due, amongst other factors, to reduced UA excretion by the kidneys, which is partly explained by restriction of sodium intake and treatment with diuretics. The decline in renal function that parallels worsening cardiac function also contributes to elevated serum UA in patients with advanced CHF. However, UA production also appears to be augmented in CHF. Because UA scavenges various reactive oxygen species, diuretic-induced elevations in serum UA could be beneficial in patients with CHF. This concept is supported by the superior performance of antihypertensive therapy with diuretics in preventing heart failure. The present hypothesis may be tested by examining the effects of add-on treatment with a thiazide-type diuretic on morbidity and mortality, or surrogate variables, in asymptomatic patients with left ventricular dysfunction but without fluid retention.

Key Words: Antioxidant capacity • Diuretics • Heart failure • Oxidative stress • Uric acid

Received July 9, 2003; Revised January 30, 2004; Accepted March 15, 2004

	1. Introduction

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
The fact that diuretic-based antihypertensive therapy decreases the risk of heart failure to a greater extent than a regimen based on an angiotensin-converting enzyme (ACE) inhibitor [1,2] requires explanation. Diuretics could be treating the symptoms of heart failure in advance of their development. Additionally or alternatively, the superiority, or at least the lack of inferiority, of diuretics might be due to their ability to increase the serum concentration of the antioxidant uric acid (UA) [3,4]. The objective of the present work is to examine the possible importance of diuretic-induced elevations in serum UA in chronic heart failure.

	2. Physiology and pathophysiology of uric acid

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
2.1. Co-formation of uric acid and reactive oxygen species
Uric acid (UA) is the final product of purine metabolism in man. The transformations of hypoxanthine into xanthine and of this metabolite into UA are catalysed by xanthine dehydrogenase or by xanthine oxidase [5]. The latter enzyme originates from xanthine dehydrogenase in conditions of low oxygen tension, in the presence of certain proinflammatory cytokines [6] and perhaps in response to some hormones. The chemical reactions catalysed by xanthine oxidase involve water and oxygen and yield superoxide anion free radicals in addition to xanthine or UA [7]. Superoxide interacts with protons and, separately, with nitric oxide; these reactions give rise to reactive oxygen species that can damage cardiovascular structures [8,9]. Additionally, superoxide increases oxidative load by reducing anti-oxidant defences such as nitric oxide [10]. In man, xanthine oxidase is expressed abundantly in the endothelium, but appears absent from the myocardium [11].

2.2. The antioxidant action of uric acid
Uric acid can scavenge various reactive oxygen species, including peroxynitrite, peroxyl radicals and hydroxyl radicals [12–15], and probably carbonate ions and nitrogen dioxide [16]. The purine metabolite accounts for a substantial portion of the antioxidant capacity of human plasma in health and disease [17–19]. Systemic administration of UA increases plasma antioxidant capacity at rest [20] and reduces exercise-associated oxidative stress in healthy subjects [21]. Diuretics increase plasma antioxidant capacity in hypertensive patients, possible due to an elevation in serum UA secondary to a reduction in uricosuria [22]. Allantoin is one of the UA products formed during free radical scavenging.

2.3. The renal excretion of uric acid and its regulation
In physiological circumstances, most UA is excreted in urine and about 30% undergoes intestinal elimination. Uric acid reaches the lumen of the tubular nephron by glomerular filtration and by secretion through the wall of the proximal tubule, where most of the pool of filtered and secreted UA undergoes reabsorption. The renal fractional excretion of UA, i.e. the excreted amount expressed as a percentage of the filtered quantity, ranges between 6% and 12% in normal circumstances [23].

The net reabsorption of UA in the proximal tubule and serum UA are increased by intravascular volume contraction and vice versa [24]. Low-sodium intakes elevate [25,26], and high-salt diets diminish [27], the net quantity of UA reabsorbed in the proximal tubule and serum UA, and have opposite effects on uricosuria [25,27]. Angiotensin II augments UA reabsorption in the tubular nephron and reduces renal UA excretion [23,28]. Noradrenaline lowers uricosuria [23,29], probably through renal haemodynamic changes and a decrease in the net proximal tubular reabsorption of UA. Uric acid and sodium reabsorption in the proximal tubule appear to be positively associated [30]; this process is enhanced by the interaction between alpha-1 adrenoceptor stimulation and angiotensin II that takes place at this nephron level [31] and by plasma insulin [32]. Insulin-mediated increases in proximal sodium and UA reabsorption are not attenuated in the insulin-resistant state [32]. The increase in the serum concentration of UA that occurs in essential hypertension is principally due to decreased renal excretion [33].

	3. Uric acid in chronic heart failure

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
3.1. Uric acid and the development of heart failure
Increased serum UA concentration is associated with variables elevation of which worsen cardiovascular prognosis, including blood pressure [34], body weight and plasma cholesterol, and with insulin resistance [32,35,36]. Nonetheless, large epidemiological studies that examined the possible direct relationships between serum UA and cardiovascular outcomes have produced inconsistent results [34,37–40]. Moreover, no mechanism whereby excessive UA could damage the heart or the vessels in man has been identified, acute increases in serum UA were found not to impair vascular function in healthy subjects [41], and it has never been investigated whether lowering serum uric acid concentration results in cardiovascular risk reduction independently of concomitant changes in other variables that matter, including those used to assess oxidants and antioxidants. For the preceding reasons, raised serum UA should not be considered an independent risk factor for cardiovascular disease or heart failure.

Increased serum UA concentration may well be an innocent bystander associated with deleterious processes including increased reabsorption of filtered sodium in the proximal tubule of the nephron [42] and insulin resistance [43], or it may constitute a compensatory response to oxidative stress [44].

3.2. Uric acid in heart failure
Serum UA concentration is increased in patients with chronic heart failure (CHF) [45,46], probably due to both reduced renal excretion and augmented production. Low-sodium diets, treatment with diuretics and insulin-resistance may all increase the net reabsorption of UA in the proximal tubule of the nephron and account for part of the elevations in serum UA observed in some patients with heart failure in the absence of renal dysfunction [47,48]. The fall in glomerular filtration rate that develops as cardiac function deteriorates leads to a reduction in renal UA excretion and may become the principal determinant of raised serum UA levels in advanced CHF [49].

Increased serum UA is associated with worse NYHA class and exercise capacity [45,46,50], greater vascular resistance [51], more evidence of cytokine activation, including tumor necrosis factor soluble receptors 1 and 2, interleukin-6, and soluble intercellular adhesion molecule-1 [52], worse cardiac function [53,54] and more cardiac cachexia [51]. Some of these relationships were found to be independent of factors that may change UA excretion, including age, diuretic dose, serum creatinine concentration and insulin sensitivity [45]. Consequently, they could be explained by increased UA production. Consistent with this interpretation, endothelial xanthine oxidase activity was found to be increased in CHF [55]; this elevation may lead to increased production of UA and of reactive oxygen species. Studies of serum UA as a possible independent predictor of increased mortality in CHF yielded inconsistent outcomes [56,57].

	4. Allopurinol in heart failure

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
Allopurinol inhibits xanthine oxidase and thus reduces the generation of xanthine, of UA and of reactive oxygen species mediated by this enzyme [58]. In addition, allopurinol and its active metabolite oxypurinol scavenge free radicals directly [59–62].

A few pilot studies have examined the actions of allopurinol on cardiovascular variables in the clinical setting. Allopurinol was found to decrease mortality and improve cardiac performance after coronary bypass grafting [63], to reduce the incidence of various complications of open heart surgery (including arrhythmias requiring treatment, heart failure requiring inotropes and myocardial infarction) [64], to lower myocardial oxygen consumption without changing myocardial contractility in patients with idiopathic dilated cardiomyopathy [65], and to decrease urinary markers of free-radical activity after coronary angioplasty for acute myocardial infarction [66]. Additionally, allopurinol improved endothelium-dependent peripheral vasodilation in small exploratory studies in patients with CHF [67,68].

The beneficial actions of allopurinol in patients with cardiac failure appear to be mainly or solely due to a diminution in oxidative stress [69–74], either due to inhibition of xanthine oxidase or by a direct effect on some reactive oxygen species [59–62]. Although allopurinol also reduces the formation of the antioxidant UA, two superoxide anion radicals are produced for each molecule of xanthine or UA [75].

	5. Diuretics and uric acid

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
5.1. General clinical pharmacology
Nearly all diuretics, including loop agents, most thiazide-type drugs and potassium-and-hydrogen retaining diuretics (the sodium channel blockers amiloride and triamterene and the aldosterone antagonists spironolactone and eplerenone), increase the net reabsorption of UA in the proximal tubule when used at doses that cause natriuresis, and thereby elevate serum UA [76–82]. The thiazide-type drug tienilic acid raises the urinary excretion and lowers the serum concentration of UA [83], and the early distal tubular diuretic cicletanine does not affect either variable even when administered at natriuretic doses [84,85].

The increase in serum UA concentration caused by diuretics is apparent at low doses and increases in dose-dependent fashion [79,86,87]. Antihypertensive treatments with dosages of diuretics that are substantially lower than those used in the past, including 12.5 mg of hydrochlorothiazide [88,89], 12.5–25 mg of chlorthalidone [38,90,91] and 1.25 mg of bendrofluazide [86] once daily, increase serum UA concentration. Indeed, serum UA may be more susceptible to change by diuretics than even serum potassium [92,93].

5.2. Diuretics and uric acid in heart failure
In patients with CHF, serum UA rises in response to the institution of diuretics [94–99]. Some ACE inhibitors (e.g. captopril and ramipril) increase the renal excretion of UA significantly by reducing its net reabsorption in the proximal tubule [100–103], but this action may be less evident with perindopril [104]. Different ACE inhibitors blunted diuretic-induced increases in serum UA in several studies carried out in hypertensive patients [92,105–107], but this effect was not apparent in other trials [108,109].

	6. Hypothesis

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
Chronic heart failure is a condition associated with increased oxidative stress, which may contribute to unfavourable changes in cardiovascular structure and function and hence adverse clinical outcomes [55,110–112]. Therefore, the rise in serum UA caused by diuretics may have a beneficial effect on prognosis, since it entails an increase in plasma antioxidant capacity and, in contrast to xanthine-oxidase-mediated UA formation, is not accompanied by the generation of reactive oxygen species.

This hypothesis may be tested by assessing the effects of add-on treatment with a diuretic on morbidity and mortality, or surrogate variables, in asymptomatic patients with major cardiac dysfunction and at high risk of developing cardiac failure. The minimal doses of diuretics known to elevate serum UA, e.g. hydrochlorothiazide 12.5 mg once daily, should be used in these studies to avoid significant side effects. If such a study failed to show a beneficial effect of diuretics on cardiovascular prognosis, the present hypothesis would be refuted. If diuretics improved prognosis, it would not be possible to ascribe this beneficial action (solely) to the increase in serum UA. Natriuresis and reduction in circulating volume could delay the appearance of certain manifestations of heart failure and could have favourable effects on cardiac remodelling, especially if diuretic-induced neuroendocrine activation is prevented with ACE inhibitors, beta-blockers and aldosterone antagonists. Further investigations would be required to identify the precise role of UA in mediating the observed effect.

6.1. The design of studies of diuretics and uric acid in heart failure
Patients with gout or at risk of gouty attacks [113,114] should not be included in the trials aimed at testing the present hypothesis. Studies should be randomised, placebo-controlled and of double-blind design. Given that serum UA varies as a function of sodium intake, dietary advice should be provided prior to the study, to obtain a steady-state baseline, and reinforced in the course of the trial. Low-purine diets may cause striking reductions in serum UA similar to the effect of allopurinol [115]; thus, prescriptions on purine intake should be kept constant throughout the studies, unless compelling reasons to modify them supervened. Patients should be treated with doses of all indicated cardiovascular agents similar to those in landmark trials. For serum UA to increase, patients who receive certain ACE inhibitors as part of their baseline therapy will possibly require higher doses of diuretics than subjects who do not. Plasma antioxidant capacity should be assessed by an appropriate technique [116], along with a set of variables aimed at evaluating the state of the balance between oxidants and antioxidants.

	7. Conclusions

Top Abstract 1. Introduction 2. Physiology and... 3. Uric acid in... 4. Allopurinol in heart... 5. Diuretics and uric... 6. Hypothesis 7. Conclusions References

 
Oxidative stress may be an important aspect of the pathophysiology of heart failure. Diuretics cause renal retention of UA that, unlike UA formation mediated by xanthine oxidase, is not accompanied by the co-generation of reactive oxygen species, and should result in a net increase in UA–mediated plasma antioxidant capacity. Thus, diuretics are likely to have a beneficial effect on prognosis in CHF. A study to test this hypothesis is feasible.

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