The plasma level of the uric acid is frequently elevated in heart failure, due to increased production and/or to reduced renal excretion of this antioxidant metabolite. The transformation of hypoxanthine to xanthine and the conversion of the latter into uric acid, which occur in purine catabolism, are catalysed by xanthine oxidoreductase. The constitutive xanthine dehydrogenase form of this enzyme generally uses NAD(+) as an electron acceptor, whereas the post-translational xanthine oxidase form uses molecular oxygen and yields four units of reactive oxygen species per unit of transformed substrate. Allopurinol and oxypurinol inhibit xanthine oxidoreductase and thus diminish the generation of reactive species and decrease plasma uric acid. In a recent study in patients with NHYA class II-III heart failure, add-on treatment with allopurinol 300 mg/day for 3 months lowered plasma uric acid but failed to improve laboratory exercise performance or the distance walked in 6 minutes. In another recent trial, which was carried out in patients with NHYA class III-IV heart failure, add-on treatment with oxypurinol 600 mg/day for 24 weeks decreased plasma uric acid concentration but did not change a composite of patient outcome and state. These results indicate that the reduction in plasma uric acid caused by allopurinol or oxypurinol does not benefit patients with heart failure. Moreover, the hypothesis that the diminution in the renal excretion of the antioxidant uric acid caused by diuretics may be salutary in cardiac failure is strengthened by the study results considered.

Allopurinol↗

PubMed2005

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

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.

Allopurinol↗

PubMed2005

The aldosterone antagonist and facultative diuretic eplerenone: a critical review.

Eplerenone is a new aldosterone-receptor blocker that differs from spironolactone by virtue of higher selectivity for the aldosterone receptor. Therefore, eplerenone treatment is associated with comparative and absolute low incidences of gynecomastia, mastodynia, and abnormal vaginal bleeding. Similarly, a lower incidence of sexual impotence than that associated with spironolactone administration may be anticipated. Eplerenone and spironolactone increase natriuresis and cause renal retention of potassium when plasma aldosterone is high, i.e., both agents are facultative diuretics. Eplerenone reduces high blood pressure effectively. The results of a recent large study and an ensuing meta-analysis on antihypertensive treatment suggest that a diuretic should be the first-choice agent in most circumstances. Low-dose eplerenone combinations with a low-dose thiazide-type diuretic appear to be options worth investigating, since the overall cardiovascular benefit brought about by reducing blood pressure with the thiazide would be increased, inter alia, by the antikaliuretic action and by the blockade of extrarenal aldosterone receptors provoked by eplerenone. Eplerenone should replace spironolactone as a natriuretic and antikaliuretic in heart failure and as add-on treatment in severe systolic cardiac insufficiency, and it is indicated after an acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The finding that hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs makes it pertinent to investigate whether diuretics in general, and eplerenone in particular, should constitute part of the initial pharmacotherapy for heart failure when there is no overt fluid retention and independent of the etiology. Eplerenone may cause hyperkalemia, and it might favor the development of metabolic acidosis or hyponatraemia in some circumstances.

Journal Article↗

PubMed2003

The increase in serum uric acid induced by diuretics could be beneficial to cardiovascular prognosis in hypertension: a hypothesis.

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Diuretics↗

PubMed2002

The ALLHAT and the cardioprotection conferred by diuretics in hypertensive patients: a connection with uric acid?

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Antihypertensive Agents↗

PubMedDate not supplied

Cardiovascular drugs and serum uric acid.

Uric acid (UA) is the final product of purine catabolism in man, and it is excreted mainly by the kidneys when renal function is not impaired. Consequently, serum (S) UA increases as a function of purine intake, and it varies inversely to uricosuria. The latter variable diminishes in response to low-sodium intakes and vice versa. Insofar as the diet is not usually controlled in studies in which the response of SUA to drugs is evaluated, most reports are to be considered cautiously. Common diuretics elevate SUA in healthy subjects, hypertensives and patients with heart failure, apparently by elevating net UA reabsorption in the nephronal proximal tubule. This drug action, which becomes noticeable shortly after the institution of treatment and remains throughout it, starts at low doses (e.g., 12.5 mg hydrochlorothiazide or 1.25 mg bendrofluazide once daily in subjects with uncomplicated hypertension) and increases in dose-dependent fashion. Beta-blockers tend to elevate SUA. The angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril and ramipril have been found to increase uricosuria mildly, likely by lowering the net reabsorption of UA in the proximal tubule. These three drugs and lisinopril can blunt the rise in SUA provoked by diuretics in hypertensives if used at sufficiently high doses relative to the dose of the diuretic. The angiotensin II antagonist losartan augments uricosuria mildly and thereby decreases SUA. The cardiovascular implications of the response of SUA to drugs remain speculative. Uric acid can scavenge various reactive oxygen species and thus reduce oxidative stress, which seems to contribute to the development and/or progress of various cardiovascular conditions, including hypertension, atherosclerosis and heart failure. Consequently, it may be theorised that the elevations in SUA induced by diuretics might contribute to the established favourable action of these agents on cardiovascular prognosis. Conversely, diuretic-induced increases in SUA are to be considered detrimental according to an old hypothesis that maintains that SUA is a cardiovascular risk factor; this construct is largely based upon the results of selected epidemiological undertakings. The cardiovascular implications of the effects of drugs on SUA, if any, should be elucidated through purposive research.

Animals↗