We performed a small, carefully controlled, double-blind study to determine if lowering uric acid with a xanthine oxidase inhibitor can lower BP in asymptomatic adolescents with high serum uric acid levels (≥6.0 mg/dL) and newly diagnosed mild essential hypertension. The study was intended as a proof of physiological mechanisms and not to establish new therapy. However, hypertension is a very common disease, affecting 30% to 35% of adults and is especially common in groups at high risk of cardiovascular disease. Despite a large number of safe and effective antihypertensive agents and useful lifestyle modification measures, optimal BP control is attained in less than 40% of patients receiving therapy.39
The results of this study represent a potentially new therapeutic approach, that of control of a biochemical cause of hypertension, rather than nonspecifically lowering elevated BP. Although not representing a fully developed therapeutic strategy, this study raises an alternative strategy that may prove to be more effective than currently available options.
One hesitation in considering allopurinol as a therapy for hypertension is its potential for adverse effects. Allopurinol is approved for use in children to treat gout and the dose used in this study is generally considered safe. Although no adverse effects were seen in our small study, about 1 in 75 children typically develop nausea, vomiting, or diarrhea. More serious rare adverse effects include liver damage, neutropenia, and Stevens-Johnson syndrome, which are generally reversible but can be life-threatening. The risks vs benefits of allopurinol remain to be studied.
Allopurinol was administered as 200 mg twice daily according to pediatric dosing guidelines.40
Uric acid levels decreased from a mean of 6.9 mg/dL to 4.2 mg/dL (P
<.001), although 8 of 30 patients continued to have serum uric acid levels 5 mg/dL or higher with allopurinol. The variability in response to allopurinol is most likely associated with differences in adherence, but individuals could vary in their biological response to the medication as well. Because of the small size of this study, we were unable to definitively determine the etiology of the variable response. Participants in the placebo phase also showed a mild nonstatistically significant decrease in serum uric acid level (6.2 mg/dL, P
=.04), which likely reflects either dietary changes made during the course of the study or that the serum uric acid was still increasing after 2 weeks of washout in the patients who received allopurinol first.
The major finding was that allopurinol treatment resulted in normal BP, by both casual and ambulatory criteria, in 20 of 30 participants, including 19 of the 22 (86%) whose uric acid levels were lowered to less than 5.0 mg/dL. In contrast, only 1 of 30 participants became normotensive while receiving placebo during the study. The primary end point (clinic BP) showed a greater mean decrease of 5 mm Hg in systolic BP and a 2.5-mm Hg decrease in diastolic BP over placebo. By ambulatory BP the differences were even greater, with a 7-mm Hg greater decline in systolic BP and a 4-mm Hg greater decline in diastolic BP.
The relative reduction in BP we observed with allopurinol was similar to what is observed with conventional antihypertensive agents in the treatment of mild hypertension. For example, in the Treatment of Mild Hypertension Study, the effect of β-blocker, calcium channel blocker,α-blocker, and angiotensin-converting enzyme inhibitors were evaluated in adults with mild hypertension.41
Over 48 months only 70% of patients responded to any given agent and the mean change in systolic BP ranged from 2.7 to 6.0 mm Hg and the change in diastolic BP from 1.1 to 3.6 mm Hg. In a meta-analysis to assess the efficacy of individual classes of antihypertensive medications in children, Simonetti et al42
found an average total BP decrease of 10 mm Hg systolic and 7 mm Hg diastolic in populations that included patients with moderate and severe hypertension. While the observed degree of reduction may appear modest, a reduction of 5 to 7 mm Hg in systolic BP can translate to as much as a 25% decrease in long-term cardiovascular mortality.43
A clue to the mechanism by which allopurinol lowered BP was the observation that systemic vascular resistance and plasma renin activity both decreased significantly with treatment. In experimental animals intrarenal renin expression has been shown to be mediated by uric acid.17
More recently, Toma et al44
reported that uric acid stimulates renin release via a macula densa dependent mechanism using an in vitro microperfused afferent arteriole-glomerular preparation. These studies suggest that lowering uric acid may act, at least in part, by reducing plasma renin activity.
There are a number of limitations to the study. First, the number of participants was small and the population limited to adolescents with mild, newly diagnosed hypertension and hyperuricemia. We do not know if the findings will extend to populations that include lower serum uric acid levels, more severe or long-standing hypertension, older patients, or different ethnic or geographic mixtures. Indeed, we have previously reported that once microvascular disease develops in the kidney, hypertension is largely driven by renal-and sodium-dependent mechanisms,45
suggesting that individuals with long-established hypertension might be expected to be resistant to hypouricemic therapy.
Second, the population was predominantly obese. Because approximately 2% to 3% of lean children and 18% to 20% of obese children have hypertension,29,46
the 70% rate of obesity in our study is representative of the adolescent hypertensive population, although it may be less representative of the general hypertensive population in the United States or worldwide.
Third, because the purpose of the study was to investigate a causal principle, the duration of treatment was short and we have no data as to whether the observed effect would be sustained over time.
Fourth, since allopurinol reduces both uric acid and xanthine oxidase–induced oxidants, it is possible that the effect of allopurinol to lower BP may not be due to the lowering of uric acid. George et al47
reported that allopurinol but not the uricosuric probenecid could improve endothelial function in patients with heart failure. However, xanthine oxidase inhibitors may be more effective at lowering uric acid within the cell where it is believed most of the effects are mediated.48,49
Fifth, we also do not know how dietary, exercise, or weight loss interventions might modify the effect of xanthine oxidase inhibition because all participants received similar counseling.
Sixth, ambulatory BP monitoring was performed only 3 times during the study: at enrollment and at the end of each of the 2 medication phases. This was done because the number of ambulatory BP monitoring procedures was the most common reason for individuals to refuse to enroll. Since both posttreatment ambulatory BPs were compared with the enrollment BP reading, there is potential concern for a carryover effect from the first to second medication phase. This is unlikely because the participants were randomized and such effects should impact both treatment groups equally. There was also no difference between casual BP measurements at the beginning of each medication phase, suggesting no carryover. Furthermore, because this was a placebo-controlled study, persistence of medication effect from those who received allopurinol first would be expected to increase the apparent placebo effect, while no placebo effect would be expected to carry over to the allopurinol treatment. Consequently, medication carryover would be expected to favor the null hypothesis, which was rejected by the data analysis.
Finally, the lack of adverse events for hypertensive participants receiving allopurinol in a small and short-term study should not be construed to suggest that allopurinol is without adverse effects or even comparable to conventional antihypertensive medications because the study was not designed to make such an evaluation.
In conclusion, we found that allopurinol treatment can reduce BP in hyperuricemic adolescents with newly diagnosed hypertension. Despite these findings, this clinical trial is a small one and allopurinol is not indicated for the treatment of hypertension in adolescents or other populations. The potential adverse effects of allopurinol, including gastrointestinal complaints and especially Stevens-Johnson syndrome, make allopurinol an unattractive alternative to available antihypertensive medications. More clinical trials are needed to determine the reproducibility of the data and whether it can be generalized to the larger hypertensive population. Nevertheless, the observation that lowering uric acid can reduce BP in adolescents with newly diagnosed hypertension raises intriguing questions about its role in the pathogenesis of hypertension.