Febuxostat, Blood Pressure and the Intrarenal Renin-Angiotensin System (RAS)
Febuxostat, Blood Pressure and the Intrarenal Renin-Angiotensin System (RAS)
In this study the investigators will recruit hypertensive subjects with higher than average
 uric acid levels to test the effect of lowering uric acid with febuxostat on several measures
 as listed below. This will be a randomized, double-blind, placebo-controlled, parallel group
 study.
Persons with hypertension (HTN) often have higher uric acid than normotensives, especially in
 hypertensives with metabolic syndrome.1-5 Recent prospective studies also suggest that
 persons with higher uric acid are at greater risk to develop hypertension.4-7 Uric acid in
 childhood appears to be particularly predictive of both early-onset hypertension and blood
 pressure later in life.4, 5, 8 While many had considered elevated uric acid as merely a
 marker for increased renal sodium reabsorption, recent data suggests a potentially causal
 role. Rats made mildly hyperuricemic by treatment with the uricase inhibitor oxonic acid
 become hypertensive. The increase in blood pressure in these rats was blocked by
 administration of renin-angiotensin system (RAS) blockers or by reduction of uric acid with
 allopurinol.9 More recently, febuxostat was also shown effective in this experimental
 model.10 Febuxostat was recently approved by the FDA as Uloric. Febuxostat is a xanthine
 oxidase (XO) inhibitor (like the older drug allopurinol), and is indicated for the chronic
 management of hyperuricemia in patients with gout.

 The investigators have reported a clear relationship between higher serum uric acid and
 increased intrarenal angiotensin II as assessed by intravenous angiotensin II (Ang II)
 infusions in human subjects.11 In this model, the change in renal blood flow in response to
 infused Ang II serves as an indirect indicator of renal vascular exposure to endogenous Ang
 II. In the setting of high endogenous intrarenal Ang II, renovascular AT1 receptors are
 down-regulated and the normal reduction in renal blood flow in response to infused exogenous
 Ang II becomes blunted. The investigators found that increased serum uric acid is strongly
 correlated to blunting of the normal response to infused Ang II. Other studies by our
 colleagues in Boston have demonstrated that treatment with ACE inhibitors or angiotensin
 receptor blockers restores normal responsiveness to infused Ang II in hypertensives with this
 blunted response and that such patients may be particularly responsive to RAS blockade.12-14
 The studies in rats and our results with the association of uric acid suggest that elevated
 uric acid may cause an increase in intrarenal Ang II or otherwise interact with Ang II and
 thereby promote hypertension. In this study, the investigators propose to explore the
 causality of uric acid in affecting blood pressure and, importantly, to begin to explore the
 underlying mechanism of such a response using our unique protocol in human subjects.

 Recent results from a randomized cross-over study of 30 hyperuricemic, hypertensive
 adolescents showed that allopurinol (200 mg twice daily) resulted in a significant reduction
 in blood pressure as compared with placebo.4, 15, 16 However, similar studies in adults are
 lacking and no study has provided insights into mechanisms whereby uric acid might raise
 blood pressure in humans. Endothelial dysfunction was consistently improved by allopurinol
 treatment in patients with congestive heart failure17, 18 and several other conditions.19 It
 would be of great scientific and clinical interest if a mechanistic role for uric acid in
 adult hypertension could be demonstrated. The investigators have a unique opportunity to
 examine uric acid as a contributor to overactivity of the intrarenal RAS and impaired nitric
 oxide production. The investigators hypothesize that hypertensives with elevated uric acid
 will experience a significant fall in uric acid in response to administration of febuxostat
 which will correlate with an improvement in vascular responses to infused Ang II, and
 improved endothelial function.

 As part of the same protocol the investigators will be able to assess the effect of
 febuxostat on proximal and distal sodium clearance by using uric acid clearance as a
 surrogate for proximal tubular sodium absorption. Uric acid reabsorption is indirectly
 coupled to sodium reabsorption: anions enter proximal tubular cells via a sodium-coupled
 electroneutral system and anions are then exchanged for urate.20 Renal uric acid clearance is
 directly and closely correlated with renal lithium clearance, a well-validated measure of
 proximal tubular sodium reabsorption, and both clearances have been used to estimate proximal
 tubular sodium handling in large, population-based studies,21, 22 as well as to measure acute
 responses to, for example, insulin infusion,23 beta-blocker treatment,24 and volume
 expansion.20, 25 Other studies have found decreased proximal tubular uric acid or lithium
 clearance associated with a positive family history of hypertension26 and with an adducin
 gene variant associated with hypertension.27 In summary, the investigators will examine the
 effects of lowering uric acid with febuxostat on both intrarenal RAS activity as measured by
 renovascular response to Ang II infusion, and on proximal tubular sodium absorption as
 measured by uric acid clearance. Potential effects on endothelial function, arterial
 stiffness, and blood pressure will also be tested.
Inclusion Criteria:

 -  Mild to moderate hypertension. For purposes of this study, the investigators define
 mild to moderate hypertension as being on no more than 1-2 antihypertensive
 medications and blood pressure &lt;140 mm Hg systolic and &lt;90 mm Hg diastolic based
 on mean seated blood pressure at the screening visit in our clinic. For these visits,
 the investigators measure blood pressure using a Dinamap automatic oscillometric cuff
 while subjects are seated quietly. The subjects are left in a quiet room without
 speaking for 5 minutes initially. The Dinamap is started and the technician leaves the
 room and 3 blood pressures are obtained at intervals of 2 minutes. The investigators
 use the mean of last 2 blood pressures for classification purposes. This is the
 approach the investigators have used in several multicenter studies including HyperGEN
 and the NHLBI Family Heart Study.

 -  Age 18 to 60.

 -  Uric acid =5.8 mg/dl. This was the mean uric acid among hypertensives in our prior
 study.11 As renal plasma flow response to Ang II infusion decreased linearly with
 higher uric acid, the investigators felt that using higher than average uric acid will
 provide greater power.

 Exclusion Criteria:

 -  Severe or poorly controlled hypertension (treated blood pressure &gt;160 mm Hg
 systolic or &gt;100 mm Hg diastolic).

 -  Diabetes (type 1 or type 2).

 -  Estimated GFR &lt;60 ml/min.

 -  Persons unable stop all medications (including antihypertensives) other than stable
 doses of thyroxine or estrogen for at least 2 weeks.

 -  Secondary hypertension.

 -  Prior history of clinically diagnosed coronary artery disease or congestive heart
 failure.

 -  Taking uric acid lowering medication within 1 month of screening visit.