Effects of Xanthine Oxidase Inhibition With Allopurinol on Endothelial Function and Peripheral Blood Flow in Hyperuricemic Patients With Chronic Heart Failure

Abstract

Background-In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results-In 10 CHF patients with normal serum uric acid (UA) levels (315Ϯ42 mol/L) and 9 patients with elevated UA (535Ϯ54 mol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 g/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (PϽ0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558Ϯ21 mol/L, range 455 to 743 mol/L), treatment reduced UA by Ͼ120 mol/L in all patients (mean reduction 217Ϯ15 mol/L, PϽ0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (ϩ24%, Pϭ0.027) and legs (ϩ23%, Pϭ0.029). Flow-dependent flow improved by 58% in arms (Pϭ0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (PϽ0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (rϭ0.63, PϽ0.05). Conclusions-In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

“…Diphenylene iodonium (DPI) nonspecifically inhibits flavoprotein-containing enzymes, including NADPH oxidases, NOS, and complex I of mitochondrial electron transport chain [57]. Allopurinol has been reported to inhibit xanthine oxidase-derived oxygen free radical production [58]. Also, rotenone inhibits mitochondrial respiratory chain complex I, specifically, electron transfer within the NADH-Q reductase complex [59].…”

The conundrum of hyperuricemia, metabolic syndrome, and renal disease

“…Hyperuricemic patients exhibit endothelial dysfunction defined as impairment of flow-mediated dilatation of the brachial artery [24]. If hyperuricemic subjects are treated with allopurinol, an improvement in endothelial function has been observed in subjects with chronic heart failure [25]. On the other hand, George et al reported that improvement of endothelial function in heart failure could be achieved with high-dose allopurinol and not probenecid (the latter drug being a uricosuric), suggesting that allopurinol may improve endothelial function via other mechanisms besides lowering uric acid levels, such as by blocking xanthine oxidase-induced oxidants [26].…”

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence

“…[57][58][59][60] Although the mechanism by which uric acid exerts its pathogenetic effect on cardiovascular and cerebrovascular complications is still unclear, high uric acid levels have been shown to induce inflammation, endothelial dysfunction, oxidative metabolism, and platelet adhesion and aggregation. [61][62][63][64][65] All these changes induced by high uric acid levels could conceivably lead to cardiovascular complications and stroke and therefore, drugs that lower uric acid levels have been shown to reverse these changes. [61][62][63][64][65] Losartan, in exception to other ARBs, lowers uric acid levels and its use for the treatment of hypertension has been shown to decrease the incidence of cardiovascular complications and strokes.…”

“…[61][62][63][64][65] All these changes induced by high uric acid levels could conceivably lead to cardiovascular complications and stroke and therefore, drugs that lower uric acid levels have been shown to reverse these changes. [61][62][63][64][65] Losartan, in exception to other ARBs, lowers uric acid levels and its use for the treatment of hypertension has been shown to decrease the incidence of cardiovascular complications and strokes. 66,67 In fact, the results from the LIFE study showed that the baseline uric acid level was significantly associated with cardiovascular complications and strokes, especially in women, and that its lowering with losartan accounted for 29% of the reduction of strokes compared to atenolol.…”