Allopurinol Normalizes Endothelial Dysfunction in Type 2 Diabetics With Mild Hypertension

Abstract

Abstract-Therapeutic strategies against free radicals have mostly focused on the augmentation of antioxidant defenses (eg, vitamins C and E). A novel approach is to prevent free radical generation by the enzyme system xanthine oxidase. We examined whether the inhibition of xanthine oxidase with allopurinol can improve endothelial function in subjects with type 2 diabetes and coexisting mild hypertension compared with control subjects of a similar age. We examined 23 subjects (11 patients with type 2 diabetes and 12 healthy age-matched control subjects) in 2 parallel groups. The subjects were administered 300 mg allopurinol in a randomized, placebo-controlled study in which both therapies were administered for 1 month. Endothelial function was assessed with bilateral venous occlusion plethysmography, in which the forearm blood flow responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators were measured. Allopurinol significantly increased the mean forearm blood flow response to acetylcholine by 30% (3.16Ϯ1.21 versus 2.54Ϯ0.76 mL ⅐ 100 mL Ϫ1 ⅐ min Ϫ1 allopurinol versus placebo; Pϭ0.012, 95% CI 0.14, 1.30) but did not affect the nitroprusside response in patients with type 2 diabetes. There was no significant impact on either endothelium-dependent or -independent vascular responses in age-matched control subjects. Allopurinol improved endothelial function to near-normal levels. Regarding markers of free radical activity, the level of malondialdehyde was significantly reduced (0.30Ϯ0.04 versus 0.34Ϯ0.05 mol/L for allopurinol versus placebo, Pϭ0.03) in patients with type 2 diabetes but not in control subjects. The xanthine oxidase inhibitor allopurinol improves endothelial dysfunction in patients with type 2 diabetes with mild hypertension but not in matched control subjects. In the former group, allopurinol restored endothelial function to near-normal levels.

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

“…Allopurinol is an established drug to inhibit the activity of this enzyme and is commonly used to block the production of uric acid. The drug has been shown to reduce the OS in DMT-2 patients (15,50,73,74). Experimental studies have also corroborated these findings.…”

“…Experimental studies have also corroborated these findings. Some workers (74) have proposed that over expression of xanthine oxidase is a major contributor in DMT-2 but significant contribution of this enzyme in the raised OS in DMT-2 or diabetic complications is questionable.…”

Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis

“…46 Allopurinol, can reverse the impaired endothelial NO production in both heart failure and type 2 diabetes. 47,48 Although allopurinol leads to significant UA reductions most investigators believe that its beneficial effect may be by reducing oxidative stress. It is possible that treating hyperuricaemia may be effective in lowering BP when hyperuricaemia has not been present for a long time (such as in children with HT and in patients given short-term treatment with cyclosporine or diuretics) or when subjects are given a lowsalt diet which would remove the renal injury.…”

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.…”