allopurinol and Diabetic-Angiopathies

The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.

Topics: Allopurinol; Animals; Antihypertensive Agents; Apolipoprotein L1; Apolipoproteins; Black People; Causality; Chronic Disease; Diabetic Angiopathies; Diabetic Nephropathies; Disease Management; Disease Models, Animal; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; Goals; Humans; Hypertension; Hypertension, Renal; Hyperuricemia; Kidney Diseases; Lipoproteins, HDL; Multicenter Studies as Topic; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Rats

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Diabetes Mellitus; Diabetic Angiopathies; Glucose; Glycation End Products, Advanced; Hexosamines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondria; NADPH Oxidases; Oxidative Stress; Polymers; Xanthine Oxidase

The aim of this study was to investigate the long-term effective control of serum uric acid by allopurinol on the carotid intima-media thickness (IMT) in patients with type 2 diabetes (T2DM) and asymptomatic hyperuricemia (HUA).. This was a randomized open parallel-controlled study. In this study, 176 patients with T2DM and asymptomatic HUA were randomly allocated to the conventional or allopurinol treatment groups on the basis of a computer-generated random number table. Changes in the carotid IMT, biochemical indexes, high sensitive C-reactive protein (hs-CRP) and the incidence of hypertension in patients before and after three years of treatment were examined and compared between the groups.. There were no statistically significant differences in the baseline characteristics of the study participants between the two treatment groups (p>0.05 for all). Nevertheless, the serum uric acid, triglyceride, and hs-CRP levels and the homeostasis assessment for insulin resistance (HOMA-IR), systolic blood pressure, diastolic blood pressure and the carotid IMT in the allopurinol group were significantly lower than those in the conventional group after three years of treatment (p<0.01 for all). The intention-to-treat analysis indicated that the incidence of new-onset hypertension in the allopurinol group showed a declining trend compared to that in the conventional treatment group (6.8% vs. 13.6%, p>0.05).. The long-term effective control of serum uric acid by allopurinol may improve insulin resistance, decrease the serum levels of hs-CRP, reduce the carotid IMT, and may delay the development of atherosclerosis in patients with T2DM and asymptomatic HUA.

Topics: Adult; Aged; Allopurinol; Asian People; Atherosclerosis; Biomarkers; Blood Pressure; C-Reactive Protein; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Gout Suppressants; Humans; Hyperuricemia; Incidence; Male; Middle Aged; Uric Acid

Type 2 diabetes increases risk of stroke, perhaps because of impaired cerebrovascular basal nitric oxide (NO) activity. We investigated whether this activity is improved by a 2-week course of the xanthine oxidase inhibitor allopurinol.. We performed a randomized, double-blind, placebo-controlled crossover study. We measured the response to infusion of NG-monomethyl-L-arginine (l-NMMA) in males with type 2 diabetes before and after allopurinol or placebo. The primary end point was the change in internal carotid artery flow following L-NMMA infusion, expressed as the area under the flow-per-time curve.. We enrolled 14 participants. Allopurinol improved responses to L-NMMA when compared with responses associated with placebo (P = 0.032; median reduction in internal carotid artery flow following L-NMMA of 3,144 ml [95% CI 375-7,143]).. Xanthine oxidase inhibition with allopurinol appears to improve cerebral NO bioavailability, as evidenced by a greater response to infusion of L-NMMA.

Topics: Allopurinol; Carotid Arteries; Cerebrovascular Circulation; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Humans; Infusions, Intravenous; Male; Nitric Oxide; omega-N-Methylarginine; Placebos; Stroke

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% (3.16+/-1.21 versus 2.54+/-0.76 mL. 100 mL(-1). min(-1) allopurinol versus placebo; P=0.012, 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 (0.30+/-0.04 versus 0. 34+/-0.05 micromol/L for allopurinol versus placebo, P=0.03) 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.

Topics: Age Factors; Aged; Allopurinol; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Free Radical Scavengers; Glycated Hemoglobin; Humans; Hypertension; Male; Malondialdehyde; Middle Aged; Nitroprusside; Plethysmography; Regional Blood Flow; Regression Analysis; Vasodilator Agents; Xanthine Oxidase

Several putative sources of reactive oxygen species could potentially contribute to diabetic neuropathy and vasculopathy. The aim was to assess the involvement of elevated xanthine oxidase activity. After 6 weeks of streptozotocin-diabetes, groups of rats were given 2 weeks of high-dose allopurinol treatment (50 and 250 mg/kg) to gauge the effect of maximal blockade of xanthine oxidase. In the final experiments, rats were subjected to sensory testing and, under butabarbital anaesthesia, measurements were made on nerve conduction velocities and neural tissue blood flow estimated by hydrogen clearance microelectrode polarography. Further groups were used to study detailed responses of the isolated mesenteric vascular bed after 4 weeks of diabetes and allopurinol (150 mg/kg) treatment. Diabetes caused 20% and 14% reduction in motor and sensory conduction velocity, which were 78% and 81% corrected by allopurinol treatment respectively, both doses giving similar results. Diabetic rats showed tactile allodynia and thermal hyperalgesia, which were completely corrected by allopurinol, whereas mechanical hyperalgesia was only 45% ameliorated. Sciatic nerve and superior cervical ganglion blood flow was halved by diabetes and allopurinol corrected this by approximately 63%. Mesenteric endothelium-dependent vascular responses to acetylcholine, which depend upon nitric oxide and endothelium derived hyperpolarizing factor, were attenuated by diabetes. Allopurinol treatment gave approximately 50% protection for both components. Thus, xanthine oxidase is an important source of reactive oxygen species that contributes to neurovascular dysfunction in experimental diabetes. Inhibition of xanthine oxidase could be a potential therapeutic approach to diabetic neuropathy and vasculopathy.

Topics: Acetylcholine; Allopurinol; Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Disease Models, Animal; Enzyme Inhibitors; Ganglia, Autonomic; Hyperalgesia; Male; Mesenteric Artery, Superior; Neural Conduction; Pain; Polarography; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Regional Blood Flow; Sciatic Nerve; Xanthine Oxidase

In diabetes mellitus, the risk for cardiovascular complications and development of atherosclerosis is increased compared with healthy individuals. Recently evidence was provided that increased production of superoxide anions occurs in endothelial cells during hyperglycemia. In order to evaluate the potential impact of the enhanced formation of this oxygen radical for vascular cell dysfunction and its role in tissue adaptation, it is essential to assess the effect of superoxide anions on endothelial cell function. Here, we present new data and review our previous work on the effects of superoxide anions on endothelial vascular function, such as intracellular Ca2+ signal cascade, formation and bioactivity of nitric oxide. Based on the presented data we discuss superoxide anion production as a two faced phenomenon. In lower concentrations, superoxide anions are mediators of an endothelium adaptation to ensure endothelial vasomotion control. However, in higher concentrations superoxide anions disrupt endothelial-smooth muscle crosstalk resulting in vessel wall dysfunction and vascular wall dysfunction.

Topics: Adaptation, Physiological; Animals; Aorta; Arteries; Calcium; Cells, Cultured; Diabetic Angiopathies; Endothelium, Vascular; Female; Glucose; Hyperglycemia; Models, Cardiovascular; Muscle, Smooth, Vascular; Nitric Oxide; Signal Transduction; Superoxides; Swine; Uterus; Xanthine; Xanthine Oxidase