Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemic and hypertensive patients have impaired endothelium-dependent vasorelaxation because of decreased nitric oxide activity, but the mechanism underlying this abnormality is unknown. This study sought to determine whether an increased breakdown of nitric oxide by xanthine oxidase-generated superoxide anions could participate in these forms of endothelial dysfunction. We studied vascular responses to intrabrachial infusion of acetylcholine (an endothelium-dependent vasodilator, 7.5 to 30 microg/min) and sodium nitroprusside (a direct smooth muscle dilator, 0.8 to 3.2 microg/min) by strain-gauge plethysmography before and during the combined administration of oxypurinol (300 microg/min), a xanthine oxidase inhibitor, in 20 hypercholesterolemic patients, 20 essential hypertensive patients, and 20 normal subjects. The vasodilator response to acetylcholine was blunted in hypercholesterolemic (highest flow, 8.2+/-8 mL x min(-1) x dL(-1)) and hypertensive (8.5+/-4 mL x min(-1) x dL(-1)) patients compared with control subjects (13.8+/- 6.6 mL x min(-1) x dL(-1)) (both P<.001); however, no differences were observed in the response to sodium nitroprusside. Oxypurinol did not change the response to acetylcholine in control subjects (P=.26) and improved, but did not normalize, its vasodilator effect in hypercholesterolemic patients (P<.01). Oxypurinol did not affect the response to acetylcholine in hypertensive patients (P=.34) and did not modify the response to sodium nitroprusside in any group. These results suggest that xanthine oxidase-generated superoxide anions are partly responsible for the impaired endothelial vasodilator function of hypercholesterolemic patients. In contrast, this mechanism does not appear to play a significant role in essential hypertension.
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PMID:Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. 923 21

A change in endothelial function is a common phenomenon in patients with essential hypertension and in animals with hypertension, whether primary or induced by a salt-rich diet. In hypertensive subjects, there may be a change in the synthesis, or the effect, of nitric oxide. Nevertheless, hypertensive vasoconstriction is at present associated, above all, with the degradation of this mediator by free radicals, such as the superoxide anion, released in the dysfunctional vascular endothelium. These radicals are also formed when hypoxanthine is turned into xanthine, and when the latter becomes uric acid, both having been catalysed by the enzyme xanthine oxidase. In physiological conditions, the concentration of superoxide radicals remains low within the organism as a result of its reaction with the superoxide dismutase enzyme. However, in pathological situations, such as arterial hypertension, there may be an increase in the production of these radicals or a deficiency of the superoxide dismutase enzyme. In hypertensive patients, the release of vasoconstrictor peroxides derived from the activity of cyclo-oxygenase in the endothelium and the vascular smooth muscle is also important. The excess free radicals released by the dysfunctional endothelium also stimulate the synthesis of these contracting agents. Moreover, it should not be forgotten that endothelin-1, which is similarly synthesized and released in the vascular endothelium, is the most powerful known endogenous vasoconstrictor. This peptide would therefore play a prominent part in some forms of hypertension. Although no changes in endothelin plasma levels have been found in essential hypertension, there may be an increase in its local concentration. It should be borne in mind that endothelin could strengthen the effect of other vasoconstrictors. Moreover, it may also provoke the release of free radicals and of cyclo-oxygenase-derived vasoconstrictor factors. The latest theories therefore indicate that the increase in vasoconstriction, which characterizes arterial hypertension, is associated with a greater production of free radicals. At the present time, antioxidant agents and xanthine oxydase-inhibiting compounds are being used to treat hypertension and other pathologies linked to endothelial dysfunction. In addition, it is thought that the therapeutic benefit of some anti-hypertensive drugs, such as calcium antagonists and angiotensin-converting enzyme inhibitors, could be in part due to the inhibition of the production of free radicals that they provoke.
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PMID:Endothelial dysfunction and hypertensive vasoconstriction. 1043 69

Obesity-induced hypertension and essential hypertension in lean patients are two different forms of hypertension. The main goal of this study was to test whether there are differences in biochemical parameters between subjects with obesity-associated hypertension and those with essential hypertension. We examined whether the biochemical responses to angiotensin-converting enzyme inhibitor (ACEI) ramipril therapy reveal properties of these two conditions that might explain the differences in clinical outcome. Before ramipril therapy, the hypertensive group exhibited increases in ACE activity (p<0.05), plasma malondialdehyde (MDA) concentration and the malondialdehyde/nitric oxide end-product ratio (MDA/NO(x)) (p<0.05), and decreases in xanthine oxidase (XO) activity (p<0.05) and plasma nitric oxide end-product (NO(x)) level (p<0.01). Before medication, plasma endothelin-1 (ET-1), plasma leptin, and leptin receptor levels were normal. Following ramipril treatment, ACE activity normalized. Before ACE inhibitor treatment, the obese-hypertensive group exhibited elevated levels of plasma ET-1 (p<0.05), plasma leptin (p<0.01), XO activity (p<0.05), plasma MDA and MDA/NO(x) (p<0.05), and reduced levels of plasma NO(x)(p<0.01) and leptin receptors (p<0.001). Following medication, the plasma NO(x) level, MDA/NO(x), and XO activity returned to normal while ACE activity decreased (p<0.001). In patients with essential hypertension, NO availability and ACE activity, and in those with obesity-associated hypertension, hyperleptinemic effects, NO level, endothelin-1 concentration and XO activity, may be important factors in the pathology.
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PMID:Different pathomechanisms of essential and obesity-associated hypertension in adolescents. 1689 99

Uric acid was first associated with primary hypertension in 1874, yet its role in this condition remains unclear. Historically, uric acid was thought to be a secondary response to hypertension or its associated conditions. However, more recent experimental and clinical studies suggest that uric acid could have a contributory role in the pathogenesis of elevated blood pressure. More studies are needed to help dissect the potential mechanisms by which uric acid could initiate this response. It remains possible that uric acid is a marker for xanthine oxidase-associated oxidants and that the latter could be driving the hypertensive response. However, the weight of the evidence suggests that uric acid is a true modifying and possibly causal factor for human primary hypertension. Hence, early management of hyperuricemia might delay the development of essential hypertension.
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PMID:Uric acid and hypertension: cause or effect? 2042 19

Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy.
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PMID:Uric acid reduction rectifies prehypertension in obese adolescents. 2300 29

Purine nucleotide liberation and their metabolic rate of interconversion may be important in the development of hypertension and its renal consequences. In the present study, blood triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) breakdown pathway was evaluated in relation to uric acid concentration and xanthine dehydrogenase/xanthine oxidase (XDH/XO) in patients with essential hypertension, patients with chronic renal diseases on dialysis, and control individuals. The pattern of nucleotide catabolism was significantly shifted toward catabolic compounds, including ADP, AMP, and uric acid in patients on dialysis program. A significant fall of ATP was more expressed in a group of patients on dialysis program, compared with the control value (p<0.001), while ADP and AMP were significantly increased in both groups of patients compared with control healthy individuals (p<0.001), together with their final degradation product, uric acid (p<0.001). The index of ATP/ADP and ATP/uric acid showed gradual significant fall in both the groups, compared with the control value (p<0.001), near five times in a group on dialysis. Total XOD was up-regulated significantly in a group with essential hypertension, more than in a group on dialysis. The activity of XO, which dominantly contributes reactive oxygen species (ROS) production, significantly increased in dialysis group, more than in a group with essential hypertension. In conclusion, the examination of the role of circulating purine nucleotides and uric acid in pathogenesis of hypertension and possible development of renal disease, together with XO role in ROS production, may help in modulating their liberation and ROS production in slowing progression from hypertension to renal failure.
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PMID:Circulating purine compounds, uric acid, and xanthine oxidase/dehydrogenase relationship in essential hypertension and end stage renal disease. 2450 20

Essential hypertension is a highly prevalent pathological condition that is considered as one of the most relevant cardiovascular risk factors and is an important cause of morbidity and mortality around the world. Despite the fact that mechanisms underlying hypertension are not yet fully elucidated, a large amount of evidence shows that oxidative stress plays a central role in its pathophysiology. Oxidative stress can be defined as an imbalance between oxidant agents, such as superoxide anion, and antioxidant molecules, and leads to a decrease in nitric oxide bioavailability, which is the main factor responsible for maintaining the vascular tone. Several vasoconstrictor peptides, such as angiotensin II, endothelin-1 and urotensin II, act through their receptors to stimulate the production of reactive oxygen species, by activating enzymes like NADPH oxidase and xanthine oxidase. The knowledge of the mechanism described above has allowed generating new therapeutic strategies against hypertension based on the use of antioxidants agents, including vitamin C and E, N-Acetylcysteine, polyphenols and selenium, among others. These substances have different therapeutic targets, but all represent antioxidant reinforcement. Several clinical trials using antioxidants have been made. The aim of the present review is to provide new insights about the key role of oxidative stress in the pathophysiology of essential hypertension and new clinical attempts to demonstrate the usefulness of antioxidant therapy in the treatment of hypertension.
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PMID:Essential hypertension and oxidative stress: New insights. 2497 7

The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout, kidney stones, and possibly vascular calcification. Mendelian randomization studies, however, indicate that serum urate is likely not the causal factor in hypertension although it does increase the risk for sudden cardiac death and diabetic vascular disease. Nevertheless, experimental evidence strongly suggests that an increase in intracellular urate is a key factor in the pathogenesis of primary hypertension. Pilot clinical trials show beneficial effect of lowering serum urate in hyperuricemic individuals who are young, hypertensive, and have preserved kidney function. Some evidence suggest that activation of the renin-angiotensin system (RAS) occurs in hyperuricemia and blocking the RAS may mimic the effects of xanthine oxidase inhibitors. A reduction in intracellular urate may be achieved by lowering serum urate concentration or by suppressing intracellular urate production with dietary measures that include reducing sugar, fructose, and salt intake. We suggest that these elements in the western diet may play a major role in the pathogenesis of primary hypertension. Studies are necessary to better define the interrelation between uric acid concentrations inside and outside the cell. In addition, large-scale clinical trials are needed to determine if extracellular and intracellular urate reduction can provide benefit hypertension and cardiometabolic disease.
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PMID:Uric Acid and Hypertension: An Update With Recommendations. 3217 96