dinoprost and Hyperuricemia

Although hyperuricemia is suggested to increase allantoin production in both pro- and antioxidant manners, it remains undetermined whether it increases the serum concentration of allantoin. In addition, since uric acid has both pro- and antioxidant actions, a decrease in the serum concentration of uric acid may have an effect on the pro-oxidant-antioxidant balance.. To examine whether serum allantoin is correlated with serum urate, we measured those levels as well as other parameters in 63 healthy subjects. In addition, to determine whether serum allantoin is correlated with reactive oxygen species (ROS) biomarkers, we measured 8-hydroxy deoxyguanosine and 15-F2t-isoprostane, markers of ROS, in urine samples from 30 gout patients before and 1 year after benzbromarone treatment (50 mg/d).. The serum concentration of allantoin was correlated with that of urate in healthy subjects (R = 0.27, p < 0.05). Benzbromarone treatment in the patients decreased the concentrations of allantoin and urate in serum by 17% (p < 0.05) and 49% (p < 0.05), respectively, and the benzbromarone-induced change in serum allantoin was correlated with that in serum urate (R = 0.39, p < 0.05). However, benzbromarone treatment did not change the ratios of 8-hydroxydeoxyguanosine/creatinine or 15-F2t-isoprostane/creatinine in urine.. Our findings suggest that hyperuricemia contributes to an increase in serum concentration of allantoin, though they do not indicate that hyperuricemia is a major factor for controlling oxidative stress in vivo.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Allantoin; Benzbromarone; Biomarkers; Case-Control Studies; Creatinine; Deoxyguanosine; Dinoprost; Gout; Humans; Hyperuricemia; Japan; Male; Middle Aged; Oxidative Stress; Time Factors; Treatment Outcome; Uric Acid; Uricosuric Agents

Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.

Topics: Allopurinol; Analysis of Variance; Animals; Antioxidants; Atrasentan; Biomarkers; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gout Suppressants; Hypertrophy, Left Ventricular; Hyperuricemia; Isoprostanes; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Superoxides; Time Factors; Up-Regulation; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Xanthine Oxidase

Hyperuricemia may play a role in the pathogenesis of cardiovascular disease, but uric acid is also a significant antioxidant. We investigated the effects of oxonic acid-induced hyperuricemia on carotid artery tone in experimental renal insufficiency.. Three weeks after 5/6 nephrectomy (NX) or Sham operation, male Sprague-Dawley rats were allocated to 2.0% oxonic acid or control diet for 9 weeks. Blood pressure was monitored using tail cuff, isolated arterial rings were examined using myographs, and blood and urine samples were taken, as appropriate. Oxidative stress and antioxidant status were evaluated by measuring urinary 8-isoprostaglandin F(2 alpha) (8-iso-PGF(2 alpha)) excretion and plasma total peroxyl radical-trapping capacity (TRAP), respectively.. Plasma creatinine was elevated twofold in NX rats, but neither NX nor oxonic acid diet influenced blood pressure. Urinary 8-iso-PGF(2 alpha) excretion was increased over 2.5-fold in NX rats on control diet. Oxonic acid diet increased plasma uric acid 2-3-fold, TRAP 1.5-fold, and reduced urinary 8-iso-PGF(2 alpha) excretion by 60-90%. Carotid vasorelaxation to acetylcholine in vitro, which could be abolished by nitric oxide (NO) synthase inhibition, was reduced following NX, whereas maximal response to acetylcholine was augmented in hyperuricemic NX rats. Vasorelaxation to nitroprusside was impaired in NX rats, whereas oxonic acid diet increased sensitivity also to nitroprusside in NX rats.. Oxonic acid-induced hyperuricemia reduced oxidative stress in vivo, as evaluated using urinary 8-iso-PGF(2 alpha) excretion, increased plasma TRAP, and improved NO-mediated vasorelaxation in the carotid artery in experimental renal insufficiency.

Topics: Animals; Carotid Arteries; Creatinine; Dinoprost; Hyperuricemia; Male; Nephrectomy; NG-Nitroarginine Methyl Ester; Oxidative Stress; Oxonic Acid; Peroxides; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Uric Acid; Vasodilation