Oxidative stress plays an important role in the development of atherosclerosis and contributes to tissue damage that occurs as a consequence, particularly in myocardial infarction and acute stroke. Antioxidant properties of uric acid have long been recognized and, as a result of its comparatively high serum concentrations, it is the most abundant scavenger of free radicals in humans. Elevation of serum uric acid concentration occurs as a physiologic response to increased oxidative stress-for example, during acute exercise-thus providing a counter-regulatory increase in antioxidant defenses. In view of its antioxidant properties, uric acid may have potentially important and beneficial effects within the cardiovascular system. We wished to investigate whether administration of uric acid was feasible and if it could have an impact on antioxidant function in vivo. We have, therefore, performed a randomized, placebo-controlled double-blind study of the effects of systemic administration of uric acid, 1,000 mg, in healthy volunteers, compared with vitamin C, 1,000 mg. We observed a significant increase in serum free-radical scavenging capacity from baseline during uric acid and vitamin C infusion, using two methodologically distinct antioxidant assays. The effect of uric acid was substantially greater than that of vitamin C.

Uric acid (UA) possesses free-radical-scavenging properties, and systemic administration is known to increase serum antioxidant capacity. However, it is not known whether this protects against oxidative stress. The effects of raising UA concentration were studied during acute aerobic physical exercise in healthy subjects, as a model of oxidative stress characterized by increased circulating 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) concentrations. Twenty healthy subjects were recruited to a randomized double-blind placebo-controlled crossover study, and underwent systemic administration of 0.5 g of UA in 250 ml of 0.1% lithium carbonate/4% dextrose vehicle or vehicle alone as control. Subjects performed high-intensity aerobic exercise for 20 min to induce oxidative stress. Plasma 8-iso-PGF2alpha concentrations were determined at baseline, after exercise and after recovery for 20 min. A single bout of high-intensity exercise caused a significant increase in plasma 8-iso-PGF2alpha concentrations from 35.0 +/- 4.7 pg/ml to 45.6 +/- 6.7 pg/ml (P<0.01). UA administration raised serum urate concentration from 293 +/- 16 to 487 +/- 16 micromol/l (P<0.001), accompanied by increased serum antioxidant capacity from 1786+/-39 to 1899 +/- 45 micromol/l (P<0.01). UA administration abolished the exercise-induced elevation of plasma 8-iso-PGF2alpha concentrations. High UA concentrations are associated with increased serum antioxidant capacity and reduced oxidative stress during acute physical exercise in healthy subjects. These findings indicate that the antioxidant properties of UA are of biological importance in vivo.

Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis. The urate molecule has antioxidant properties, which could influence endothelial function. The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes, eight healthy regular smokers, and eight age-matched healthy control subjects in a randomized, four-way, double-blind, placebo-controlled study. Subjects received 1,000 mg uric acid i.v. in vehicle, 1,000 mg vitamin C as a control antioxidant, vehicle alone, or 0.9% saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography. Responses to acetylcholine, but not sodium nitroprusside, were impaired in patients with diabetes (P < 0.001) and in smokers (P < 0.005) compared with control subjects. Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes (P < 0.01) and in regular smokers (P < 0.05). Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers, suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk. Diabetes 55:3127-3132, 2006

Supplementary oxygen is commonly administered in current medical practice. However, attention has recently been drawn to the potentially disadvantageous hemodynamic consequences in certain patients. Possible mechanisms underlying the cardiovascular responses to acute hyperoxia are unclear. The effects of acute oxygen administration on heart rate, blood pressure, cardiac output, systemic vascular resistance, and baroreflex sensitivity were studied in a series of randomised, placebo-controlled studies in healthy individuals, using validated, non-invasive techniques. The effects of oxygen administration on forearm blood flow responses to locally administered acetylcholine, an endothelium-dependent vasodilator, sodium nitroprusside, an endothelium-independent vasodilator, and l-NG-monomethylarginine, a nitric oxide synthase inhibitor, were studied using venous occlusion plethysmography. Oxygen administration for 1 hour caused a reduction in heart rate (P< 0.01) and cardiac index (P < 0.05), and an increase in mean arterial pressure (P < 0.01), systemic vascular resistance (P < 0.05), large artery stiffness (P < 0.05), and baroreflex sensitivity (P < 0.05). There were no effects on vascular responses in the isolated forearm bed. These findings indicate that oxygen administration causes acute effects on cardiovascular function, which might be important in the context of acute illness.

Novel biomarkers appear capable of offering a more sensitive means of detecting acute kidney injury than existing approaches. Certain of these allow discrimination between the various mechanisms and anatomical site of acute injury. Ultimately, clinical assessment might incorporate a panel of different biomarkers, each informing on the integrated aspects of glomerular, tubular and interstitial function. Presence of biomarkers may in some cases detect mild or transient renal dysfunction that is presently undetected, and the clinical relevance needs further exploration. Whilst many potentially useful biomarkers have been proposed, comparatively few clinical data exist to support their validity in routine practice. Further prospective clinical studies are required to examine the validity of biomarkers after acute drug or toxin exposure, and to establish whether they might offer improved clinical outcomes in the setting of clinical toxicology.

Severity of adverse effects correlates with the extent of histamine release. Histamine release appears independent of tryptase suggesting a non-mast cell source. Acetaminophen is protective against adverse effects of NAC, and mechanisms by which acetaminophen might lessen histamine release require further attention.

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. Effects of short-term isocapnic hyperoxia and hypoxia on cardiovascular function. J Appl Physiol 101: 809 -816, 2006; doi:10.1152/japplphysiol.01185.2005.-Both hypoxia and hyperoxia have major effects on cardiovascular function. However, both states affect ventilation and many previous studies have not controlled CO 2 tension. We investigated whether hemodynamic effects previously attributed to modified O 2 tension were still apparent under isocapnic conditions. In eight healthy men, we studied blood pressure (BP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI) and arterial stiffness (augmentation index, AI) during 1 h of hyperoxia (mean end-tidal O 2 79.6 Ϯ 2.0%) or hypoxia (pulse oximeter oxygen saturation 82.6 Ϯ 0.3%). Hyperoxia increased SVRI (18.9 Ϯ 1.9%; P Ͻ 0.001) and reduced HR (Ϫ10.3 Ϯ 1.0%; P Ͻ 0.001), CI (Ϫ10.3 Ϯ 1.7%; P Ͻ 0.001), and stroke index (SI) (Ϫ7.3 Ϯ 1.3%; P Ͻ 0.001) but had no effect on AI, whereas hypoxia reduced SVRI (Ϫ15.2 Ϯ 1.2%; P Ͻ 0.001) and AI (Ϫ10.7 Ϯ 1.1%; P Ͻ 0.001) and increased HR (18.2 Ϯ 1.2%; P Ͻ 0.001), CI (20.2 Ϯ 1.8%; P Ͻ 0.001), and pulse pressure (13.2 Ϯ 2.3%; P ϭ 0.02). The effects of hyperoxia on CI and SVRI, but not the other hemodynamic effects, persisted for up to 1 h after restoration of air breathing. Although increased oxidative stress has been proposed as a cause of the cardiovascular response to altered oxygenation, we found no significant changes in venous antioxidant or 8-iso-prostaglandin F 2␣ levels. We conclude that both hyperoxia and hypoxia, when present during isocapnia, cause similar changes in cardiovascular function to those described with poikilocapnic conditions.