ferric-oxide--saccharated and 3-nitrotyrosine

Intravenous iron is commonly used in conjunction with erythropoietic agents to treat anemia in patients with chronic kidney disease. Iron has been proposed to promote oxidative stress and endothelial dysfunction in vascular tissues. We studied the acute effects of intravenous iron sucrose on homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. In all, 40 healthy subjects received intravenous iron sucrose 100 mg or placebo over 30 min immediately before ingestion of 100 mg/kg of oral methionine in a double-blind, randomized study. Flow- and nitroglycerin-mediated dilation in the brachial artery, serum markers of iron stores, and homocysteine and nitrotyrosine levels were measured before and after study drug administration. Intravenous iron significantly increased transferrin saturation and non-transferrin-bound iron (NTBI) when compared with placebo. Flow-mediated dilation significantly decreased from baseline 1 h after administration of iron sucrose when compared with placebo (from 6.66+/-0.47 to 1.93+/-0.35% after iron sucrose vs from 6.00+/-0.40 to 5.61+/-0.46% after placebo, P<0.001), but did not differ between groups at 4 h (1.10+/-0.39 vs 1.33+/-0.51%). Nitroglycerin-mediated vasodilation, and homocysteine and 3-nitrotyrosine levels did not differ after administration of iron sucrose and placebo. Intravenous administration of iron sucrose in the setting of transient hyperhomocysteinemia induced by methionine ingestion significantly increased transferrin saturation and plasma levels of NTBI and significantly attenuated flow-mediated dilation in the brachial artery when compared with placebo. This potential mechanistic link between intravenous iron and endothelial dysfunction warrants further study of cardiovascular effects of intravenous iron in anemic chronic kidney disease populations.

Topics: Adult; Anemia, Iron-Deficiency; Brachial Artery; Cardiovascular Diseases; Chelating Agents; Double-Blind Method; Endothelium, Vascular; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Homocysteine; Humans; Iron; Male; Methionine; Nitroglycerin; Oxidative Stress; Razoxane; Regional Blood Flow; Risk Factors; Transferrin; Tyrosine; Vasodilation

According to recent clinical trial data, correction of iron deficiency with intravenous (i.v.) iron has favorable outcomes on cardiac function. We evaluated whether i.v. iron treatment of anemic rats has favorable effect on the left ventricular (LV) performance and remodeling and the role of oxidative/nitrosative stress and inflammation in the process.. After weaning, Sprague-Dawley rats were fed low iron diet for 16weeks, after which the treatment group received five weekly doses of i.v. iron sucrose (10mg Fe/kg body weight). Echocardiography of LV was performed and hematology parameters were assessed before treatment (baseline, day 0) and at the end of the study (day 29). On day 29, rats were sacrificed and extracellular expansion and fibrosis in LV and interventricular septum were evaluated together with oxidative/nitrosative stress, pro-inflammatory, and repair process markers.. Although iron sucrose treatment did not fully correct the anemia, it reversed anemia-induced cardiac remodeling as indicated by echocardiographic and tissue Doppler parameters. Treatment with iron sucrose also prevented anemia-induced myocardial fibrosis as indicated by extracellular expansion and fibrosis markers. Anemia-induced inflammation was prevented by iron sucrose as indicated by the levels of proinflammatory (TNF-α, NF-κB65) and repair process markers (HSP27, HSP70). In addition, iron sucrose treatment significantly reduced (p<0.01) anemia-induced oxidative and nitrosative stress.. Intravenous iron sucrose treatment reversed anemia-induced remodeling of LV, prevented myocardial fibrosis, and improved cardiac function by attenuating oxidative/nitrosative stress and inflammation in the heart.

Topics: Anemia; Animals; Cardiotonic Agents; Ferric Compounds; Ferric Oxide, Saccharated; Fibrosis; Glucaric Acid; Inflammation; Infusions, Intravenous; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tyrosine; Ventricular Remodeling

Iron is involved in the formation as well as in the scavenging of reactive oxygen and nitrogen species. Thus, iron can induce as well as inhibit both oxidative and nitrosative stress. It also has a key role in reactive oxygen and nitrogen species-mediated apoptosis. We assessed the differences in tyrosine nitration and caspase 3 expression in the liver, heart, and kidneys of rats treated weekly with intravenous ferumoxytol, iron isomaltoside 1000, iron dextran, iron sucrose and ferric carboxymaltose (40 mg iron/kg body weight) for 5 weeks. Nitrotyrosine was quantified in tissue homogenates by Western blotting and the distribution of nitrotyrosine and caspase 3 was assessed in tissue sections by immunohistochemistry. Ferric carboxymaltose and iron sucrose administration did not result in detectable levels of nitrotyrosine or significant levels of caspase 3 vs. control in any of the tissue studied. Nitrotyrosine and caspase 3 levels were significantly (p<0.01) increased in all assessed organs of animals treated with iron dextran and iron isomaltoside 1000, as well as in the liver and kidneys of ferumoxytol-treated animals compared to isotonic saline solution (control). Nitrotyrosine and caspase 3 levels were shown to correlate positively with the amount of Prussian blue-detectable iron(III) deposits in iron dextran- and iron isomaltoside 1000-treated rats but not in ferumoxytol-treated rats, suggesting that iron dextran, iron isomaltoside 1000 and ferumoxytol induce nitrosative (and oxidative) stress as well as apoptosis via different mechanism(s).

Topics: Administration, Intravenous; Animals; Apoptosis; Caspase 3; Disaccharides; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Iron-Dextran Complex; Kidney; Liver; Male; Maltose; Models, Animal; Myocardium; Rats; Tyrosine

The objective of this study was to compare the oxidative stress induced in rat internal organs by the administration of the following clinically used intravenous (IV) iron (Fe) containing compounds: iron sucrose (IS), iron dextran (ID), ferric carboxymaltose and ferumoxytol. Groups of six adult rats received 1 mg/kg of each compound weekly for 5 doses. Seven days following the last dose, animals were euthanized and tissue samples of heart, lung, liver, and kidney were obtained, washed in warmed saline and frozen under liquid nitrogen and stored at -80 °C for analysis for nitrotyrosine (NT) and dinitro phenyl (DNP) as markers of oxidative stress. All tissues showed a similar pattern of oxidative stress. All Fe products stimulated an increase in the tissue concentration of both NT and DNP. In general, DNP was stimulated significantly less than NT except for IS. DNP was stimulated to an equal degree except for ID where NT was significantly higher than the NT concentrations in all other Fe compounds. ID produced over 10-fold the concentration of NT than any other Fe. IV Fe compounds present a risk of oxidative stress to a variety of internal organs. However, we found that IS was the least damaging and ID was the worst.

Topics: Administration, Intravenous; Animals; Dinitrobenzenes; Dose-Response Relationship, Drug; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Iron-Dextran Complex; Maltose; Oxidative Stress; Rats; Tissue Distribution; Tyrosine