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PubMed1984

Acute effects of iron on contractile function in isolated rabbit myocardium.

Changes in contractile function following exposure to iron (Fe) salts were evaluated in isolated isometrically contracting rabbit left atrial strips and right ventricular papillary muscles. Fe acutely depressed myocardial contractility as evidenced by dose-related declines in developed force and maximal rate of force development. There were no significant changes in duration of contraction or resting force. The tissue Fe content was increased nearly 3-fold after a 60 min exposure to Fe and subsequently was not decreased by repeated washing or by treatment with deferoxamine. Isoproterenol, but not deferoxamine, reversed the Fe-mediated impairment of myocardial contractility. These findings suggest that in cases of severe acute iron poisoning, depression of cardiac contractility might occur which may be improved by treatment with isoproterenol.

Animals↗

PubMed1995

Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein(a). Role of oxygen-derived radicals.

BACKGROUND: Hyperlipoproteinemia is associated with impairment of nitric oxide (NO)-mediated, endothelium-dependent dilation in renal arteries. In the present study, we assessed and compared the effects of human lipoprotein(a) and LDL on endothelium-dependent and -independent dilation in vitro. METHODS AND RESULTS: Dilator responses were detected in isolated, saline-perfused, preconstricted arterial segments by a photoelectric device. Acetylcholine-induced, endothelium-dependent dilator responses of rabbit renal arteries were not significantly attenuated after 150 minutes of incubation with native lipoprotein(a) (30 and 100 micrograms/mL). However, exposure to in vitro oxidized lipoprotein(a) (150 minutes, 30 and 100 micrograms/mL) suppressed acetylcholine-induced dilator responses in a dose-dependent manner. At similar concentrations, native and oxidized LDL had no effect. Endothelium-independent dilations induced by the NO-donor sodium nitroprusside were also impaired by oxidized lipoprotein(a), whereas forskolin-induced dilator responses were unaffected, indicating that smooth muscle dilator capacity was not impaired. Attenuation of dilator responses by oxidized lipoprotein(a) was potentiated in the presence of superoxide dismutase (SOD). The SOD effect was completely blunted by coincubation with catalase (100 U/mL) or deferoxamine. In the absence of SOD, catalase or deferoxamine had no effect on dilator responses. Using a chemiluminescence assay, we could detect increased O2- production by arteries pretreated with oxidized lipoprotein(a), which suggested that enhanced NO inactivation by O2- could be the underlying mechanism for impairment of endothelium-dependent dilations. CONCLUSIONS: These data indicate that oxidized lipoprotein(a) impairs endothelium-dependent dilation and is more potent than oxidized LDL in this effect. The mechanism of the impairment may involve formation of O2- and inactivation of NO.

Animals↗

PubMed1992

Hydrogen peroxide-induced cardiovascular reflexes. Role of hydroxyl radicals.

Mesenteric ischemia reflexly activates the cardiovascular system. In addition, mesenteric ischemia and reperfusion generate reactive oxygen species. However, the ability of these short-lived reactive oxygen species to generate cardiovascular reflexes is unknown. We therefore investigated cardiovascular reflexes induced by serosal application of hydrogen peroxide (H2O2) to the gallbladder, stomach, or duodenum in anesthetized cats. Serosal application of hydrogen peroxide (44 mumols) to the gallbladder (n = 14) significantly (p less than 0.05) increased mean arterial blood pressure (MAP) by 37 +/- 6 mm Hg, left ventricular dP/dt by 1,893 +/- 416 mm Hg/sec, heart rate by 6 +/- 1 beats per minute, and systemic vascular resistance from 0.34 +/- 0.01 to 0.42 +/- 0.04 peripheral resistance units. The cardiovascular effects were dose-dependent over a range of 0.4 pmol to 132 mumols H2O2. Celiac and superior mesenteric ganglionectomy abolished H2O2-induced cardiovascular effects. Dimethylthiourea (10 mg/kg), a reactive oxygen species scavenger, significantly (p less than 0.05) attenuated 44 mumols H2O2-induced increases in MAP from 36 +/- 3 to 2 +/- 2 mm Hg. Deferoxamine (10 mg/kg) also significantly attenuated 44 mumols H2O2-induced increases in MAP from 40 +/- 7 to 19 +/- 10 mm Hg, but iron-loaded deferoxamine did not. Aspirin (50 mg/kg) did not attenuate H2O2-induced excitation of the cardiovascular system. These data suggest that H2O2 activates abdominal visceral afferents to reflexly stimulate the cardiovascular system by a mechanism involving hydroxyl radicals. Thus, reactive oxygen species could modulate systemic vascular tone by stimulating abdominal visceral afferents during mesenteric ischemia and reperfusion.

Animals↗

PubMed2001

Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase.

BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect. METHODS AND RESULTS: Short-term treatment with the antioxidants vitamin C (10 micromol/L) or deferoxamine (500 micromol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dt(min)) by -6.8+/-1.7 ms in the presence of vitamin C and by -8.9+/-2.2 ms in the presence of deferoxamine compared with -0.8+/-2.2 ms in the absence of antioxidants (P<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 micromol/L), but not with tetrahydrobiopterin or L-arginine. Protein expression of the NADPH oxidase subunits gp91-phox and p67-phox and myocardial NADPH oxidase activity were significantly increased (P<0.05) in the banded group compared with shams. CONCLUSIONS: An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.

Animals↗

PubMed1988

Asbestos-induced endothelial cell activation and injury. Demonstration of fiber phagocytosis and oxidant-dependent toxicity.

Vascular endothelial cell injury is important in the development of a variety of chronic interstitial lung disorders. However, the involvement of such injury in the inflammatory response associated with the inhalation of asbestos fibers is unclear and the mechanism of asbestos fiber cytotoxicity remains unknown. In the present study, human umbilical vein endothelial cells were challenged with amosite asbestos and several parameters of cellular function were examined. Electron microscopic examination revealed that endothelial cell exposure to asbestos resulted in active phagocytosis of these particulates. Biochemical evidence of dose-dependent asbestos-mediated endothelial cell activation was indicated by increased metabolism of arachidonic acid. For example, amosite asbestos (500 micrograms/ml) produced a ninefold increase in prostacyclin (PGI2) levels over those levels in non-exposed cells. Incubation of human endothelial cells with asbestos fibers induced specific 51Cr release in both a dose- and time-dependent fashion indicative of cellular injury. Injury induced by amosite asbestos was not significantly attenuated by treatment of the endothelial cell monolayer with either the iron chelator deferoxamine, which prevents hydroxyl radical (.OH) formation, or by the superoxide anion (O2-) scavenger, superoxide dismutase. However, significant dose-dependent protection was observed with the hydrogen peroxide (H2O2) scavenger, catalase. Chelation of elemental iron present within amosite asbestos fibers by deferoxamine produced a 33% reduction in asbestos cytotoxicity, suggesting a potential role for hydroxyl radical-mediated injury via the iron-catalyzed Haber-Weiss reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1983

Evidence for role of hydroxyl radical in complement and neutrophil-dependent tissue injury.

Using our recently described model of acute lung injury in rats after systemic activation of complement by cobra venom factor (CVF), we demonstrated that pretreatment of animals with human milk apolactoferrin (in its native or derivatized form), but not iron-saturated lactoferrin, provides significant protection against complement- and neutrophil-mediated lung injury. The synthetic iron chelator deferoxamine mesylate also affords protection from lung injury. The protective effects of apolactoferrin are not related to a blocking of CVF-induced complement activation. We also demonstrated that infusion of ionic iron, especially Fe3+, greatly potentiates lung vascular injury after systemic complement activation. Finally, protection from lung injury occurs in animals pretreated with the potent scavenger of hydroxyl radicals (OH.), dimethyl sulfoxide. Based on transmission electron microscopy, CVF-treated rats show leukoaggregates and endothelial cell destruction in interstitial pulmonary capillaries, along with intraalveolar hemorrhage and fibrin deposition. In animals protected with apolactoferrin, deferoxamine mesylate, or dimethyl sulfoxide, the morphological studies reveal leukoaggregates but no endothelial cell damage, hemorrhage, or fibrin deposition. These data support the concept that tissue injury that is complement and neutrophil dependent may be related to generation of OH. derived from H2O2 after leukocytic activation.

Acute Disease↗

PubMed1994

Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis.

We investigated the role of intracellular iron on the capacity of Histoplasma capsulatum (Hc) yeasts to multiply within human macrophages (Mphi). Coculture of Hc-infected Mphi with the iron chelator deferoxamine suppressed the growth of yeasts in a concentration-dependent manner. The effect of deferoxamine was reversed by iron-saturated transferrin (holotransferrin) but not by iron-free transferrin (apotransferrin). Chloroquine, which prevents release of iron from transferrin by raising endocytic and lysosomal pH, induced human Mphi to kill Hc. The effect of chloroquine was reversed by iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH, but not by holotransferrin, which releases iron only in an acidic environment. Chloroquine (40-120 mg/kg) given intraperitoneally for 6 d to Hc-infected C57BL/6 mice significantly reduced the growth of Hc in a dose-dependent manner. At 120 mg/kg there was a 17- and 15-fold reduction (P < 0.01) in CFU in spleens and livers, respectively. The therapeutic effect of chloroquine also correlated with the length of treatment. As little as 2 d of chloroquine therapy (120 mg/kg), when started at day 5 after infection, reduced CFU in the spleen by 50%. Treatment with chloroquine for 10 d after a lethal inoculum of Hc protected six of nine mice; all control mice were dead by day 11 (P = 0.009). This study demonstrates that: (a) iron is of critical importance to the survival and multiplication of Hc yeasts in human Mphi; (b) in vitro, chloroquine induces Mphi killing of Hc yeasts by restricting the availability of intracellular iron; and (c) in vivo, chloroquine significantly reduces the number of organisms in the spleens and livers of Hc-infected mice and can protect mice from a lethal inoculum of Hc yeasts. Thus, chloroquine may be effective in the treatment of active histoplasmosis and also may be useful in preventing relapse of histoplasmosis in patients with acquired immunodeficiency syndromes.

Animals↗

PubMed1995

Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents.

Oxygen free radical activity is elevated in diabetes mellitus and has been implicated in the etiology of vascular complications. Recent studies have shown that impaired perfusion of nerve endoneurium is a major cause of nerve fiber dysfunction in experimental diabetes. Free radical scavenger treatment prevents the development of nerve conduction abnormalities in diabetic rats. In vitro experiments suggest that autoxidation reactions of glucose, catalyzed by free transition metal ions, are a potential source of free radicals in diabetes. We investigated whether chronic treatment with deferoxamine and trientine, transition metal chelating agents which can prevent autoxidation, could correct nerve conduction and blood flow changes in streptozotocin-diabetic rats. A 20% reduction in sciatic nerve motor conduction velocity after 2 mo diabetes was 90% ameliorated by 2 wk of treatment with deferoxamine or trientine. Sciatic endoneurial nutritive blood flow was 45% reduced by diabetes, but was completely corrected by treatment. In contrast, transition metal chelation had no effect on blood flow or conduction velocity in nondiabetic rats. Thus, the data support the hypothesis that increased free radical activity by glucose autoxidation as a result of impaired transition metal handling is a major cause of early neurovascular deficits in diabetes.

Animals↗

PubMed1992

Effect of pentoxifylline on treatment of lower limb ulcers in patients with thalassemia major.

The possible healing effect of deferoxamine and pentoxifylline on persisting lower limb ulcers was studied in 51 patients with thalassemia major. The results indicated that the regular use of deferoxamine at an intravenous dose of 20 mg/kg did not affect the healing progress and the recurrence rate of these ulcers significantly. On the contrary, the oral administration of pentoxifylline at a dose of 1,200 mg daily during the ulcer's healing time and at a low long-term maintenance dose of 400 mg daily during the ulcer-free intervals improved their healing ability impressively and diminished their recurrence rate significantly.

Adult↗

PubMed1997

Application of oxygen free radical scavengers to diminish the occurrence of myringosclerosis.

The present study was designed to establish whether or not an increased production of oxygen-derived free radicals is involved in the causation of myringosclerosis. Sclerotic lesions in the tympanic membrane were experimentally elicited by keeping rats with perforated tympanic membranes in an atmosphere containing roughly 40% oxygen. The animals were treated daily with a solution containing either copper zinc-superoxide dismutase plus catalase, deferoxamine, or copper sulfate plus iron chloride, applied to the traumatized area. After 1 week the extension of myringosclerotic plaques was determined otomicroscopically. The pars tensa and pars flaccida were then dissected free and prepared for light microscopic studies. The results showed that treatment with copper zinc-superoxide dismutase plus catalase and deferoxamine inhibited or reduced the development of myringosclerosis, whereas the ears treated with copper sulfate plus iron chloride appeared unaffected. Consequently, the findings support the hypothesis that the formation of oxygen free radicals contributes significantly to the development of myringosclerosis.

Animals↗

PubMed2006

New advances in iron chelation therapy.

The emergence of new chelators is likely to have a major impact on the treatment of thalassemia major, sickle cell disease and other hematologic disorders for which regular red cell transfusions are required either to correct severe anemia or to prevent major complications of the underlying disease. In comparison with deferoxamine, which requires prolonged parenteral infusion to achieve negative iron balance, orally active chelators offer the promise of easier administration and better compliance. Moreover, the availability of more than one iron chelator opens up the possibility of combination therapy to target iron in specific organs and to enhance overall iron excretion. Long-term studies, employing new technologies to measure tissue iron, are required to determine whether the new chelators will be as safe and effective as deferoxamine in maintaining control of iron stores and preventing iron-induced cardiac disease, the major complication of transfusional iron overload.

Administration, Oral↗

PubMed2005

A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia.

Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.

Administration, Oral↗

PubMed2005

T2* magnetic resonance and myocardial iron in thalassemia.

Magnetic resonance T2* values of the myocardium are directly related to tissue iron levels. Minor effects from myocardial oxygenation and fibrosis are overwhelmed by the highly dominant iron effect in clinically relevant levels of myocardial iron overload. Myocardial T2* values less than 20 ms indicate iron overload, and this is considered severe when T2* is less than 10 ms. Decreasing myocardial T2* levels are associated with systolic and diastolic ventricular dysfunction. Most recorded cases of heart failure in thalassemia to date have occurred in patients with very low T2* values (in the severe range). Exceptions to this have occurred in patients with other causes of heart failure such as concomitant congenital heart disease. In patients presenting with heart failure who undergo aggressive chelation with continuous intravenous deferoxamine, longitudinal studies show that myocardial T2* increases, and this is accompanied by increases in ejection fraction and relief of heart failure. In cross-sectional studies, the myocardial T2* and ejection fraction of patients on deferiprone was superior to that of patients on deferoxamine. Randomized controlled prospective trials comparing these two drugs for their action in clearing myocardial iron, as measured by myocardial T2*, are under way and should report in 2005/2006. These trials will clarify the role of different chelators in the management of myocardial iron overload and may be valuable in reducing the toll of death in thalassemia from heart failure.

Adult↗

PubMed1993

Adriamycin-induced lipid peroxidation of erythrocyte membranes in the presence of ferritin and the inhibitory effect of ceruloplasmin.

When erythrocyte membranes were incubated with adriamycin (ADM) in the presence of ferritin, lipid peroxidation occurred with release of iron from the ferritin. In the presence of apoferritin, ADM did not cause lipid peroxidation. Deferoxamine inhibited the ADM-induced lipid peroxidation in the presence of ferritin. These results indicate that lipid peroxidation depends upon the release of iron from ferritin. Even when the iron content in ferritin was very low, ADM could induce lipid peroxidation. Superoxide dismutase, catalase and hydroxyl radical scavengers did not substantially affect lipid peroxidation, indicating that the peroxidation reaction was independent of superoxide, H2O2 and hydroxyl radicals. Ceruloplasmin, a ferroxidase, markedly inhibited lipid peroxidation but did not affect the release of iron from ferritin. ADM-Fe(3+)-binding erythrocyte membranes were readily formed during the incubation of erythrocyte membranes with ADM in the presence of ferritin, and deferoxamine removed iron from the ADM-Fe(3+)-binding membranes, indicating that the iron moiety of the ADM-Fe(3+) complex is exposed at the membrane surface. These results may suggest that the peroxidation reaction occurs in a site-specific manner.

Animals↗

PubMed1994

Activation of microsomal glutathione S-transferase in tert-butyl hydroperoxide-induced oxidative stress of isolated rat liver.

The activation of microsomal glutathione S-transferase in oxidative stress was investigated by perfusing isolated rat liver with 1 mM tert-butyl hydroperoxide (t-BuOOH). When the isolated liver was perfused with t-BuOOH for 7 min and 10 min, microsomal, but not cytosolic, glutathione S-transferase activity was increased 1.3-fold and 1.7-fold, respectively, with a concomitant decrease in glutathione content. A dimer protein of microsomal glutathione S-transferase was also detected in the t-BuOOH-perfused liver. The increased microsomal glutathione S-transferase activity after perfusion with t-BuOOH was reversed by dithiothreitol, and the dimer protein of the transferase was also abolished. When the rats were pretreated with the antioxidant alpha-tocopherol or the iron chelator deferoxamine, the increases in microsomal glutathione S-transferase activity and lipid peroxidation caused by t-BuOOH perfusion of the isolated liver was prevented. Furthermore, the activation of microsomal GSH S-transferase by t-BuOOH in vitro was also inhibited by incubation of microsomes with alpha-tocopherol or deferoxamine. Thus it was confirmed that liver microsomal glutathione S-transferase is activated in the oxidative stress caused by t-BuOOH via thiol oxidation of the enzyme.

Animals↗

PubMed1994

Comparison of the toxic effects of hydrogen peroxide and ozone on cultured human bronchial epithelial cells.

In this study, we compared the cytotoxic and genotoxic effects of hydrogen peroxide and ozone on cultured human airway epithelial cells in primary culture. Both agents caused a dose-dependent loss in the replicative ability of epithelial cells and at higher levels of exposure caused acute cytotoxicity as measured by release of lactate dehydrogenase. Differences were seen, however, between the agents' effects with regard to induction of DNA single strand breaks as measured by alkaline elution:; whereas single-strand breaks were detected in significant amounts at concentration of hydrogen peroxide that cause acute cytotoxicity, none were detected at any of the levels of ozone exposure examined. A difference was also seen in the ability of the iron chelator deferoxamine to protect cells from the effect of the two oxidants. Preincubation of cultures with deferoxamine appreciably attenuated the toxicity of hydrogen peroxide but not of ozone. These data suggest that ozone has significant toxic effects on bronchial epithelial cells not mediated through the generation of hydrogen peroxide or hydroxyl radical. Furthermore, the data indicate that the inhibiting action of ozone on cell replicative ability is not mediated through a mechanism related to DNA single strand breaks.

Bronchi↗

PubMed2005

Role of iron-ATP complex in lymphocyte proliferation and infiltration.

The roles of sodium-ATP (NaATP) and ferric-ATP complex (FeATP) on the proliferation and infiltration of lymphocytes have been studied by evaluation of the hypertrophy and histopathologic examination of spleen and liver, as well of the modifications in the elemental balance of iron, calcium, magnesium, and phosphorus. The results showed that in the implicated biochemical processes, calcium and magnesium have a principal role. An in vitro study on a cell model has permited one to evaluate the effects of deferoxamine, a known iron chelator and inhibitor of human lymphocyte proliferation, on FeATP-modified cellular calcium fluxes. These findings showing a reduced 45Ca2+ uptake in the presence of deferoxamine appear to indicate that in vivo the chelation of blood-borne iron by ATP might play a key role in proliferation and infiltration of lymphocytes, leading to lymphoma development.

Adenosine Triphosphate↗

PubMed2005

Baroreflex function in conscious rats submitted to iron overload.

Our hypothesis is that iron accumulated in tissue, rather than in serum, may compromise cardiovascular control. Male Fischer 344 rats weighing 180 to 220 g were divided into 2 groups. In the serum iron overload group (SIO, N = 12), 20 mg elemental iron was injected ip daily for 7 days. In the tissue iron overload group (TIO, N = 19), a smaller amount of elemental iron was injected (10 mg, daily) for 5 days followed by a resting period of 7 days. Reflex heart rate responses were elicited by iv injections of either phenylephrine (0.5 to 5.0 microg/kg) or sodium nitroprusside (1.0 to 10.0 microg/kg). Baroreflex curves were determined and fitted to sigmoidal equations and the baroreflex gain coefficient was evaluated. To evaluate the role of other than a direct effect of iron on tissue, acute treatment with the iron chelator deferoxamine (20 mg/kg, iv) was performed on the TIO group and the baroreflex was re-evaluated. At the end of the experiments, evaluation of iron levels in serum confirmed a pronounced overload for the SIO group (30-fold), in contrast to the TIO group (2-fold). Tissue levels of iron, however, were higher in the TIO group. The SIO protocol did not produce significant alterations in the baroreflex curve response, while the TIO protocol produced a nearly 2-fold increase in baroreflex gain (-4.34 +/- 0.74 and -7.93 +/- 1.08 bpm/mmHg, respectively). The TIO protocol animals treated with deferoxamine returned to sham levels of baroreflex gain (-3.7 +/- 0.3 sham vs -3.6 +/- 0.2 bpm/mmHg) 30 min after the injection. Our results indicate an effect of tissue iron overload on the enhancement of baroreflex sensitivity.

Animals↗