Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, Tempol

Mitchell, James B.; DeGraff, William; Kaufman, Dwight; Krishna, Murali C.; Samuni, Amram; Finkelstein, Eli; Ahn, Min Soo; Hahn, Stephen M.; Gamson, Janet; Russo, Angelo

doi:10.1016/0003-9861(91)90442-l

Cited by 208 publications

(162 citation statements)

References 38 publications

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“…As would be expected, the hydroxylamine did not confer any radioprotectivity in vitro [19]. It was hypothesized, however, that following administration Tempol-H would be oxidized in vivo to the active, and radioprotective, form of the compound.…”

Section: Radioprotectionmentioning

confidence: 88%

“…Furthermore, it was found that although Tempol-H exhibited antioxidant effects against H 2 O 2 -induced radicals, it did not confer radiation protection even at a concentration of 100 mM. This suggests that nitroxides more readily react with the radical species produced by radiation than hydroxylamines [19]. To examine if this differential activity is a general phenomenon, three other nitroxide/hydroxylamine pairs were studied.…”

Section: Nitroxides As Modifiers Of Cellular Radiation Responsementioning

confidence: 99%

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The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

459

387

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Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

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Section: Radioprotectionmentioning

confidence: 88%

Section: Nitroxides As Modifiers Of Cellular Radiation Responsementioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

459

387

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“…It catalyzes the conversion of O 2 · Ϫ radicals to hydroperoxides (30,31). Tempol has been used to investigate the role of O 2 · Ϫ radicals in several pathophysiologic conditions, such as ischemia-reperfusion (40,41), radiation (42,43), diabetes mellitus (44), and hypertension (32,45,46). Tempol significantly reduced the effect of sub-pressor dose of AngII on the renal excretion of 8-iso PGF 2␣ .…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model of Angiotensin II Slow Pressor Response

Kawada

Imai

Karber³

et al. 2002

Journal of the American Society of Nephrology

181

183

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Abstract. The slow pressor response to prolonged infusions of angiotensin II (AngII) entails a delayed rise in BP. This study investigated the hypothesis that the response depends on the generation of oxidative stress. The BP and renal functional response of mice to graded doses (200, 400, and 1000 ng · kg Ϫ1 · min Ϫ1 ) of subcutaneously infused AngII was studied. The SBP of conscious mice increased by day 3 at AngII1000 but showed a delayed rise by days 9 to 13 (slow pressor response) at the lower rates of AngII infusion. By day 13, there was a graded increase in SBP with the rate of AngII infusion (Vehicle, Ϫ2.6 Ϯ 2.6%; AngII200, ϩ14.1 Ϯ 5.0%; AngII400, ϩ31.9 Ϯ 1.9%; AngII1000, ϩ43.2 Ϯ 5.5%). The MAP measured under anesthesia rose significantly (P Ͻ 0.001) with AngII400 at 14 d (Vehicle, 85 Ϯ 2 mmHg; AngII400, 100 Ϯ 3 mmHg). When studied at day 6, the MAP of AngII400 rats was not elevated (88 Ϯ 2 mmHg; NS versus vehicle), yet the GFR was higher (1.05 Ϯ 0.05 versus 1.25 Ϯ 0.05 ml · min Ϫ1 · g Ϫ1 ; P Ͻ 0.05) accompanied by an increase in the filtration fraction (FF) (28.8 Ϯ 1.2 versus 37.2 Ϯ 0.8%; P Ͻ 0.001). From day 6 through day 14, the MAP had increased (P Ͻ 0.01) in AngII400, accompanied by a significant reduction in GFR to 1.05 Ϯ 0.04 ml · min Ϫ1 · g Ϫ1 (P Ͻ 0.01) and elevation of renal vascular resistance (RVR) (day 6 versus day 14, 15.3 Ϯ 0.6 versus 19.2 Ϯ 1.2 mmHg · ml Ϫ1 · min Ϫ1 · g Ϫ1 ; P Ͻ 0.05). Renal excretion of 8-iso PGF 2␣ was increased in AngII400 group at day 12 (2.52 Ϯ 0.35 versus 5.85 Ϯ 0.78 pg · day Ϫ1 ; P Ͻ 0.01). The permeant superoxide dismutase mimetic tempol reduced the effects of AngII400 on the SBP (Ϫ1.7 Ϯ 5.8%; P Ͻ 0.01), the MAP (87 Ϯ 4 mmHg; P Ͻ 0.01), and the RVR (15.2 Ϯ 0.5 mmHg · ml Ϫ1 · min Ϫ1 · g Ϫ1 ; P Ͻ 0.05) at day 14 and the renal 8-iso PGF 2␣ excretion (3.53 Ϯ 0.71 pg · d Ϫ1 ; P Ͻ 0.05) at day 12. It is concluded that the AngII infused mouse is a valid model for the slow pressor response. There is an early rise in GFR and FF, consistent with increased postglomerular vascular resistance and a late rise in RVR with a fall in GFR, consistent with increased preglomerular vascular resistance that is accompanied by a rise in BP. There is evidence of increased oxidative stress that is implicated in the increase in the BP and RVR in this model.The angiotensin II (AngII) slow pressor response is a gradually developing increase in BP (BP) with an initially subpressor rate of infusion (1-4). The slow pressor response was first described in rats in 1963, (1) and subsequently has been demonstrated in rabbits, dogs and man (5). Whereas the plasma AngII levels increase by about 80-fold during an immediate pressor response, they are elevated within a physiologic level of 2-to sixfold during a slow pressor response (6). A slow pressor response is seen also with the thromboxane A2/prostaglandin H2 (TP) receptor mimetic, U-46619 (7,8). This slow pressor response has been considered an excellent model for renal hypertension in which both AngII type I (AT1) and TP receptor have been implica...

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“…Clonogenic Assay-Cell survival/proliferation was measured by clonogenic assay with plating efficiency ranging between 85 and 95% as previously described (33). Briefly, stock cultures of each cell type were plated (7 ϫ 10 6 cells/100-cm 2 dish) and incubated for 24 h prior to treatment.…”

Section: Methodsmentioning

confidence: 99%

Superoxide Fluxes Limit Nitric Oxide-induced Signaling

Thomas

Ridnour

Espey

et al. 2006

Journal of Biological Chemistry

Self Cite

105

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Independently, superoxide (O 2 ؊) and nitric oxide (NO) are biologically important signaling molecules. When co-generated, these radicals react rapidly to form powerful oxidizing and nitrating intermediates. Although this reaction was once thought to be solely cytotoxic, herein we demonstrate using MCF7, macrophage, and endothelial cells that when nanomolar levels of NO and O 2 ؊ were produced concomitantly, the effective NO concentration was established by the relative fluxes of these two radicals. Differential regulation of sGC, pERK, HIF-1␣, and p53 were used as biological dosimeters for NO concentration. Introduction of intracellular-or extracellular-generated O 2 ؊ during NO generation resulted in a concomitant increase in oxidative intermediates with a decrease in steady-state NO concentrations and a proportional reduction in the levels of sGC, ERK, HIF-1␣, and p53 regulation. NO responses were restored by addition of SOD. The intermediates formed from the reactions of NO with O 2 ؊ were non-toxic, did not form 3-nitrotyrosine, nor did they elicit any signal transduction responses. H 2 O 2 in bolus or generated from the dismutation of O 2 ؊ by SOD, was cytotoxic at high concentrations and activated p53 independent of NO. This effect was completely inhibited by catalase, suppressed by NO, and exacerbated by intracellular catalase inhibition. We conclude that the reaction of O 2 ؊ with NO is an important regulatory mechanism, which modulates signaling pathways by limiting steady-state levels of NO and preventing H 2 O 2 formation from O 2 ؊ .

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Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, Tempol

Cited by 208 publications

References 38 publications

The chemistry and biology of nitroxide compounds

The chemistry and biology of nitroxide compounds

A Mouse Model of Angiotensin II Slow Pressor Response

Superoxide Fluxes Limit Nitric Oxide-induced Signaling

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