1-3-dimethylthiourea and Disease-Models--Animal

Reactive oxygen metabolites (ROMs) are thought to play a key role in the pathogenesis of the adult respiratory distress syndrome (ARDS). Accordingly, the use of ROM scavengers, such as N-acetyl-cysteine or dimethylthiourea, as therapeutic adjuncts to prevent oxidant-mediated damage to the lung have been evaluated extensively in animal models of ARDS. Results with this approach have been quite variable among studies. Another strategy that has been examined in animal models of ARDS is the administration of various enzymes, particularly superoxide dismutase (SOD) or catalase (CAT), in an effort to promote the conversion of ROMs to inactive metabolites. In theory, this strategy should be more effective than the use of ROM scavengers since a single molecule of a catalytically active molecule can neutralize a large number of molecules of a reactive species, whereas most scavengers act in a stoichiometric fashion to neutralize radicals on a mole-for-mole basis. This notion is supported by studies showing that prophylactic treatment with CAT provides impressive protection against acute lung injury induced in experimental animals by the administration of lipopolysaccharide (LPS). Results with SOD have been more variable. Recently, we have utilized a porcine model of LPS-induced ARDS to investigate the therapeutic potential of EUK-8, a novel, synthetic, low molecular salen-manganese complex that exhibits both SOD-like and CAT-like activities in vitro. Using both pre- and post-treatment designs, we have documented that treatment with EUK-8 significantly attenuates many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance, and pulmonary edema. These findings support the view that salen-manganese complexes warrant further evaluation as therapeutic agents for treatment or prevention of sepsis-related ARDS in humans.

Topics: Acetylcysteine; Adult; Animals; Catalase; Disease Models, Animal; Endotoxins; Ethylenediamines; Free Radical Scavengers; Humans; Lipopolysaccharides; Lung; Lung Injury; Organometallic Compounds; Oxidative Stress; Reactive Oxygen Species; Respiratory Distress Syndrome; Superoxide Dismutase; Swine; Thiourea

Neuroinflammation and oxidative stress are hallmarks of neurodegenerative diseases. Microglia, the major important regulators of neuroinflammation, are activated in response to excessive generation of reactive oxygen species (ROS) from damaged cells and resulting in elevated and sustained damages. However, the relationship between microglia and ROS-regulatory system in the early stages of neuroinflammation prior to the appearance of neuronal damages have not been elucidated in detail. In this study, we analyzed the time-dependent changes in ROS generation during acute neuroinflammation in rats that were given an intrastriatal injection of lipopolysaccharide (LPS). We evaluated the effects of minocycline, an anti-inflammatory antibiotic, and N,N'-dimethylthiourea (DMTU), a radical scavenger, to understand the correlation between activated microglia and ROS generation. Ex vivo fluorescence imaging using dihydroethidium (DHE) clearly demonstrated an increased ROS level in the infused side of striatum in the rats treated with LPS. The level of ROS was changed in time-dependent manner, and the highest level of ROS was observed on day 3 after the infusion of LPS. Immunohistochemical studies revealed that time-dependent changes in ROS generation were well correlated to the presence of activated microglia. The inhibition of microglial activation by minocycline remarkably reduced ROS levels in the LPS-injected striatum, which indicated that the increased ROS generation caused by LPS was induced by activated microglia. DMTU decreased ROS generation and resulted in remarkable inhibitory effect on microglial activation. This study demonstrated that ROS generation during acute neuroinflammation induced by LPS was considerably associated with microglial activation, in an intact rat brain. The results provides a basis for understanding the interaction of ROS-regulatory system and activated microglia during neuroinflammation underlying neurodegenerative diseases.

Topics: Acute Disease; Animals; Brain; Disease Models, Animal; Ethidium; Fluorescent Dyes; Free Radical Scavengers; Lipopolysaccharides; Male; Microglia; Minocycline; Neuroinflammatory Diseases; Optical Imaging; Rats, Wistar; Reactive Oxygen Species; Thiourea

Reactive oxygen species (ROS) are the essential mechanism involving in the ischemic process. Due to their complex characteristics, the precise effects of ROS on post-ischemic neurons remain uncertain. This study aimed to investigate the potential role of ROS in brain ischemia.. Dynamic ROS levels in the perifocal cortex were evaluated after right middle cerebral artery occlusion (MCAO) of SD rats. Furthermore the role of ROS was assessed following delayed treatment with the ROS scavenger dimethylthiourea (DMTU) after brain ischemia.. ROS levels markedly increased at 1 hr after reperfusion and then gradually decreased as the post-reperfusion time interval increased. ROS levels reached their lowest point at 3 days after reperfusion before increasing and showing a second peak at 7 days after reperfusion. ROS levels negatively correlated with neurological function scores. Delayed DMTU treatment after stroke worsened neurological outcomes, decreased microvessel density and inhibited stress-activated protein kinase activation.. ROS may play a biphasic role in cerebral ischemia. Namely, ROS may induce damage during the injury phase of brain ischemia and participate in improving neurological function during the recovery phase.

Topics: Animals; Brain; Brain Ischemia; Disease Models, Animal; Free Radical Scavengers; Humans; Infarction, Middle Cerebral Artery; Male; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Recovery of Function; Thiourea; Time Factors

Spinal synaptic plasticity is believed to drive central sensitization that underlies the persistent nature of neuropathic pain. Our recent data showed that synaptic plasticity in the dorsal horn is cell type specific: intense afferent stimulation produced long-term potentiation (LTP) in excitatory spinothalamic tract neurons (STTn), whereas it produced long-term depression (LTD) in inhibitory GABAergic interneurons (GABAn). In addition, reactive oxygen species (ROS) were shown to be involved in LTP in STTn (STTn-LTP) and in LTD in GABAn (GABAn-LTD). This study examined the roles of 2 biologically important ROS--superoxide [·O2] and hydroxyl radicals [·OH]--in neuropathic mechanical hyperalgesia and cell type-specific spinal synaptic plasticity. The [·O2] donor induced stronger mechanical hyperalgesia than the [·OH] donor in naive mice. The [·O2] scavenger showed greater antihyperalgesic effect than [·OH] scavengers in the spinal nerve ligation (SNL) mouse model of neuropathic pain. In addition, the [·O2] donor induced both STTn-LTP and GABAn-LTD, but the [·OH] donor induced only GABAn-LTD. On the other hand, the [·O2] scavenger inhibited STTn-LTP and GABAn-LTD induction in naive mice and alleviated SNL-induced potentiation in STTn and depression in GABAn. The [·OH] scavenger, however, inhibited depression in GABAn but did not interfere with potentiation in STTn. These results indicate that mechanical hyperalgesia in SNL mice is the result of the combination of STTn-LTP and GABAn-LTD. Behavioral outcomes compliment electrophysiological results which suggest that [·O2] mediates both STTn-LTP and GABAn-LTD, whereas [·OH] is involved primarily in GABAn-LTD.

Topics: Afferent Pathways; Animals; Cyclic N-Oxides; Disease Models, Animal; Free Radical Scavengers; GABA Agents; GABAergic Neurons; Glutamate Decarboxylase; Hydroxyl Radical; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuralgia; Neuronal Plasticity; Reactive Oxygen Species; Spin Labels; Spinal Nerves; Superoxides; Synaptic Potentials; Thiourea

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics ('urearetics') with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10-20 μM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2-3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 h, and a urine concentration of 20-40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of syndrome of inappropriate antidiuretic hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.

Topics: Animals; Binding Sites; Disease Models, Animal; Diuresis; Diuretics; Dogs; Drug Evaluation, Preclinical; Female; Furosemide; Hypokalemia; Hyponatremia; Inappropriate ADH Syndrome; Inhibitory Concentration 50; Madin Darby Canine Kidney Cells; Membrane Transport Proteins; Molecular Structure; Osmolar Concentration; Rats; Rats, Wistar; Sodium Chloride; Thiourea; Time Factors; Urea Transporters; Urine

The aims of the present study were to elucidate whether oxidative stress has a role in Con A-induced hepatitis and to examine if antioxidants may protect against liver damage in this model.. Hepatitis was induced in Balb/c mice by administration of Con A (18 mg/kg) to the tail vein. Liver enzymes and histology were determined 24 h after Con A injection. Tumor necrosis factor alpha (TNFalpha) and interleukin-10 (IL-10) levels were assayed 2 h after Con A injection. Hepatic malondialdehyde levels were measured at 1, 3, 8, 12, 18, and 24 h after Con A injection in order to examine the timing of free-radicals formation. Nuclear factor kappa B (NF-kappabeta) activation was determined by electrophoresis mobility shift assay (EMSA) 1 and 2 h after Con A injection. In separate experiments, mice were pretreated with either dimethylsulfoxide or dimethylthiourea before Con A inoculation. The antioxidant and NF-kappabeta inhibitor pyrrolidine dithiocarbamate (PDTC) was used as positive control.. Hepatic malondialdehyde levels increased 12, 18, and 24 h after Con A inoculation but not earlier. Serum levels of liver enzymes and TNFalpha, hepatic malondialdehyde, and protein carbonyls and the histologic necroinflammatory score were significantly reduced in the antioxidants-treated mice, while IL-10 levels were increased. Dimethylsulfoxide, dimethylthiourea, and PDTC inhibited oxidative stress, but only PDTC inhibited Con A-induced NF-kappaB activation.. Reactive oxygen species play a role in immune-mediated Con A-induced hepatitis probably secondary to immune-mediated liver damage. Scavenging of reactive oxygen species by antioxidants prevents hepatitis independently of NF-kappaB inhibition and may be a new therapeutic target in this experimental model.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Concanavalin A; Dimethyl Sulfoxide; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Free Radical Scavengers; Interleukin-10; Liver; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; NF-kappa B; Oxidative Stress; Proline; Thiocarbamates; Thiourea; Tumor Necrosis Factor-alpha

To investigate the neuroprotective effects and dose-response relation by combining JAK-STAT signal pathway inhibitor (AG490) with free radical scavenger dimethylthiourea (DMTU) in rats subjected to focal cerebral ischemia/reperfusion (I/R) injury.. In all rats, the middle cerebral artery occlusion (MCAO) was produced by occlusion of right internal carotid artery with a nylon monofilament. One hundred male Sprague-Dawley (SD) rats were divided into ten groups according to random digits table, 10 rats were in each group. The first experiment involved I/R model control, dimethyl sulfoxide (DMSO) control, normal saline (NS) control, AG490, DMTU and combination of AG490 and DMTU (A+D) groups. The second experiment involved model group and three experimental groups in which various doses of DMTU and AG490 were administered. The neurological behavior scores (NBS) were assessed at 24, 48 and 72 hours after reperfusion respectively in both experiments, and all the animals were then decapitated to determine the brain infarct volume after 72 hours.. The values of NBS in A+D group, AG490 group and DMTU group were higher than those in model group at 24, 48 and 72 hours after I/R, and their brain infarct volumes were obviously smaller than model group as well (all P<0.05). The brain infarct volume in A+D group was obviously smaller compared with AG490 and DMTU alone (all P<0.05). The values of NBS were higher and the brain infarct volumes were smaller in both high dose and medium dose combination groups than those in low dose combination and model groups respectively (all P<0.05). In addition, brain infarct volumes in high dose group were smaller than medium dose group (P<0.05), but there was no statistically significant difference between low dose and model groups.. The combined application of AG490 and DMTU produces a dose-dependent synergistic neuroprotective effect.

Topics: Animals; Brain; Brain Ischemia; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Male; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Thiourea; Tyrphostins

Hepatic drug metabolism is impaired in experimental animals and humans with renal diseases. An anticancer drug, cisplatin induces acute renal failure (ARF) in rats. Under the same experimental conditions, cisplatin causes down-regulation of hepatic cytochrome P450 (P450) enzymes in an isozyme selective manner. The present study examined the pathological role of ARF in the down-regulation of hepatic P450 enzymes in the cisplatin-treated rats. Male rats with single dose of intraperitoneally cisplatin (5 mg/kg) caused marked changes in renal parameters, BUN and serum creatinine but not hepatic parameters, serum alanine aminotransferase or aspartate aminotransferase. The rats also suffered from down-regulation of hepatic microsomal CYP2C11 and CYP3A2, male specific P450 isozymes, but not CYP1A2, CYP2E1, or CYP2D2. The decrease in serum testosterone level was also observed in injured rats, which was consistent with the selective effects on male specific P450 enzymes. Protection of rats against cisplatin-induced ARF by dimethylthiourea, a hydroxyl radical scavenger, also protected rats against the decrease in serum testosterone levels and the down-regulation of CYP2C11 and CYP3A2. Carboplatin, an analogue to cisplatin but no ARF inducer, did not cause decrease in serum testosterone levels and down-regulation of hepatic male specific P450 enzymes. These results suggest that down-regulation of hepatic P450 enzymes in male rats given cisplatin is closely related to the cisplatin-induced ARF and the resultant impairment of testis function.

Topics: Acute Disease; Animals; Antineoplastic Agents; Blood Urea Nitrogen; Cisplatin; Creatinine; Cytochrome P-450 Enzyme System; Disease Models, Animal; Down-Regulation; Drug Antagonism; Injections, Intraperitoneal; Liver; Male; Microsomes, Liver; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Testosterone; Thiourea

Glomerular epithelial cell (GEC) injury has been considered to play an important role in puromycin aminonucleoside (PAN)-induced nephrosis. We studied the effect of PAN on rat as well as human GEC apoptosis. Morphogic evaluation of GEC apoptosis and necrosis was carried out by staining with H-33342 and propidium iodide. GEC apoptosis was further confirmed by DNA fragmentation assay (by both agarose gel electrophoresis and end-labeling). To determine the dose- and time-response effect of PAN, GECs were treated with variable concentrations of PAN (10 to 500 microg/ml) for variable time periods (6 to 48 h). To determine the role of gene synthesis, we studied the effect of actinomycin D (a transcriptional inhibitor) on PAN-induced GEC apoptosis. To determine the role of free radicals, we evaluated the effect of superoxide dismutase (SOD), dimethylthiourea (DMTU), and catalase on PAN-induced GEC apoptosis. PAN induced GEC apoptosis in a dose- and time-dependent manner. PAN at a high concentration (PAN, 100 microg/ml) also induced a moderate degree of GEC necrosis. In DNA fragmentation assays PAN-treated GECs showed the classic ladder pattern. PAN-induced GEC apoptosis was partly attenuated with free radical scavengers, such as SOD, DMTU, and catalase. In addition, actinomycin D attenuated PAN-induced GEC apoptosis. PAN induces GEC apoptosis, which may be mediated through the generation of reactive oxygen species.

Topics: Animals; Apoptosis; Catalase; Cells, Cultured; Dactinomycin; Disease Models, Animal; DNA; DNA Fragmentation; Dose-Response Relationship, Drug; Electrophoresis, Agar Gel; Epithelial Cells; Free Radical Scavengers; Humans; In Situ Nick-End Labeling; Kidney Glomerulus; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiourea

Heme oxygenase-1 (H(mox-1)) has been implicated in protection of cells against ischemia/reperfusion injury.. To examine the physiological role of H(mox-1), a line of heterozygous H(mox-1)-knockout mice was developed by targeted disruption of the mouse H(mox-1) gene. Transgene integration was confirmed and characterized at the protein level. A 40% reduction of H(mox-1) protein occurred in the hearts of H(mox-1)(+/)(-) mice compared with those of wild-type mice. Isolated mouse hearts from H(mox-1)(+/)(-) mice and wild-type controls perfused via the Langendorff mode were subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. The H(mox-1)(+/)(-) hearts displayed reduced ventricular recovery, increased creatine kinase release, and increased infarct size compared with those of wild-type controls, indicating that these H(mox-1)(+/)(-) hearts were more susceptible to ischemia/reperfusion injury than wild-type controls. These results also suggest that H(mox-1)(+/)(-) hearts are subjected to increased amounts of oxidative stress. Treatment with 2 different antioxidants, Trolox or N:-acetylcysteine, only partially rescued the H(mox-1)(+/)(-) hearts from ischemia/reperfusion injury. Preconditioning, which renders the heart tolerant to subsequent lethal ischemia/reperfusion, failed to adapt the hearts of the H(mox-1)(+/)(-) mice compared with wild-type hearts.. These results demonstrate that H(mox-1) plays a crucial role in ischemia/reperfusion injury not only by functioning as an intracellular antioxidant but also by inducing its own expression under stressful conditions such as preconditioning.

Topics: Acetylcysteine; Animals; Antioxidants; Chromans; Creatine Kinase; Disease Models, Animal; Gene Targeting; Heart; Heart Rate; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Heterozygote; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Malondialdehyde; Membrane Proteins; Mice; Mice, Transgenic; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardium; Reperfusion Injury; Thiourea

We recently reported that wood smoke inhalation initially (within 5 min) causes airway injury and subsequently produces both airway and parenchymal injury after a delay (within 2 h). In this study, we investigated the mediator mechanisms of this delayed smoke-induced lung injury in 126 anesthetized and artificially ventilated guinea pigs who received challenges of either air or 40 tidal breaths of wood smoke. Two hours after inhalation, wood smoke produced various injurious responses, including increases in alveolar-capillary permeability, microvascular permeabilities, and histological injury scores, in airway and parenchymal tissues. Pre-treatment given before smoke challenge with CP-96,345 [a tachykinin NK1 receptor antagonist; (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine], dimethylthiourea (a hydroxyl radical scavenger), or a combination of these two drugs largely alleviated both the airway and parenchymal responses, whereas pre-treatment with SR-48,968 [a tachykinin NK2 receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl)benzamide] or a combination of CP-96,344 and SR-48,965 (inactive enantiomers) failed to do so. Post-treatment given at 5 min after smoke challenge with CP-96,345 or dimethylthiourea significantly alleviated the parenchymal responses, while having no effect on the airway responses. Pre-treatment with dimethylthiourea prevented the smoke-induced reduction in airway neutral endopeptidase activity (an enzyme for tachykinin degradation). We concluded that (1) tachykinins and hydroxyl radical play important roles in producing smoke-induced delayed lung injury in guinea pigs, and both may be involved in the spread of injury from the airways to the pulmonary parenchyma, and (2) the contribution of tachykinins is mediated via the activation of tachykinin NK1 receptors, and is associated with the hydroxyl radical-induced inactivation of airway neutral endopeptidase.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Disease Models, Animal; Free Radical Scavengers; Guinea Pigs; Hydroxyl Radical; Male; Neprilysin; Receptors, Tachykinin; Respiratory Distress Syndrome; Tachykinins; Thiourea; Wood

Focal segmental glomerulosclerosis is a steroid-resistant glomerular disease characterized by foot process flattening and heavy proteinuria. A similar disease was found to occur spontaneously in mice in which the Mpv17 gene was inactivated by retroviral insertion (Mpv17-/- mice). Here evidence is provided that glomerular damage in this murine model is due to overproduction of oxygen radicals and accumulation of lipid peroxidation adducts that were found in isolated glomeruli of Mpv17-/- mice. The development of glomerular disease in Mpv17-/- mice was inhibited by scavengers of oxygen radicals (dithiomethylurea) and lipid peroxidation (probucol), but not by steroid treatment. Although the glomerular polyanion was greatly reduced in proteinuric Mpv17-/- mice, it was preserved by antioxidative therapy. These results indicate that the glomerular disease in Mpv17-/- mice qualifies as a model of steroid-resistant focal segmental glomerulosclerosis and that experimental therapies with scavengers of oxygen radicals and lipid peroxidation efficiently ameliorate glomerular damage.

Topics: Aging; Albuminuria; Animals; Disease Models, Animal; Free Radical Scavengers; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Kidney Glomerulus; Lipid Peroxidation; Lipid Peroxides; Membrane Proteins; Methylprednisolone; Mice; Mice, Inbred BALB C; Mice, Knockout; Probucol; Proteins; Proteinuria; Reactive Oxygen Species; Sialoglycoproteins; Superoxides; Thiourea

The effects of anti-inflammatory non-steroidal therapy combined with free-radical scavengers were studied and compared to corticosteroid use in the treatment of experimental corneal injury.. Eighty New Zealand albino rabbits were used in this study. A corneal alkali burn was induced by applying 1-N NaOH filter paper on the central axis of the right cornea for 30 s. Animals were distributed into five treatment groups: group 1 (control group) was only given gentamicin; group 2 was treated with 0.5% dimethylthiourea (DMU); group 3 received 1% dexamethasone; group 4 was given combined 0.5% DMU and 1% indomethacin; group 5 was treated with 0.5% DMU and 0.1% diclofenac sodium. One 50-microliter drop of gentamicin was instilled every 12 h, whereas the other drugs were instilled every 6 h (50 microliters). All groups received the same antibiotic treatment as the control group. The animals were killed on the 5th day. Inflammatory index, area and perimeter of the wounded corneal zone, and corneal transparency were evaluated.. No significant differences in the inflammatory index were found between the treatment groups and the control group after 72 h. Significant differences (p < 0.001) were observed at 24 h in groups 3-5 when compared with the control group. Planimetry showed significant differences in group 4 when compared with the other groups (p < 0.05). Corneal transparency study showed statistically significantly better values in groups 4 and 5, when compared with the other groups, including group 3 (p < 0.05).. The use of 0.5% DMU combined with 1% indomethacin can be considered an alternative to corticosteroid treatment in our experimental chemical corneal injury.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Burns, Chemical; Cornea; Corneal Injuries; Dexamethasone; Diclofenac; Disease Models, Animal; Drug Therapy, Combination; Eye Burns; Free Radical Scavengers; Glucocorticoids; Indomethacin; Ophthalmic Solutions; Rabbits; Thiourea; Wound Healing

The effects of EUK-8, a synthetic, catalytic scavenger of reactive oxygen species, on isolated iron-overloaded rat hearts submitted to ischemia-reperfusion were studied. In the absence of EUK-8, functional parameters (systolic and diastolic pressures, oxygen consumption as estimated by the product heart rate times left ventricular diastolic pressure) were severely impaired 1 minute and 15 minutes after reperfusion following a 15 minute ischemic episode. Dimethylthiourea (10 mM), a hydroxyl radical scavenger, had a minimally protective effect. In contrast, EUK-8 at a concentration of 50 microM in the perfusion medium maintained these parameters at close to their preischemia values. Electron microscopic analysis of heart tissues after 15 minutes ischemia followed by 15 minutes reperfusion showed extensive damage to mitochondria and sarcomeres in untreated hearts, while the extent of damage was significantly lower in EUK-8-treated hearts. The functional and structural protection afforded by EUK-8 were significantly better than those induced by dimethylthiourea. These data suggest that EUK-8 may be therapeutically useful in preventing heart damage induced by ischemia-reperfusion, for example, during thrombolytic treatment of myocardial infarction.

Topics: Animals; Blood Pressure; Dextrans; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Ethylenediamines; Female; Free Radical Scavengers; Heart Rate; Heart Ventricles; Iron; Manganese; Microscopy, Electron; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Organometallic Compounds; Oxygen Consumption; Rats; Rats, Wistar; Reactive Oxygen Species; Thiourea

Local intra-arterial infusion of high doses of the nitric oxide (NO) donor, nitroprusside (10-40 micrograms kg-1 min-1 for 15 min) induced dose-dependent haemorrhagic injury to the rat gastric mucosa and reduced systemic arterial blood pressure, whereas intragastric nitroprusside (10-50 mg ml-1), which caused similar falls in blood pressure, failed to induce such injury. The mucosal damage induced by nitroprusside was reduced by local concurrent infusion of superoxide dismutase (500-4000 i.u. kg-1). Local superoxide dismutase also abolished the mucosal injury induced by local infusion of the NO donor, S-nitroso-N-acetyl-penicillamine (40 micrograms kg-1 min-1), but not that induced by local infusion of endothelin-1 (5 pmol kg-1 min-1) indicating specific actions. Intravenous infusion of the iron chelator and peroxyl scavenger, desferrioxamine (0.25-1 mg kg-1 min-1) or the hydroxyl radical scavenger, dimethylthiourea (20 mg kg-1 min-1) also reduced the mucosal damage induced by the local administration of the NO donors, but not that induced by endothelin-1. These findings implicate the involvement of superoxide and possibly other oxygen-derived free radicals in the injurious actions of high levels of nitric oxide generated from NO donors, and may reflect a role of the cytotoxic peroxynitrite moiety.

Topics: Animals; Blood Pressure; Catalase; Deferoxamine; Disease Models, Animal; Drug Overdose; Drug Synergism; Endothelins; Free Radical Scavengers; Gastric Mucosa; Infusions, Intra-Arterial; Infusions, Intravenous; Male; Nitrates; Nitric Oxide; Nitroprusside; Penicillamine; Rats; Rats, Wistar; Reactive Oxygen Species; S-Nitroso-N-Acetylpenicillamine; Stomach Ulcer; Superoxide Dismutase; Thiourea; Vasodilator Agents

To test the effect that the treatment with topical antioxidants may have on corneal infection, we have studied the effect of topically applied antioxidants, such as dimethylthiourea 0.5% (DMTU) and dismutase superoxide 0.2% (SOD), on infectious experimental keratitis caused by Staphylococcus aureus. We have quantified the results of the incubated corneas in ex vivo as well as in in vivo treated with antioxidants by using the luminol amplified chemiluminescence technique (LAC). The evaluation of corneal inflammation was performed calculating the average inflammatory index obtained from the clinical observation of the corneal secretion, corneal edema and ciliary injection. The evolution of the corneal infiltration was evaluated by means of computerized planymetry. The antioxidants used in this study demonstrated a significant reduction of the LAC values when compared with a control group both in the in vivo as well as in ex vivo studies. No significant differences in the clinical evaluation of the average inflammatory index were observed between the study and the control groups. However, a significant increase in the corneal infiltration was registered in the antioxidant treated group (p < 0.001) evaluated by computerized planymetry. Our results indicate that the use of antioxidants as antiinflammatory drugs may have a potential negative influence on the course of infectious keratitis.

Topics: Administration, Topical; Animals; Antioxidants; Disease Models, Animal; Eye Infections, Bacterial; Keratitis; Ophthalmic Solutions; Rabbits; Staphylococcal Infections; Superoxide Dismutase; Thiourea

Early allograft dysfunction remains a frequently encountered problem in clinical lung transplantation. Lung ischemia-reperfusion injury is associated with increased vascular permeability, which may be due in part to oxygen (O2) free radicals. However, it is not clear whether O2 free radicals are produced during ischemia under storage conditions in clinical lung transplantation.. Using an isolated ex vivo rabbit lung model, we studied the effects of preservation temperature on pulmonary capillary filtration coefficient (Kf) and lipid peroxidation in rabbit lungs inflated with 100% O2 after preservation with or without the O2 free radical scavenger dimethylthiourea. New Zealand white rabbits weighing 2.7 to 3.1 kg were intubated and ventilated with room air or 100% O2 (tidal volume = 25 mL). After heparinization and sternotomy, the pulmonary artery was flushed with low-potassium-dextran-1% glucose solution (200 mL). The heart-lung block was excised, submerged, and stored for 24 hours at 1 degree or 10 degrees C. After 24-hour preservation, the heart-lung block was suspended from a strain-gauge force transducer and ventilated with room air. The pulmonary artery cannula was connected to a reservoir of hetastarch solution. The lungs were flushed briefly with the hetastarch solution, and the reservoir was raised sequentially at 8-minute intervals to achieve 1.0 to 1.5 mm Hg increments in pulmonary artery pressure. Lung weight gain, airway pressure, pulmonary artery pressure, and left atrial pressure were measured continuously. The slope of steady-state lung weight gain was used to determine Kf (g.min-1.cm H2O-1 x 100 g-1 wet weight).. Twenty-four-hour lung preservation at both 1 degree and 10 degrees C increased Kf. A similar increase in Kf was observed in lungs stored at 1 degree C while inflated with 100% O2. However, a significant increase in Kf was observed when lungs inflated with 100% O2 were stored at 10 degrees C. This increase in Kf was ameliorated by dimethylthiourea. Thiobarbituric acid-reactive substance levels were increased in lungs stored at 10 degrees C while inflated with 100% O2. This finding was eliminated by dimethylthiourea.. These results indicate that free radical injury occurs during the ischemic phase when lungs are stored at moderate hypothermia while inflated with 100% O2.

Topics: Animals; Capillary Permeability; Cryopreservation; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Lipid Peroxidation; Lung; Lung Transplantation; Organ Preservation; Organ Size; Oxygen; Rabbits; Reperfusion Injury; Temperature; Thiobarbituric Acid Reactive Substances; Thiourea

To ascertain the effectiveness of topical antioxidant therapy on acute corneal inflammation, we have studied the effectiveness of topical treatment with a saline solution and with antioxidants such as 0.2% superoxide dismutase and 0.5% dimethylthiourea (DMTU) in a controlled experimental study. The evolution of the inflammatory process was evaluated by a multimodel approach, including computer-assisted planimetry of the corneal ulcer and infiltrate, ultrasonic pachymetry, luminol-amplified chemiluminescence and the study of corneal transparency by direct spectral spectrophotometry transmittance. The experimental model was a corneal ulcer created by a 60-second application of 1 N sodium hydroxide. Topical treatment with DMTU was shown to significantly improve all parameters tested, while superoxide dismutase reduced only the corneal ulcers. Antioxidant topical therapy with DMTU was shown to be efficient in reducing the inflammatory reaction that occurs during acute corneal inflammation. This suggests that antioxidant therapy could be considered as a complementary treatment in the pharmacological modulation of acute corneal inflammation.

Topics: Acute Disease; Administration, Topical; Animals; Antioxidants; Burns, Chemical; Cornea; Corneal Ulcer; Disease Models, Animal; Eye Burns; Free Radical Scavengers; Ophthalmic Solutions; Rabbits; Sodium Hydroxide; Superoxide Dismutase; Thiourea

This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.

Topics: Animals; Chemotactic Factors; Complement Activation; Complement C5a; Deferoxamine; Disease Models, Animal; Hydroxyl Radical; Intestines; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thiourea

Combined sepsis and rhabdomyolysis result in a mortality rate much higher than that caused by each process alone. An analogous rat model is obtained by simultaneous i.p. administration of a nonlethal dose of lipopolysaccharide (LPS 0.025 mg/100 g) and a nonlethal i.m. injection of glycerol (1 ml/100 g). The aim of this study was to determine the factors contributing to the high mortality rate in this rat model. The factors examined include: Dehydration, plasma volume expansion, 'immunization' to glycerol, induction of LPS tolerance and the effect of free radicals formed in this model. Neither dehydration nor volume expansion affected mortality. 'Immunization' with glycerol was also not effective. In contradistinction, tolerance to LPS achieved by a daily injection with gradual increasing doses of LPS (from 0.05 mg/100 g to 1 mg/100 g) for 6 days reduced the mortality rate by 60% (P < 0.001). Moreover, decreasing free radical activity using the natural antioxidant (NAO) (5 mg/100 g) reduced mortality rates by 50%. A different antioxidant, dimethylthiourea (DMTU) (50 mg/100 g) failed to reduce mortality rates. This study suggests that the synergism between glycerol and LPS is apparently due to an increase in the rats' sensitivity to endotoxin following glycerol injection. However, endotoxin apparently does not enhance sensitivity to glycerol in the rat. The new antioxidant NAO significantly reduced the high mortality rate.

Topics: Animals; Creatine Kinase; Disease Models, Animal; Drug Synergism; Endotoxins; Free Radical Scavengers; Glycerol; Lipoxygenase; Male; Plasma Volume; Rats; Rhabdomyolysis; Sepsis; Thiourea

Attempts have been made to characterize conditions under which oxygen free radicals contribute to ischemic brain damage. According to one hypothesis, free radicals are likely mediators of damage only when ischemia is of such long duration that infarction develops or when either preischemic hyperglycemia or hyperthermia is present. The objective of the present study was to explore whether 15 minutes of forebrain ischemia, an insult that leads to selective neuronal vulnerability but not to infarction, is accompanied by production of pathogenetically important free radicals.. Using a histopathological end point, we studied amelioration of damage by a free radical scavenger, dimethylthiourea, administered in a dose of 750 mg/kg i.p. 60 minutes before ischemia. To study whether this insult leads to detectable protein oxidation we assessed the activity of glutamine synthetase and of carbonyl compounds in the soluble protein fraction.. In control animals, the transient ischemia resulted in the expected damage to vulnerable neurons in hippocampus, caudoputamen, and neocortex after 7 days of recovery. Glutamine synthetase activity in caudoputamen and hippocampus and carbonyl content in the soluble protein fraction after 90 minutes of recovery were not affected. However, dimethylthiourea significantly reduced damage to hippocampus and caudoputamen (p < 0.001) and neocortex (p < 0.005).. Lack of evidence of protein oxidation supports the notion that 15 minutes of forebrain ischemia results in a limited insult, confined to the neurons. Provided that unspecific effects can be excluded, the results obtained with dimethylthiourea suggest that free radicals contribute to selective neuronal necrosis.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Glutamate-Ammonia Ligase; Hippocampus; Male; Neurons; Prosencephalon; Putamen; Rats; Rats, Wistar; Thiourea

After 6-h tourniquet ischaemia of one hindlimb in male Sprague-Dawley rats, gastrocnemius muscle blood flow was measured following 10, 120 and 240 min of reperfusion using radiolabelled microspheres. A perfusion index was calculated (experimental limb: contralateral limb) for each of these times. Comparison of perfusion indices in ten control animals (6 h ischaemia, 4 h reperfusion) with similar measurements in ten normal rats with no ischaemia and in ten ischaemic animals with the tourniquet in situ demonstrated low median (interquartile range (i.q.r.)) reflow after 10 min (control 0.12 (0.02-0.43), ischaemia 0.04 (0.00-0.07), normal 1.05 (0.68-1.18); control versus ischaemia, P not significant; control versus normal, P < 0.01). Relative reperfusion occurred at 120 min (control 0.48 (0.11-0.70), ischaemia 0.02 (0.01-0.07), normal 0.97 (0.79-1.13); control versus ischaemia, P < 0.05; control versus normal, P < 0.05) and reperfusion injury after 240 min of revascularization, with muscle blood flow being little different from that in the ischaemic group (control 0.05 (0.01-0.38), ischaemia 0.03 (0.00-0.07), normal 1.01 (0.73-1.16); control versus ischaemia, P not significant; control versus normal, P < 0.01). Two groups of 12 rats were given either intravenous superoxide dismutase and catalase or dimethylthiourea 30 min before tourniquet release, continuing throughout the period of reperfusion. Superoxide dismutase and catalase reversed low reflow, producing a median (i.q.r.) perfusion index of 0.94 (0.54-1.12) (P < 0.01 versus control, P not significant versus normal), but had no effect on relative reperfusion (0.66 (0.42-1.01), P not significant versus control) or on reperfusion injury (0.27 (0.01-0.35), P not significant versus control). In contrast, dimethylthiourea had no effect on perfusion at either 10 min (0.10 (0.03-0.15), P not significant versus control) or 240 min (0.04 (0.00-0.11), P not significant versus control), but abolished the phase of relative reperfusion at 120 min (0.04 (0.02-0.21), P < 0.01 versus control). These results indicate that, although superoxide radicals are harmful during postischaemic reperfusion, hydroxyl radicals may be beneficial.

Topics: Animals; Catalase; Disease Models, Animal; Free Radical Scavengers; Hindlimb; Male; Muscles; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion; Reperfusion Injury; Superoxide Dismutase; Thiourea

An experimental model of optic nerve ischemia was designed in the rabbit to determine early biochemical alterations, i.e.--changes of high energy phosphate metabolites (ATP and phosphocreatine)--in occlusive and peri-occlusive areas. Vascular occlusion provoked a rapid fall of ATP and phosphocreatine in the optic nerve. Free radicals scavengers, superoxide dismutase plus catalase or dimethylthiourea were able to counteract the drop of phosphate metabolites in the peri-occlusive area. These results show that hypoxia leads to oxygen-derived free radical generation which can be responsible for cell damage and emphasize the role of free radicals in the pathogenesis of ocular diseases related to vascular dysfunction.

Topics: Adenosine Triphosphate; Animals; Catalase; Disease Models, Animal; Free Radical Scavengers; Free Radicals; Ischemia; Optic Nerve; Oxygen Consumption; Phosphocreatine; Rabbits; Superoxide Dismutase; Thiourea

The hydroxyl radical scavengers dimethylthiourea (DMTU), sodium benzoate, and dimethylsulfoxide (DMSO) were administered to rats before doxorubicin hydrochloride (ADR) (5 mg/kg, IV) to probe the role of free radicals in mediating proteinuria in doxorubicin hydrochloride nephrosis (AN). Because ADR stimulates free radical production, the role of renal glutathione was also evaluated; glutathione metabolism is involved in tissue detoxification processes. DMTU administration to rats with AN caused a significant (p less than 0.01) reduction in their proteinuria after 7 days (52.84 +/- 13.21 mg/24 hours) when they were compared with ADR controls (155.81 +/- 20.16 mg/24 hours). In similar fashion, their urine albumin excretion was also significantly reduced when compared with that of ADR controls (11.13 +/- 2.75 mg/24 hours vs 32.08 +/- 4.14 mg/24 hours; p less than 0.01). DMTU-treated rats also had significantly (p less than 0.001) reduced urinary protein and albumin excretion at 14 days when compared with rats that received ADR alone. The urinary excretion of lysozyme and N-acetyl-glucosaminidase, markers of renal tubular injury, were significantly increased after 7 or 14 days in rats with AN, despite DMTU treatment. Creatinine clearance was significantly reduced (p less than 0.05) in rats receiving ADR alone (0.223 +/- 0.011 ml/min/100 gm) when compared with that in normal controls (0.331 +/- 0.027 ml/min/100 gm) or DMTU-treated rats (0.289 +/- 0.035 ml/min/100 gm). Unlike DMTU, neither sodium benzoate nor DMSO reduced proteinuria in rats with AN.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylglucosaminidase; Albuminuria; Animals; Benzoates; Benzoic Acid; Creatine; Dimethyl Sulfoxide; Disease Models, Animal; Doxorubicin; Free Radical Scavengers; Glomerular Filtration Rate; Glutathione; Hydroxides; Hydroxyl Radical; Injections, Intravenous; Kidney Cortex; Male; Muramidase; Nephrosis; Proteinuria; Rats; Rats, Inbred Strains; Thiourea

The mechanism by which bacteria are cleared by the pulmonary circulation and the relation of this process to development of hemodynamic abnormalities are not understood. This study tested the hypotheses that clearance of Group B Streptococcus (GBS) during transit through the pulmonary circulation of infant piglets is related to oxygen radical-dependent bacterial killing and that killing of the organism is linked to development of pulmonary hypertension. GBS were radiolabeled with 111In and infused intravenously for 15 min (10(8) organisms/kg/min) into infant piglets ranging in age from 5 to 14 days. Lung specimens were excised at termination of the GBS infusion or 45 min thereafter, and both the relative deposition and viability of the bacteria were determined. The percentage of infused GBS recovered in lung tissue did not differ between the two time points (26 +/- 7% versus 29 +/- 8%), but the relative viability at termination of the infusion, 50 +/- 11%, was reduced to 19 +/- 4% within 45 min. Treatment with an oxygen radical scavenger, dimethylthiourea (DMTU), failed to influence the pulmonary deposition of GBS but significantly increased viability of the organism from 21.4 +/- 2.6 to 33.3 +/- 5.3%. As expected, GBS infusion was accompanied by pulmonary hypertension and arterial hypoxemia; DMTU attenuated these responses by 52 and 78%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Free Radicals; Hemodynamics; Hypertension, Pulmonary; Lung; Oxygen; Pulmonary Circulation; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea

Dimethylthiourea (DMTU), a putative hydroxyl radical scavenger, attenuates thromboxane generation and pulmonary hypertension in the piglet model of group B streptococcal (GBS) sepsis. This study tested the hypothesis that DMTU reverses ongoing GBS-induced pulmonary hypertension coincident with decreased thromboxane production. Piglets (n = 15) received a 60 min infusion of GBS (10(-8) cfu/kg/min). Mean pulmonary artery pressure (Ppa), arterial blood gases (ABGs), and thromboxane B2 (TXB) levels were measured at 10 min intervals throughout the study. GBS infusion resulted in a marked increase in pulmonary artery pressure (mean delta Ppa = 31 mm Hg) and a significant decline in PaO2 (mean = -80 torr) within 10 min of beginning the infusion. pH decreased from a mean of 7.47 to 7.37. DMTU, 750 mg/kg, or normal saline vehicle was infused over 10-15 min beginning 10 min after initiating GBS. Ppa decreased significantly within 10 min of DMTU infusion. Piglets receiving vehicle had a slow decline in Ppa. Piglets receiving DMTU also had an improvement in PaO2 and showed no further drop in pH. Piglets receiving vehicle had no improvement in PaO2 and demonstrated a continued decline in pH. TXB levels did not differ between the groups at any time interval. We conclude that DMTU can partially reverse GBS-induced pulmonary hypertension, but may function through mechanisms independent of thromboxane generation.

Topics: Animals; Animals, Newborn; Blood Pressure; Disease Models, Animal; Hypertension, Pulmonary; Oxygen; Partial Pressure; Pulmonary Circulation; Sepsis; Streptococcal Infections; Swine; Thiourea; Thromboxane B2

Free radicals have been shown to play an important role in ischemia-reperfusion injury in several organ systems; however, the role of free radicals in central nervous system ischemia has been less well studied. Many potential free radical-generating systems exist. The primary products of these reactions, superoxide and hydrogen peroxide, may combine to produce hydroxyl radicals. Of the many potential sources of free radical generation, the enzyme xanthine oxidase has been shown to be important in ischemia in noncerebral tissue. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea and the xanthine oxidase inhibitor allopurinol on infarct volume in a model of continuous partial ischemia. Male Sprague-Dawley rats were treated with dimethylthiourea or allopurinol before middle cerebral artery occlusion. Infarct volume was measured by triphenyltetrazolium chloride staining of brains removed 3 or 24 hours after occlusion. Stroke volume was reduced by 30% after dimethylthiourea treatment and by 32-35% after allopurinol treatment. At 24 hours after stroke, cortical tissue was more effectively protected than caudate tissue with both agents. Pretreatment with dimethylthiourea and allopurinol also significantly reduced cerebral edema formation and improved blood-brain barrier function as measured by fluorescein uptake. Our results imply that hydroxyl radicals are important in tissue injury secondary to partial cerebral ischemia and that xanthine oxidase may be the primary source of these radicals.

Topics: Allopurinol; Animals; Arterial Occlusive Diseases; Blood-Brain Barrier; Brain Chemistry; Cerebral Arteries; Cerebral Infarction; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Rats; Rats, Inbred Strains; Staining and Labeling; Stroke Volume; Thiourea; Time Factors

Reactive oxygen metabolites, in particular hydroxyl radical, have been shown to be important mediators of tissue injury in several models of acute renal failure. The aim of the present study was to examine the role of hydroxyl radical in glycerol-induced acute renal failure, a model for myoglobinuric renal injury. Rats injected with glycerol alone (8 mg/kg im following dehydration for 24 h) developed significant renal failure compared with dehydrated controls. Rats treated with glycerol and a hydroxyl radical scavenger, dimethylthiourea (DMTU), had significantly lower blood urea nitrogen (BUN) and creatinine. In contrast, urea, which is chemically similar to DMTU but is not a hydroxyl radical scavenger, provided no protection. In addition, DMTU prevented the glycerol-induced rise in renal cortical malondialdehyde content (a measure of lipid peroxidation that serves as a marker of free radical-mediated tissue injury). A second hydroxyl radical scavenger, sodium benzoate, had a similar protective effect on renal function (as measured by both BUN and creatinine). Because the generation of hydroxyl radical in biological systems requires the presence of a trace metal such as iron, we also examined the effect of the iron chelator, deferoxamine on glycerol-induced renal failure. Deferoxamine was also protective. The interventional agents were also associated with a marked reduction in histological evidence of renal damage. The protective effects of two hydroxyl radical scavengers as well as an iron chelator implicate a role for hydroxyl radical in glycerol-induced acute renal failure.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Free Radicals; Glycerol; Hydroxides; Hydroxyl Radical; Kidney; Male; Rats; Rats, Inbred Strains; Reference Values; Thiourea

We previously demonstrated that in vivo reperfusion of a dog lung after 48 h of pulmonary arterial (PA) ischemia results in pulmonary edema with a significant infiltrate of polymorphonuclear leukocytes. We hypothesized that the injury resulted from production of hydroxyl radical by activated neutrophils. In the current study, we attempted to prevent the injury in both dogs and rabbits with dimethylthiourea (DMTU), a scavenger of hydroxyl radical. After 48 h of left PA occlusion in 18 dogs, DMTU was administered to 9 animals and 9 were not treated. The occlusion was then released, and the dogs were killed 4 h later. Reperfusion resulted in a drop in leukocyte count and left lung edema, but there was no difference between treated and untreated animals. The wet-to-dry ratios of the lungs in the treated group were 5.76 +/- 0.44 (SE) on the reperfused left side and 4.50 +/- 0.06 (P less than 0.05) on the right side. In the untreated groups the comparable ratios were 5.73 +/- 0.31 and 4.92 +/- 0.10 (P less than 0.05 for right vs. left). Histological examination revealed significant differences between the right and left lungs in the extent of intra-alveolar granulocytes and macrophages but did not reveal differences between the treated and untreated animals. To ensure that neither the model nor the lack of response to DMTU was species specific, we then developed a rabbit model of reperfusion edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Dogs; Hydroxides; Hydroxyl Radical; Ischemia; Leukopenia; Lung; Lung Injury; Macrophages; Neutrophils; Pulmonary Edema; Rabbits; Thiourea