1-3-dimethylthiourea and Body-Weight

This study sought to determine whether oxygen radical scavengers of dimethylthiourea (DMTU), superoxide dismutase (SOD), or catalase (CAT) pretreatment attenuated ischemia-reperfusion (I/R)-induced lung injury. After isolation from a Sprague-Dawley rat, the lungs were perfused through the pulmonary artery cannula with rat whole blood diluted 1:1 with a physiological salt solution. An acute lung injury was induced by 10 minutes of hypoxia with 5% CO2-95% N2 followed by 65 minutes of ischemia and then 65 minutes of reperfusion. I/R significantly increased microvascular permeability as measured by the capillary filtration coefficient (Kfc), lung weight-to-body weight ratio (LW/BW), and protein concentration in bronchoalveolar lavage fluid (PCBAL). DMTU pretreatment significantly attenuated the acute lung injury. The capillary filtration coefficient (P<.01), LW/BW (P<.01) and PCBAL (P<.05) were significantly lower among the DMTU-treated rats than hosts pretreated with SOD or CAT. The possible mechanisms of the protective effect of DMTU in I/R-induced lung injury may relate to the permeability of the agent allowing it to scavenge intracellular hydroxyl radicals. However, whether superoxide dismutase or catalase antioxidants showed protective effects possibly due to their impermeability of the cell membrane not allowing scavenging of intracellular oxygen radicals.

Topics: Animals; Body Weight; Edema; Free Radical Scavengers; Lung; Lung Injury; Microcirculation; Organ Size; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thiourea

We attempted to evaluate whether the antioxidants 1,3-dimethyl-2-thiourea (DMTU) and hexa(sulfobutyl)fullerenes (FC(4)S) attenuate monocrotaline (MCT)-induced pulmonary hypertension (PH) by lowering lung substance P (SP) in Wistar rats. Sixty-three rats weighing 297 +/- 8 g were divided into six groups: control; MCT; capsaicin + MCT; MCT + DMTU-1; MCT + DMTU-2; and MCT + FC(4)S. Three weeks before the functional study, saline was injected into each control rat, whereas each MCT rat received 60 mg/kg sc MCT. Rats in the third group received capsaicin pretreatment followed by MCT. A 3-day injection of DMTU was performed during the early (DMTU-1) or the late (DMTU-2) post-MCT period. For the last group, each MCT-treated rat received a daily FC(4)S injection until the commencement of the functional study. Compared to the control group, MCT caused significant increases in pulmonary arterial pressure (Ppa), right ventricular hypertropy, pulmonary arterial medial thickness, lung SP level, and luminol-enhanced chemiluminescence counts in bronchoalveolar lavage. Both capsaicin and antioxidants significantly attenuated the above MCT-induced alterations. SP-induced acute increase in Ppa was exaggerated in MCT-treated rats. These results suggest that oxygen radicals play an important role in MCT-induced PH via elevating lung SP level.

Topics: Animals; Body Weight; Carbon; Free Radical Scavengers; Hematocrit; Hypertension, Pulmonary; Immunoenzyme Techniques; Luminescent Measurements; Male; Monocrotaline; Muscle, Smooth, Vascular; Poisons; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Reactive Oxygen Species; Substance P; Thiourea

Oxidative stress might play an important role in the progression of left ventricular (LV) remodeling and failure that occur after myocardial infarction (MI). We determined whether reactive oxygen species (ROS) are increased in the LV remodeling and failure in experimental MI with the use of electron spin resonance spectroscopy and whether the long-term administration of dimethylthiourea (DMTU), hydroxyl radical (.OH) scavenger, could attenuate these changes. We studied 3 groups of mice: sham-operated (sham), MI, and MI animals that received DMTU (MI+DMTU). Drugs were administered to the animals daily via intraperitoneal injection for 4 weeks.OH was increased in the noninfarcted myocardium from MI animals, which was abolished in MI+DMTU. Fractional shortening was depressed by 65%, LV chamber diameter was increased by 53%, and the thickness of noninfarcted myocardium was increased by 37% in MI. MI+DMTU animals had significantly better LV contractile function and smaller increases in LV chamber size and hypertrophy than MI animals. Changes in myocyte cross-sectional area determined with LV mid-free wall specimens were concordant with the wall thickness data. Collagen volume fraction of the noninfarcted myocardium showed significant increases in the MI, which were also attenuated with DMTU. Myocardial matrix metalloproteinase-2 activity, measured with gelatin zymography, was increased with MI after 7 and 28 days, which was attenuated in MI+DMTU. Thus, the attenuation of increased myocardial ROS and metalloproteinase activity with DMTU may contribute, at least in part, to its beneficial effects on LV remodeling and failure. Therapies designed to interfere with oxidative stress might be beneficial to prevent myocardial failure.

Topics: Animals; Body Weight; Cyclic N-Oxides; Echocardiography; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Hemodynamics; Male; Matrix Metalloproteinases; Mice; Myocardial Infarction; Myocardium; Organ Size; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Spin Labels; Thiourea; Ventricular Dysfunction, Left; Ventricular Remodeling

Antioxidants attenuate noncholinergic airway constriction. To further investigate the relationship between tachykinin-mediated airway constriction and oxygen radicals, we explored citric acid-induced bronchial constriction in 48 young Hartley strain guinea-pigs, divided into six groups: control; citric acid; hexa(sulphobutyl)fullerenes + citric acid; hexa(sulphobutyl)fullerenes + phosphoramidon + citric acid; dimethylthiourea (DMTU) + citric acid; and DMTU + phosphoramidon + citric acid. Hexa(sulphobutyl)fullerenes and DMTU are scavengers of oxygen radicals while phosphoramidon is an inhibitor of the major degradation enzyme for tachykinins. Animals were anaesthetized, paralyzed, and artificially ventilated. Each animal was given 50 breaths of 4 ml saline or citric acid aerosol. We measured dynamic respiratory compliance (Crs), forced expiratory volume in 0.1 (FEV0.1), and maximal expiratory flow at 30% total lung capacity (Vmax30) to evaluate the degree of airway constriction. Citric acid, but not saline, aerosol inhalation caused marked decreases in Crs, FEV0.1 and Vmax30, indicating marked airway constriction. This constriction was significantly attenuated by either hexa(sulphobutyl)fullerenes or by DMTU. In addition, phosphoramidon significantly reversed the attenuating action of hexa(sulphobutyl)fullerenes, but not that of DMTU. Citric acid aerosol inhalation caused increases in both lucigenin- and t-butyl hydroperoxide-initiated chemiluminescence counts, indicating citric acid-induced increase in oxygen radicals and decrease in antioxidants in bronchoalveolar lavage fluid. These alterations were significantly suppressed by either hexa(sulphobutyl)fullerenes or DMTU. An elastase inhibitor eglin-c also significantly attenuated citric acid-induced airway constriction, indicating the contributing role of elastase in this type of constriction. We conclude that both oxygen radicals and elastase play an important role in tachykinin-mediated, citric acid-induced airway constriction.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chelating Agents; Citric Acid; Forced Expiratory Volume; Free Radical Scavengers; Guinea Pigs; Pancreatic Elastase; Peak Expiratory Flow Rate; Proteins; Reactive Oxygen Species; Respiratory Function Tests; Serpins; tert-Butylhydroperoxide; Thiourea; Vital Capacity

Because chronic hypoxia increases the production of oxygen radicals, we hypothesized that antioxidants attenuate chronic hypoxic pulmonary hypertension. In part 1, we examined the temporal progress in chronic hypoxic pulmonary hypertension in 46 Wistar rats exposed to hypoxia from 0-3 weeks. In part 2, we tested whether antioxidants attenuated chronic hypoxic pulmonary hypertension in 82 rats divided into 10 groups: control, fullerenol-1, U-83836E, dimethylthiourea-1, dimethylthiourea-2, hypoxia, hypoxia + fullerenol-1, hypoxia + U83836E, hypoxia + dimethylthiourea-1, and hypoxia + dimethylthiourea-2. Control animals breathed room air and were injected intraperitoneally with saline for 2 weeks. Fullerenol-1, U-83836E, and dimethylthiourea are antioxidants and were administered intraperitoneally for 2 weeks, except that dimethylthiourea was given either on days 3, 5, and 7 (dimethylthiourea-1), or on days 8, 10, and 12 (dimethylthiourea-2). Hypoxic animals were placed into a hypobaric chamber with a barometric pressure of 380 Torr for 2 weeks. Hypoxia + antioxidant groups were administered antioxidants during hypoxic exposure. We observed a gradual increase in pulmonary artery pressure, the weight ratio of right ventricle to left ventricle plus septum, and hematocrit during the 3 weeks of chronic hypoxia. These hypoxia-induced alterations were significantly attenuated by U-83836E and dimethylthiourea, but not by fullerenol-1. Neither the temporal alterations nor the antioxidant effects can be explained by the change in either tracheal neutral endopeptidase activity or the lung or plasma substance P level, perhaps because of the time lag in sampling. These results indicate that oxygen radicals play an important role in the development of chronic hypoxic pulmonary hypertension.

Topics: Animals; Antioxidants; Body Weight; Chronic Disease; Free Radicals; Hypertension, Pulmonary; Hypoxia; Male; Rats; Rats, Wistar; Substance P; Thiourea

Long-term treatment with dimethylthiourea (DMTU), a scavenger of hydroxyl radical (.OH) and hypochlorous acid (HOCl), suppressed the age-related development of autoimmune disease in NZB x NZWF1 mice. Treatment reduced autoantibody production, retarded increase in blood urea nitrogen, and prolonged life. The results suggest that .OH and HOCl may, at least in part, enhance the development of autoimmune diseases in NZB x NZWF1 mice.

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Blood Urea Nitrogen; Body Weight; Female; Free Radical Scavengers; Mice; Mice, Inbred NZB; Survival Rate; Thiourea

Whether a reduction in urinary protein excretion in rats coadministered puromycin aminonucleoside and antioxidants was associated with a reduction in alterations to glomerular epithelial cell (podocyte) ultrastructure was examined. Daily urinary protein excretion was measured in rats that received a single i.v. injection of saline or puromycin aminonucleoside with or without coadministration of antioxidants. The coadministration of alpha-tocopherol/ascorbic acid, dimethyl thiourea, or superoxide dismutase to puromycin aminonucleoside-treated rats reduced proteinuria by approximately 90, 40, and 60%, respectively, over the 18-day period studied. For a second group of rats, daily urinary protein excretion was measured and kidneys were processed for light microscopy and transmission and scanning electron microscopy 4, 5, and 10 days after injection. Transmission electron microscopic morphometric analysis of glomeruli from puromycin aminonucleoside-treated rats coadministered antioxidants revealed significantly reduced foot process effacement on Days, 4, 5, and 10 compared with rats that received puromycin aminonucleoside alone. Thus, at Day 10, puromycin aminonucleoside-treated rats coadministered alpha-tocopherol/ascorbic acid, dimethyl thiourea, or superoxide dismutase contained 90, 74, and 88% (P < 0.01 in all cases) more glomerular epithelial cell filtration slits per unit length of glomerular basement membrane than rats treated with puromycin aminonucleoside alone. In contrast, by scanning electron microscopy, the antioxidants were found to provide no protection against the changes occurring in glomerular epithelial cell bodies and major processes. These results provide further evidence of a role for reactive oxygen species in puromycin aminonucleoside nephrosis and indicate that the antioxidants provide protection against the changes occurring in glomerular epithelial cell foot processes.

Topics: Animals; Antioxidants; Ascorbic Acid; Body Weight; Diuresis; Female; Kidney Glomerulus; Microscopy, Electron; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiourea; Vitamin E

Study was made to determine whether oxygen free radicals mediate uranium-induced acute renal failure (ARF). Superoxide dismutase (SOD), a superoxide anion scavenger, did not prevent uranium acetate (UA) (5 mg/kg, i.v.)-induced renal injury 48 h after injection. In contrast, dimethylthiourea (DMTU), a hydroxyl radical scavenger, significantly attenuated UA-induced rise in serum creatinine concentration (1.11 +/- 0.05 (DMTU) vs. 1.40 +/- 0.06 mg/dl (control), p < .05), and tubular necrosis. Dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, decreased UA-induced tubular damage. UA injection caused no increase in renal cortical malondialdehyde (MDA) content. DMTU and DMSO did not modify intrarenal MDA content. UA administration brought about significant increase in plasma renin activity but not in renal cortical renin content. Treatment with DMTU and DMSO had no effect on plasma renin activity or intrarenal renin content. It follows from these findings that DMTU and DMSO may attenuate UA-induced renal injury. Such a protective effect would not be mediated through modulation of lipid peroxidation or renin activity.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Blood Urea Nitrogen; Body Weight; Creatinine; Dimethyl Sulfoxide; Free Radical Scavengers; Hematocrit; Kidney; Kidney Cortex; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Renin; Superoxide Dismutase; Systole; Thiourea; Uranium

Dimethylthiourea (DMTU) is a small, highly diffusible molecule that effectively scavenges toxic oxygen metabolites in vitro and reduces oxidative injury in many biologic systems. Nonetheless, for unknown reasons, DMTU has occasionally failed to decrease damage in some systems where injury is presumed to be mediated by oxygen metabolites. We hypothesized that the inconsistent pattern of protection might partially reflect a direct toxicity of DMTU. Our results supported this premise. We found that rats treated with commonly used doses of highly purified DMTU had increased lung accumulation of intravenously injected iodine 125-labeled albumin (4 hours after DMTU treatment) and decreased blood glutathione levels (24 hours after DMTU treatment) when compared with saline-injected control rats. In contrast, rats treated with dimethylurea, a analog of DMTU, did not develop increased accumulation of labeled albumin in the lungs or decreased blood glutathione levels. We conclude that DMTU has intrinsically toxic effects in rats and that DMTU toxicity may at times obscure its protective action.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Glutathione; Lung; Male; Methylurea Compounds; Organ Size; Rats; Rats, Sprague-Dawley; Serum Albumin; Stomach; Thiourea

A rat model of endotoxic shock was used to evaluate the effects of dimethylthiourea, a putative hydroxyl radical scavenger, in the alterations of lung phosphatidylcholine biosynthesis found during endotoxemia. Treatment of rats with dimethylthiourea, just before lipopolysaccharide injection, resulted in a decreased lipid peroxidation and an increase in phosphatidylcholine biosynthesis, although it did not prevent the body weight loss or the increase in lung weight and lung protein content associated with the lung injury induced by lipopolysaccharide. Our results suggest that phosphatidylcholine biosynthesis is impaired by processes in which hydroxyl radicals are implicated, although other oxygen free radical species, not removed by dimethylthiourea, can be also involved in lipopolysaccharide mediated lung injury.

Topics: Animals; Body Weight; Hydroxyl Radical; Lipid Peroxidation; Lipopolysaccharides; Lung; Male; Organ Size; Phosphatidylcholines; Rats; Rats, Wistar; Shock, Septic; Superoxide Dismutase; Thiourea

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB/Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.

Topics: Allopurinol; Animals; Body Weight; Diabetes Mellitus, Type 1; Diet; Female; Free Radical Scavengers; Male; Rats; Rats, Inbred BB; Thiourea; Tiopronin; Vitamin E; Weight Gain

Sprague-Dawley rats were administered ethylenethiourea (ETU), 1,3-dimethyl-2-thiourea (DMT), 1,3-dibutyl-2-thiourea (DBT), or 1,3-diphenyl-2-thiourea (DPT) by gavage from Days 6 to 20 of gestation. Daily dosage levels (mg/kg/day) were ETU at 0, 15, 25 and 35; DMT at 0, 15, 25, 50, 100, and 200; DBT at 0, 15, 25, 50, 100, and 200; and DPT at 0, 25, 50, 100, and 200. There was evidence of maternal toxicity at all doses of DMT and at doses greater than or equal to 50 mg DBT/kg/day. DPT was embryolethal at 200 mg/kg/day. Fetotoxicity was observed at doses greater than or equal to 15 mg DMT/kg/day, greater than or equal to 15 mg DBT/kg/day, and greater than or equal to 100 mg DPT/kg/day. ETU was the only chemical tested that proved to be teratogenic.

Topics: Animals; Behavior, Animal; Body Weight; Embryo, Mammalian; Ethylenethiourea; Female; Gestational Age; Intubation, Gastrointestinal; Pregnancy; Rats; Rats, Inbred Strains; Reproduction; Teratogens; Thiourea

We studied the effects of a hydroxyl radical scavenger, dimethylthiourea (DMTU), on syngeneic islet grafts. Six hundred fresh islets taken from two Wistar rats were transplanted intraportally into other Wistar rats made diabetic with streptozotocin. DMTU was given to five recipients intraperitoneally for a month while nine controls received only intraperitoneal saline. The DMTU-treated group had significantly lower fasting plasma glucose levels at 1.5, 4.5, 5, 5.5, 6, 7, 9 and 11 weeks and had higher mean fasting body weights between the 2.5th week and their eventual sacrifice. Their islets also survived significantly longer than did those of the controls (73.6 +/- 3.4 vs. 21.6 +/- 9.4 days). This suggests that oxygen free radical production endangers graft survival and that the hydroxyl radical scavenger DMTU protects syngeneic islet grafts.

Topics: Animals; Blood Glucose; Body Weight; Graft Survival; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Rats; Rats, Inbred Strains; Reference Values; Thiourea; Transplantation, Isogeneic

Lung injury induced by phorbol myristate acetate (PMA) is closely associated with toxic oxidants released from activated granulocytes. But the major toxic oxidant causing lung damage is not really known. We have, therefore, conducted investigations using various oxygen radical scavengers. The intravenous administration of dimethylthiourea (DMTU), a potent hydroxyl radical scavenger, or of superoxide dismutase (SOD), a superoxide anion scavenger, plus catalase, a hydrogen peroxide scavenger, to rabbits intravenously injected with PMA prevented biochemical data and cellularity indicative of lung damage in lung lavages. Morphologically, the lungs of PMA-injected rabbits revealed mild interstitial edema, aggregates of granulocytes within the interstitial capillaries, and the increase of granulocytes in alveolar spaces. Furthermore, there was direct morphologic evidence of pulmonary endothelial cell disruption. In rabbits treated with DMTU or SOD plus catalase, there was no evidence of destructive changes in the lungs. SOD-treated rabbits did not show evidence of protection from PMA-induced lung injury. Only a little protection was provided by catalase treatment. Moreover, in the ultracytochemical study for examination of hydrogen peroxide (H2O2) generation, the number of H2O2-generated granulocytes remarkably decreased in lung lavages of catalase-treated rabbits, but destructive changes were observed in the lungs. In contrast, though the number of H2O2-generated granulocyte was not decreased in lung lavages of DMTU-treated rabbits, treatment with DMTU could afford protection from lung injury. These data indicate that the hydroxyl radical, a toxic oxidant derived from stimulated granulocytes, is deeply involved in the pathogenesis of PMA-induced lung injury.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Catalase; Cell Count; Free Radicals; Granulocytes; Histocytochemistry; Hydrogen Peroxide; Hydroxides; Hydroxyl Radical; Lung; Lung Diseases; Male; Organ Size; Rabbits; Superoxide Dismutase; Superoxides; Tetradecanoylphorbol Acetate; Thiourea