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PubMedDate not supplied

Cimetidine as a scavenger of ethanol-induced free radicals.

Free radical generation and the mobilization of catalytic iron are important in the pathogenesis of alcohol-induced liver injury. Cimetidine is a free radical scavenger in thermal skin injury and cobra venom-induced lung injury, and was therefore investigated as a scavenger of ethanol-induced free radicals. In vitro cimetidine inhibited iron-mediated cleavage of DNA as well as the potentiation of such cleavage by bleomycin. Peroxidation of microsomes by xanthine-xanthine oxidase, acetaldehyde-xanthine oxidase, as well as by the addition of low-molecular weight iron chelates were inhibited (17-100%) by cimetidine (0.1-1 mM). Free radical generation due to ethanol in isolated rat hepatocytes was studied by measuring ethane and pentane production. Cimetidine (1 mM) significantly decreased ethane and pentane production due to ethanol: 1 mM (2.2 +/- 0.3 vs. 1.0 +/- 0.2 pmol ethane per 10(6) cells/h; p less than 0.01, 4.2 +/- 0.4 versus 1.6 +/- 0.3 pmole per 10(6) cells/h pentane; p less than 0.001). Similar inhibitions were observed in the isolated perfused liver. Studies of superoxide reduction of ferricytochrome-C as well as hydroxyl radical generation by Fe(+)+/EDTA/ascorbate revealed that cimetidine was an effective hydroxyl radical scavenger. In summary, in a variety of in vitro systems, as well as in isolated hepatocytes and perfused liver, cimetidine inhibits ethanol-induced free radical injury. These findings may warrant its investigation as a therapeutic agent.

Animals↗
PubMed1992

Importance of oxygen free radicals during ischemia and reperfusion in the experimental and clinical setting. Oxygen free radicals and the heart.

In recent years there has been considerable interest concerning the role of oxygen radicals in myocardial ischemia and reperfusion injury. The sequential univalent reduction of oxygen gives rise to very reactive intermediate products. Normally, the tissue concentration of these intermediate products of oxygen is limited and the aerobic myocardium survives because of the existence of a delicate balance between the generation of the various oxidants and the maintenance of the antioxidant defense mechanism. Several possible sources have been identified for the production of active oxygen species after ischemia and reperfusion and these sources may be mutually interactive. The ability of scavengers of oxygen free radicals to improve mechanical, mitochondrial, and sarcoplasmic reticulum function in animal models of ischemic-reperfusion injury also suggests that oxygen free radicals are partly responsible for myocardial damage in these models, although caution in the interpretation of these data is necessary. Evidence in favour of and against this hypothesis is described in detail in the present article.

Animals↗
PubMed1992

[Biological roles of free radicals: introduction].

Free radicals are produced during cellular oxidations. The primary ones are superoxide anions (O2-) and hydroxyl radicals (OH). They generate in vivo various secondary radicals. Radical mechanisms are invoked in a number of biological processes including, phagocytosis, ischemia or ageing.

Free Radicals↗
PubMedDate not supplied

[Free radical oxidation of biological membrane lipids. VII. Effect of ultraviolet radiation on free radical oxidation of lipids complexed with protein and in biomembranes].

Promoting effect of protein component on the development of free radical oxidation in the systems ethylarahidonate--bovine serum albumin and mitochondria suspension under UV irradiation has been shown. Connection between the processes of peroxide formation and the change of the functional activity of organells has been followed.

Arachidonic Acids↗
PubMed1992

Physico-chemical modeling of the role of free radicals in photo-dynamic therapy. I. Utilization of quantum yield data of singlet oxygen formation for the study of the interaction between excited photosensitizer and stable free radicals.

The measurement of the relative quantum yield of singlet oxygen formation, a simple process without tedious sample deoxygenation, is shown to furnish data on the interaction of the excited photosensitizer with any additive (in this case stable free radicals) given to the sample. The rate constants derived from such measurements are in good agreement with direct determination of the corresponding values.

Free Radicals↗
PubMed1991

Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts.

Free radicals have been implicated in the pathogenesis of reperfusion injury, but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before, during, and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i, fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5,5'-difluoro derivative of 1,2-bis-(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1,026 +/- 295 nM 4 min after free radical generation (means +/- SEM, n = 7), and remained elevated thereafter. We conclude that free radicals induce clear-cut, specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.

Adenosine Triphosphate↗
PubMed1992

[Oxygen free radicals in cardiology].

Oxygen free radicals are extremely toxic chemical entities derived from oxygen metabolism. This is a physiological process which explains a great deal of the phenomenon of phagocytosis. Under normal conditions, the body's natural defense mechanism neutralise the oxygen-free radicals as they are produced. In certain pathological situations, a disequilibrium is observed between the free radical aggression and the defense systems which creates an oxidative stress and organ damage. In cardiology, the oxidative stress occurs essentially in the phenomenon of reperfusion ischaemia. It is partially responsible for the reperfusion arrhythmias and myocardial stunning. An irreversible myocardial disease such as myocardial infarction, the responsibility of the oxidative stress is more uncertain. In myocardial protection during cardiac surgery the radical-induced damage occurs without it being possible to demonstrate the phenomenon in irreversible myocardial disease. The role of oxidative stress is unquestionable in myocardial reperfusion ischaemia. The detection of sensitive biological markers and a better understanding of the physiopathology should increase our knowledge of oxygen free radicals and enable effective treatment of their complications.

Arrhythmias, Cardiac↗
PubMed1992

Free radical theory of aging.

Free radical reactions are ubiquitous in living things. Studies on the origin and evolution of life provide a reasonable explanation for the prominent presence of this unruly class of chemical reactions. These reactions have been implicated in aging. This phenomenon is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. Aging changes are attributed to the environment and disease, and to an inborn process, the aging process. The latter produces aging changes at an exponentially increasing rate with advancing age. Past improvements in general living conditions have decreased the chances for death so that they are now near limiting values in the developed countries. In these countries the intrinsic aging process is the major cause of disease and death after about age 28. The free radical theory of aging postulates that aging changes are caused by free radical reactions. The data supporting this theory indicate that average life expectancy at birth may be increased by 5 or more years, by nutritious low caloric diets supplemented with one or more free radical reaction inhibitors.

Aging↗
PubMedDate not supplied

Free radicals in physiology and pathology.

Free radicals are molecules with odd number of electrons and a high instability. Free radicals, which can occur in both organic (i.e., quinones) and inorganic molecules (i.e., O2-), are very reactive and their reactions are critical for the normal activity of a wide spectrum of biologic processes. They are also produced in the catalytic action of a variety of cellular enzymes and electron transport processes and are implicated in a number of physiologic and pathologic processes. Organisms can be exposed to free radicals in many ways other than through the processes of normal metabolism. Irradiation of organisms with electromagnetic radiation generates primary radicals (e-aq, OH., and H.), which can then undergo secondary reactions with dissolved O2 or with cellular solutes. In addition, a wide variety of environmental agents (drugs capable of redox cycling, and xenobiotics that can form free radical metabolites) including the aging process cause free radical damage to cells. This review deals with the reactions they can undergo and discusses the free radicals related to toxicology.

Aldehydes↗
PubMed1992

Neutrophil accumulation in ischemic reperfused rat liver: evidence for a role for superoxide free radicals.

Oxygen-derived free radicals and leukocytes have been implicated in the pathogenesis of ischemia-reperfusion injury. This study aimed at determining, by using biochemical and histochemical techniques, whether an accumulation of neutrophils occurs in the ischemic reperfused rat liver and whether superoxide free radicals play a role in mediating this neutrophil accumulation. Hepatic ischemia was induced by occluding blood supply to the left and median lobes, and reperfusion was reinstituted by releasing the occlusion. Myeloperoxidase activity of the liver was measured with a tetramethylbenzidine-H2O2 assay after removal of glutathione (by dialysis) and in the presence of 3-aminotriazole (catalase inhibitor). A modification of Graham and Karnovsky's method was used to stain neutrophils in liver frozen sections, and the number of neutrophils was counted. Results showed that ischemia-reperfusion of the liver produced a 4.4-fold increase in myeloperoxidase activity (from 0.073 +/- 0.009 to 0.320 +/- 0.017 units/mg liver, means +/- SE), which was proportional to the number of neutrophils (3.1-fold increase from 18 +/- 7 to 57 +/- 4 cells/mm2) in the liver tissue. Pretreatment with long-acting superoxide dismutase significantly attenuated the elevated myeloperoxidase activity and the number of neutrophils. These results indicate that reperfusion after a period of ischemia induces an accumulation of neutrophils in the liver, and superoxide anion free radicals are important mediators in the mechanism of this neutrophil accumulation.

Animals↗
PubMed1991

ESR spin trapping studies on the free radicals in gasphase of cigarette smoking.

Free radicals in the gasphase of cigarette smoke were determined by spin trapping agent PBN (N-tert-butyl-2-phenyl nitrone) and DMPO (5,5-dimethyl-1-pyrroline-oxide) on electron spin resonance spectrometer. They were identified according to the spectrum parameters calculated from the spectra. The free radicals mainly consist of alkoxyl and alkyl free radicals, of which alkoxyl free radicals make up 60-70% of the total spectral components. These free radicals are very active and reactive. They can damage cells and lead to some diseases. This work points out the importance of scavenging the free radicals of cigarette smoke to prevent diseases caused by them.

Cyclic N-Oxides↗
PubMed1992

Oxygen free radicals and cardiac reperfusion abnormalities.

Oxygen free radicals are highly reactive compounds causing peroxidation of lipids and proteins and are thought to play an important role in the pathogenesis of reperfusion abnormalities including myocardial stunning, irreversible injury, and reperfusion arrhythmias. Free radical accumulation has been measured in ischemic and reperfused myocardium directly using techniques such as electron paramagnetic resonance spectroscopy and tissue chemiluminescence and indirectly using biochemical assays of lipid peroxidation products. Potential sources of free radicals during ischemia and reperfusion have been identified in myocytes, vascular endothelium, and leukocytes. In several different experimental models exogenous free radical-generating systems have been shown to produce alterations in cardiac function that resemble the various reperfusion abnormalities described above. Injury to processes involved in regulation of the intracellular Ca2+ concentration may be a common mechanism underlying both free radical-induced and reperfusion abnormalities. Direct effects of free radicals on each of the known Ca(2+)-regulating mechanisms of the cell as well as the contractile proteins and various ionic membrane currents have been described. Free radicals also inhibit critical enzymes in anaerobic and aerobic metabolic pathways, which may limit the metabolic reserve of reperfused myocardium and contribute to intracellular Ca2+ overload. Inhibiting free radical accumulation during myocardial ischemia/reperfusion with free radical scavengers and inhibitors has been demonstrated to reduce the severity of myocardial stunning, irreversible injury, and reperfusion arrhythmias in many, but not all, studies. This evidence strongly implicates free radical accumulation during myocardial ischemia/reperfusion as an important pathophysiological mechanism of reperfusion abnormalities, although many issues remain unresolved.

Animals↗
PubMed1992

Evidence for free radical mechanisms of brain injury resulting from ischemia/reperfusion-induced events.

Free radicals have been implicated in the injury that occurs to brain tissue in response to ischemia and reperfusion insults. Confirmatory in vivo studies have been limited by the difficulty in measuring free radicals in brain tissue. This review discusses potential mechanisms for free radical production in brain tissue and the evidence supporting the therapeutic efficacy of free radical scavengers. Free radicals may be produced during ischemia/reperfusion as a result of multiple mechanisms involving normal regulatory systems of intra-/extracellular metabolism. For example, metabolism of free fatty acids by the cyclo-oxygenase pathway and adenine nucleotides by xanthine oxidase has been proposed to produce free radical adducts during reperfusion. Therapeutic strategies aimed at decreasing brain injury from free radical production include administration of free radical scavengers at the time of reperfusion. Pharmacologic interventions for protection from free radical injury in brain are hindered because of limited access to the site of free production.

Animals↗
PubMedDate not supplied

Oxygen free radical damage of isolated cardiomyocytes: comparative protective effect of radical scavengers and calcium antagonists.

Oxygen free radicals have been shown to play a major role in the development of perfusion abnormalities, contractile dysfunction, and irreversible injury in ischemic-reperfused myocardium. The aim of this study was to assess the direct protective effects of radical scavengers, calcium antagonists, and combination of these substances against free radical induced myocyte damage. Viability (% of rod-shaped cells) and adenine nucleotide content (AdN, high-pressure liquid chromatography) of isolated adult rat cardiomyocytes were measured after exposure to hypoxanthine (2 mM) and xanthine oxidase (25 mU/ml). After 90 min, viability of myocytes decreased to 4.2 +/- 3.4% (mean +/- SEM) of pre-exposure control, and AdN decreased from 28.2 +/- 1.8 to 8.09 +/- 1.1 nmol/mg protein. Addition of catalase (1500 U/ml) resulted in the preservation of viability (77 +/- 6% of pre-exposure control, n = 6, mean +/- SEM), and AdN 84 +/- 6%, p less than 0.001. These values are not significantly different from those measured in myocytes not exposed to free radicals (88 +/- 9% and 79 +/- 6%, respectively). Superoxide dismutase (2400 U/ml), dimethylthiourea (10 mM), and desferrioxamine (1 mM) did not preserve either viability or AdN. The calcium antagonist verapamil (10 microM) also preserved myocyte viability significantly (23 +/- 9.7%, p less than 0.05 vs unprotected cells), but failed to prevent the loss of AdN (13.2 +/- 4%, not significant as compared to unprotected cells). Viability and AdN in myocytes treated with nifedipine (10 microM) or diltiazem (10 microM) were not higher than in unprotected cells. All combined treatment forms which included catalase resulted in the preservation of myocyte viability as well as AdN. These data show that only the hydrogen peroxide scavenger catalase protects isolated cardiomyocytes against free radicals generated in the purine catabolic pathway.

Adenine Nucleotides↗
PubMed1992

Free radicals, lipid peroxidation, SOD activity, neurotransmitters and choline acetyltransferase activity in the aged rat brain.

The mechanism of aging is suggested to be related to oxygen free radicals. Free radicals, lipid peroxidation and SOD activity have been reported to be increased in the aged brain. A Japanese herbal medicine, Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960), which has scavenging activities against hydroxyl radicals, superoxide, 1,1-diphenyl-2-picrylhydrazyl radicals, carbon-centered radicals and alpha-tocopheroxyl radicals, decreased carbon-centered radicals and thiobarbituric acid reactive substances (TBARS) levels in the aged rat brain after a 3-week oral administration of 5% TJ-960 solution. TJ-960 elevated superoxide dismutase (SOD) activity in the cytosol fraction of the hippocampus and hypothalamus of aged rats. It decreased norepinephrine and 5-hydroxytryptamine (5-HT) levels in the hypothalamus and increased the 5-HT level in the cerebellum. TJ-960 treatment increased choline acetyltransferase activity in aged rats. As herbal medicines do not generally have harmful side effects, antioxidant TJ-960 appears to be a suitable prophylactic agent against some neuronal symptoms of aging.

Aging↗