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PubMed1981

Correlation between vascular smooth muscle relaxation and increase in cyclic GMP induced by some organic nitro esters.

Three different nitro compounds glyceryl mononitrate (GMN), glyceryl dinitrate (GDN) and ethylene glycol dinitrate (EGDN) were tested on histamine contracted bovine mesenteric artery. GDN and EGDN caused a dose-dependent relaxation which was accompanied by an increase in the endogenous cGMP level. The ED50-value for GDN and EGDN with regard to the relaxant action was 1.06 X 10(-6) M and 4.20 X 10(-8), respectively. GMN was almost completely ineffective as a relaxing agent and did not cause any significant change in cGMP. Regression analysis revealed a significant correlation between relaxation and increase in cGMP for both GDN and EGDN. The regression model for EGDN could be significantly improved by including the squared cGMP change, indicating a non-linear relationship. With regard to GDN a hyperbolic relationship between relaxation and cGMP increase was found. A slight improvement of the regression model was found for EGDN when the change in cAMP was included. For GMN and GDN no improvement of the regression model could be revealed by including the change of cAMP. It is suggested that the present data give further evidence for cGMP as a mediator of vascular smooth muscle relaxation induced by nitro compounds.

Animals↗
PubMed1994

Effects of CD-832, a dihydropyridine derivative with a nitrate ester moiety on rabbit femoral artery and vein.

We investigated the effects of CD-832 ((4R)-(-)-2-(nicotinoyl-amino)ethyl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a dihydropyridine derivative with a nitrate ester moiety, on contractile responses in rabbit femoral arteries and veins. CD-832 (10(-8) to 10(-6) M and nifedipine inhibited the 64 mM KCl-induced and 10(-6) M norepinephrine-induced contractions of rabbit femoral arteries, while nitro compounds had no effect on the contractions. CD-832 (10(-8) to 10(-6) M) and nitro compounds inhibited the 10(-6) M norepinephrine-induced contractions in rabbit femoral veins, while other Ca2+ channel antagonists had little effect. The inhibitory effects of CD-832 (10(-7) M) on norepinephrine-induced contractions were antagonized by treatment with methylene blue (10(-5) M). These results indicate that CD-832 potently relaxes venous smooth muscle, and that it may be a useful agent for the treatment of angina pectoris.

Animals↗
PubMed1990

Nitro analogues of chlorambucil as potential hypoxia-selective anti-tumour drugs.

The chlorambucil isomer 4-[3-[N,N-bis(2-chloroethyl)amino]phenyl] butanoic acid (m-chlorambucil) has been synthesized for the first time, and the two isometric nitro derivatives of both m-chlorambucil and chlorambucil itself have been prepared as potential hypoxia-selective cytotoxins. Reduction potentials (E1/2) of the two nitro compounds were determined by cyclic voltammetry, and one-electron reduction potentials (E(1] were estimated. Both the chlorambucil isomers and the derived nitro compounds crosslink DNA, as determined by their cytotoxicity ratios in DNA repair-proficient and -deficient cell lines, but neither of the nitro derivatives showed selective toxicity under hypoxic conditions, probably due to their rather low reduction potentials.

Animals↗
PubMed1991

Temperature effects on the one-electron reduction potentials of nitroaryl compounds.

Pulse radiolysis was used to establish one-electron transfer equilibria between radical cations of methyl or benzyl viologens (V2+) and nitroaryl compounds (ArNO2): a nitroimidazole (misonidazole or metronidazole), 4-nitrobenzoate or nitrofurazone. The equilibrium constants in water at pH 8 were estimated over the temperature range approximately 5 to 75 degrees C. The difference delta E in mid-point one-electron reduction potentials between the nitro compounds and the viologens varied with temperature T; increasing temperature made the nitro compounds apparently less electron-affinic compared to the effects of temperature on the viologen potential. Values of delta(delta E)/delta T were in the range -0.7 to -1.1 mV K-1 at 25 degrees C. If delta[E(V2+/V.+)]/delta T = -0.9 mV K-1 for methyl viologen then delta[E(ArNO2/ArNO2.-)]/delta T is about -2 mV K-1 for these compounds.

Benzyl Viologen↗
PubMed1988

In vitro and in vivo mutagenicity studies with airborne particulate extracts.

The contribution of nitro compounds to airborne particulate mutagenicity was studied with Salmonella typhimurium strains TA98, TA98NR, TA98/1,8DNP6. The results obtained indicate that nitropyrenes play a minor role in air particulate mutagenicity. Seasonal variations indicate a relatively greater contribution of nitro compounds to the mutagenicity of spring and summer samples. Fractionation of extracts into acidic, neutral and basic components shows that neutral compounds account for about two-thirds of the total mutagenic activity. Attempts to extract mutagens adsorbed onto particulate matter with aqueous media were almost completely negative. No significant mutagenicity was detected in urine and faecal extracts and in plasma samples of Sprague-Dawley rats treated with air particulate extracts at 80 mg/kg either per os or by i.p. injection. Negative results were obtained in the micronucleus test with Swiss mice treated at 200 and 400 mg/kg (twice by i.p. injection). A significant decrease in liver aminopyrine-N-demethylase was observed in Swiss mice injected with air particulate extracts or its basic and neutral fractions. In vitro experiments suggest a direct interaction of test materials with microsomal cytochrome P-450.

Aerosols↗
PubMed1977

Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations.

Nitric oxide gas (NO) increased guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity in soluble and particulate preparations from various tissues. The effect was dose-dependent and was observed with all tissue preparations examined. The extent of activation was variable among different tissue preparations and was greatest (19- to 33-fold) with supernatant fractions of homogenates from liver, lung, tracheal smooth muscle, heart, kidney, cerebral cortex, and cerebellum. Smaller effects (5- to 14-fold) were observed with supernatant fractions from skeletal muscle, spleen, intestinal muscle, adrenal, and epididymal fat. Activation was also observed with partially purified preparations of guanylate cyclase. Activation of rat liver supernatant preparations was augmented slightly with reducing agents, decreased with some oxidizing agents, and greater in a nitrogen than in an oxygen atmosphere. After activation with NO, guanylate cyclase activity decreased with a half-life of 3-4 at 4 degrees but re-exposure to NO resulted in reactivation of preparations. Sodium azide, sodium nitrite, hydroxylamine, and sodium nitroprusside also increased guanylate cyclase activity as reported previously. NO alone and in combination with these agents produced approximately the same degree of maximal activation, suggesting that all of these agents act through a similar mechanism. NO also increased the accumulation of cyclic GMP but not cyclic AMP in incubations of minces from various rat tissues. We propose that various nitro compounds and those capable of forming NO in incubations activate guanylate cyclase through a similar but undefined mechanism. These effects may explain the high activities of guanylate cyclase in certain tissues (e.g., lung and intestinal mucosa) that are exposed to environmental nitro compounds.

Animals↗
PubMed2005

The mechanistic origin of regiochemical changes in the nitrosative N-dealkylation of N,N-dialkyl aromatic amines.

The regioselectivity of the nitrous acid mediated dealkylation of 4-substituted-N-ethyl-N-methylanilines is a function of the acidity of the reaction mixture. At high acidity deethylation predominates, whereas demethylation is the predominant reaction in nitrosamine formation at pH 2 and above. In some cases the regioselectivity of nitrosative dealkylation changes as the run proceeds. Through the use of the corresponding 4-nitroaniline as the primary substrate, CIDNP, kinetics, kinetic deuterium isotope effects and other transformations involving nitrosations with NO2 or NOBF4 in aprotic solvents, a new mechanism of tertiary amine nitrosation has been deduced and proposed to explain regioselective deethylation. The mechanism involves the oxidation of the substrate to the amine radical cation by NO+. This is followed by the abstraction of a hydrogen atom from the carbon adjacent to the amine nitrogen by NO2 to produce an iminium ion which reacts further to produce the corresponding aldehyde and the nitrosamine. Depending upon the acidity, this process competes with three other mechanistic pathways, two of which give the nitrosamine through the iminium ion, and one leads to the formation of C-nitro compounds. The competing pathways to nitrosamine formation involve NOH elimination from a nitrosammonium ion and deprotonation of the radical cation to give an alpha-amino radical which rapidly oxidized to the iminium ion. Predominant, but not highly regioselective demethylation occurs by these pathways. Nitro compound formation principally arises from the reaction of NO2 with the radical cation followed by deprotonation, but also occurs by para C-nitrosation followed by oxidation.

Amines↗
PubMed1992

Simultaneous determination of nitroglycerin and its dinitrate metabolites by capillary gas chromatography with electron-capture detection.

A major problem in the analysis of nitroglycerin (propanetriol trinitrate, GTN) and its metabolites [propanetriol 1,2-dinitrate (1,2-GDN) and propanetriol 1,3-dinitrate (1,3-GDN)] has been the adsorption of the nitro compounds to glass apparatus during sample preparation or injection. In this paper we present a method determining GTN, 1,2-GDN and 1,3-GDN in plasma at low nanomolar level using capillary gas chromatography with electron-capture detection. The detection limits are about 0.2 nM in plasma. Adsorption of the nitro compounds to glassware is prevented by using triethylamine, giving a simple sample preparation and accurate results. Thus, the laborious and time-consuming silanization of the glassware is avoided.

Chromatography, Gas↗
PubMed1994

Reduction and mutagenic activation of nitroaromatic compounds by a Mycobacterium sp.

Mycobacterium sp. strain Pyr-1 cells, which were grown to the stationary phase in media with and without pyrene, were centrifuged and resuspended in a medium containing 1-nitropyrene. Cells that had been grown with pyrene oxidized up to 20% of the added 1-nitropyrene to 1-nitropyrene-cis-9,10- and 4,5-dihydrodiols. However, cells that had been grown without pyrene reduced up to 70% of the 1-nitropyrene to 1-aminopyrene but did not produce dihydrodiols. The nitroreductase activity was oxygen insensitive, intracellular, and inducible by nitro compounds. Nitroreductase activity was inhibited by p-chlorobenzoic acid, o-iodosobenzoic acid, menadione, dicumarol, and antimycin A. Extracts from cells that had been grown without pyrene activated 1-nitropyrene, 1-amino-7-nitrofluorene, 2,7-dinitro-9-fluorenone, 1,3-dinitropyrene, 1,6-dinitropyrene, and 6-nitrochrysene to DNA-damaging products, as shown in Salmonella typhimurium tester strains by the reversion assay and by induction of the umuC gene. Activation of nitro compounds, as shown by the umu test, was enhanced by NADPH. This study shows that Mycobacterium sp. strain Pyr-1 metabolizes nitroaromatic compounds by both oxidative and reductive pathways. During reduction, it generates products that are mutagenic.

Bacterial Proteins↗
PubMed1986

Biochemistry of reduction of nitro heterocycles.

Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Toxicity of Kalanchoe spp to chicks.

Leaves of Kalanchoe daigremontiana, K tubiflora, K fedtschenkoi, K tomentosa, K tomentosa X K beharensis, and 4 cultivars of K blossfeldiana were tested for toxicity to 2-week-old Leghorn chicks. These species were analyzed for percentage of alkaloids, aliphatic nitro compounds, soluble oxalates, and nitrates and were examined qualitatively for cyanogenic glycosides. The solubility of the toxic principle in K daigremontiana was determined. Leaves of K daigremontiana, K tubiflora, and K fedtschenkoi were toxic to chicks at dosage levels of 8 to 12 mg/g of body weight. Toxic signs included depression, muscular incoordination, twitching and spiraling of the neck, tremors, convulsions, paralysis, and death. Kalanchoe tomentosa, K tomentosa X K beharensis, and 4 cultivars of K blossfeldiana were nontoxic at the highest dosage levels tested. Aliphatic nitro compounds and cyanogenic glycosides were not detected in any species. Alkaloids, nitrates, and soluble oxalates were present only in nontoxic concentrations. The toxic principle in K daigremontiana was soluble in 50%, 80%, and 100% ethanol, slightly soluble in water and acetone, and insoluble in benzene, chloroform, and ether.

Animals↗
PubMed1999

Nitroreductase A is regulated as a member of the soxRS regulon of Escherichia coli.

Nitroreductase A catalyzes the divalent reduction of nitro compounds, quinones, and dyes by NADPH. In this paper, nitroreductase A is induced in Escherichia coli by exposure to paraquat in a manner that depends on the expression of soxR. Nitroreductase activity was only slightly induced by paraquat in a strain bearing a mutational defect in the gene encoding nitroreductase A, but it was approximately 3-fold induced in the parental strain. Nitroreductase A thus appears to be a member of the soxRS regulon and probably contributes to the defenses against oxidative stress by minimizing the redox cycling attendant upon the univalent reduction of nitro compounds, quinones, and dyes.

Drug Resistance, Neoplasm↗
PubMed1988

Metabolism of drugs in the eye. Drug-reducing activity of preparations from bovine ciliary body.

Drug-metabolizing activities, especially the reductase activities towards N-oxide, hydroxamic acid, sulfoxide and nitro compounds were comparatively examined with bovine ciliary body. As described previously, the cytosol from the ocular tissue exhibits the nicotinamide N-oxide reductase activity when supplemented with 2-hydroxypyrimidine, an electron donor of aldehyde oxidase. When the cytosol was fractionated with ammonium sulfate, followed by assays of aldehyde oxidase and nicotinamide N-oxide reductase activities in each fraction, the distribution of aldehyde oxidase activity in the resultant ammonium sulfate fractions was nearly parallel to that of nicotinamide N-oxide reductase activity. Furthermore, reductase activities towards drugs such as sulfoxide, hydroxamic acid and nitro compounds were observed with the cytosol in the presence of 2-hydroxypyrimidine or N1-methylnicotinamide. In general, these reductase activities of the fraction were markedly inhibited by menadione, an inhibitor of aldehyde oxidase. These results suggest that aldehyde oxidase present in ciliary body plays an important role in the reduction of a variety of xenobiotics in mammalian eyes. However, in the case of imipramine N-oxide, its reduction in the ocular tissue appears to be more readily catalyzed by a menadione-linked enzyme different from aldehyde oxidase.

Aldehyde Oxidoreductases↗
PubMed2004

Myoglobin as an efficient electrocatalyst for nitromethane reduction.

Xenobiotic metabolizing heme enzymes are thought to take a crucial part in the activation of a variety of carcinogens, including nitro compounds, through catalytic electron-transfer reactions, especially under anaerobic conditions. Myoglobin (Mb), as a model heme enzyme, is found to act as an efficient electrocatalyst for the reduction of nitromethane in thin surfactant films on pyrolytic graphite electrodes. The electrocatalytic process is characterized by cyclic voltammetry. The Mb-Fe(II)-nitrosomethane complex, a possible intermediate in the catalysis, is characterized spectroscopically in the surfactant film on indium tin oxide electrodes. Bulk electrolysis indicates the formation of mainly methylhydroxylamine as an end aqueous product. A rationale for the catalysis invokes the highly reduced Fe(I) state of myoglobin in surfactant film; the latter engages in efficient inner-sphere electron transfers to the nitro compound coupled to proton transfers.

Animals↗
PubMedDate not supplied

[Intracellular signal systems in the epithelium- and endothelium-dependent relaxation of smooth muscles].

The research of mechanisms of a regulation electrical and contractile of properties of unstriated muscles of an internals remains by an actual problem of modern physiology and medicine. Already now it is possible to state that the efficacy of means of correction of distresses of an internals depends on a degree of a level of scrutiny of these mechanisms. Among physiologically active substances effecting on smooth muscle cells (SM), the special relaxing factor synthesized by endotheliocytes, epithelial cells and SM. Identified by the majority of the explorers as oxide of nitrogen (NO), relaxing factor responds for exhibiting of many myogenic responses of pots and pneumatic routes. The mechanisms of synthesis and implementation of effects of this factor in SM cells up to the extremity are not clarified. The considerable advance in learning mechanisms of operation relaxing factor on SM is connected to discovering of ability of some nitro compounds to replicate NO-dependent relaxing effects in these cells. The main systems of intracellular regulation are involved in mechanisms of implementation endothelial and epithelial local regulatory effects on SM. The majority of the explorers bind an epithelium-dependent release phenomenon SM to an activation of a solvable fraction guanilatcyclase, found in the majority of cells, and effects of cGMP-dependent protein kinases. There are reports on ability of inhibitors NO-sintase to depress a release phenomenon SM of pots and bronchuses, about dependence of a mechanical strain SM of pots and respiratory tract from a contents cGMP in cells. However there are datas giving establishments to guess, that alongside with guanilatciclase in a release phenomenon SM, induced relaxing factors or nitro compounds, the immediate involvement is accepted by cAMP-dependent protein kinases. The most probable point of interaction cAMP and cGMP-dependent processes is phospodiesterase of cyclic nucleotides. It citosolium the enzyme labilized by calmodulin, is capable to carry out a hydrolysis of both cyclic nucleotides, and the affinity native phospodiesterase to cGMP exceeds affinity to cAMP more, than on the order. It is impossible to eliminate immediate interference of NO-dependent processes in a regulation of activity contractile proteins. The ability cGMP-dependent processes to depressing mechanisms of phosphorylation and intensifying of a dephosphorylization of contraktion proteins SM is shown. At these processes can variate and affinity of the acto-miosin complex to ions of calcium, producing a release phenomenon of smooth muscles. On all visibility, production relaxing of the factor and the implementation is epithelial and endothelium-SM of mutual relation in a respiratory tract and pots comes true by modulating influence at the calcium signal system of other systems. For example, production relaxing of the factor by an epithelium and endothelium, being calcium-dependent process, is regulated at involvement calmodulin-similar Ca(2+)-connecting proteins and protein kinase C. Control of tone SM through change of membrane potential relaxing factor carries out by paravariation of potassium conduction of a membrane SM, and, is more probable than all through calcium-dependent and ATP-sensitive components. Potencial-dependent control of a muscle tone comes true through change of efficacy of an operation from a branch of the calcium signal system and calcium pompes at submaximal concentrations of free calcium in citosolium.

Animals↗
PubMed1984

Nitroheterocycle metabolism in mammalian cells. Stimulation of the hexose monophosphate shunt.

Misonidazole, SR-2508, nitrofurazone and other nitroheterocycles stimulated release of 14CO2 from [1-14C]glucose but not from [6-14C]glucose when incubated with mouse Ehrlich ascites cells or human A549 lung carcinoma cells in vitro. This demonstrated that the nitro compounds activated the hexose monophosphate shunt and is evidence that an important pathway of nitro reduction in these cell lines is electron transfer from NADPH-dependent cytochrome c reductase to the nitro group. Shunt activity was stimulated under both aerobic and anaerobic conditions. For catalase-free Ehrlich cells, aerobic effects were greater than anaerobic, indicating that NADPH was used for reduction of H2O2, via GSH peroxidase and reductase, as well as for one-electron nitro reduction, under aerobic conditions. Several of the compounds tested stimulated 14CO2 release from [2-14C]glucose as well as from [1-14C]-glucose. This shows that the cellular requirement for NADPH, in the presence of nitro drug, was great enough to cause recycling of pentose phosphates. Recycling could decrease the availability of ribose-5-P needed for nucleic acid synthesis, which could partly explain the inhibition of DNA synthesis observed upon prolonged aerobic incubation of cells with nitro compounds. Comparison of the rate of disappearance of nitrofurazone from anaerobic A549 cell suspensions with the rate of 14CO2 release suggests that the drug reduction in this cell line was catalyzed almost entirely by NADPH-requiring enzymes.

Anaerobiosis↗
PubMed1989

Coronary vasodilation with nitrocompounds--is there a maximum?

The maximal extent of the dilation of epicardial coronary arteries attainable with nitro-compounds was investigated in 12 patients with coronary artery disease. Before and 5, 10, 15, 19, 60 and 64 min after onset of a 4-min-intravenous infusion of 0.025 mg SIN-1/kg bodyweight coronary angiograms were performed in identical projection; simultaneously, the mean pulmonary wedge pressure (PWP) was measured. At 15 and 60 min, 0.8 mg nitroglycerin (NTG) were additionally administered as sublingual spray. Mean diameters of angiographically normal coronary segments were analyzed with the computer-assisted contour detection system CAAS; they increased by an average maximum of 29 +/- 5% prior to NTG (p less than 0.001). PWP decreased from 9.2 +/- 3.1 mmHg to an average minimum of 4.3 +/- 1.6 mmHg (p less than 0.01) prior to NTG. Neither of these SIN-1-effects was significantly augmented by additional NTG: at 19 min coronary dilation amounted to 28 +/- 7% (p less than 0.001), PWP to 3.9 +/- 1.0 mmHg (p less than 0.01). At 60 min coronary dilation still amounted to 24 +/- 8% (p less than 0.001), PWP to 6.2 +/- 2.5 mmHg (p less than 0.05). By the second administration of NTG the maximal effects attained before could be reproduced: coronary dilation 28 +/- 8% (p less than 0.001), PWP 4.6 +/- 2.2 mmHg (p less than 0.01). Thus, the dilation reserve of epicardial coronary arteries for nitrocompounds is approximately 30% on average. These results suggest the possibility of a reproducible maximal activation of the enzyme guanylate cyclase which seems to be the mediator of the nitro-compound-induced vasodilation.

Administration, Sublingual↗