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PubMed1986

Cyanide-induced neurotoxicity: role of neuronal calcium.

The effect of cyanide on whole-brain calcium levels was determined in mice administered KCN and correlated with the neurotoxic signs manifested during acute cyanide poisoning. KCN (10mg/kg, sc) significantly increased whole-brain total calcium levels from 48.1 +/- 1.8 to 66.5 +/- 3.9 micrograms/g dry wt within 15 min after administration. The levels remained elevated for 3 hr and returned to control readings after 12 hr. Dose-response studies revealed KCN, at doses of 10-15 mg/kg, produced significant elevations of whole-brain calcium 30 min after administration. No measurable effect was obtained from lower doses which suggested a threshold effect. Pretreatment 15 min before KCN with diltiazem, a calcium channel blocker, prevented the cyanide-induced rise in whole-brain total calcium. Cyanide-induced tremors, which are centrally mediated symptoms of intoxication, were quantified and correlated with the observed changes in whole-brain calcium. Tremors were detected at 10 and 12 mg/kg KCN and peak intensity was observed at 15 min postcyanide. Pretreatment with diltiazem markedly attenuated the cyanide-induced tremors. It appears that a correlation exists between cyanide-induced change in whole-brain calcium and tremors. This study suggests that intraneuronal calcium may play an important role in mediating cyanide neurotoxicity and calcium channel blocking agents may be useful in limiting the severity of the centrally mediated symptoms of acute cyanide intoxication.

Animals↗
PubMed2001

The binding of cyanide to cytochrome d in intact cells, spheroplasts, membrane fragments and solubilized enzyme from Salmonella typhimurium.

This investigation focused on the kinetics of cyanide binding to oxidized and reduced cytochrome d in Salmonella typhimurium intact cells, spheroplasts, membrane fragments and solubilized enzyme, and on the effect of pH on this binding. Cyanide bound to the oxidized form of cytochrome d under all experimental conditions, inducing a trough at 649 nm in the oxidized-cyanide-minus-oxidized difference absorption spectra. V(max) of cyanide binding to oxidized cytochrome d at pH 7.0 was 14.0+/-2.0 pmol/min/mg protein (prot.) in intact cells, 37.0+/-3.5 pmol/min/mg prot. in spheroplasts, 125.0+/-6.0 pmol/min/mg prot. in membrane fragments, and 538.0+/-8.5 pmol/min/mg prot. in solubilized cytochrome d. The pseudo-first order rate constants were 0.004 s(-1) for intact cells, 0.005 s(-1) for spheroplasts, 0.007 s(-1) for membrane fragments and 0.025 s(-1) for the solubilized enzyme. The V(max) value was highest at pH 7.0 for intact cells and solubilized cytochrome d and at pH 8.0 for both spheroplasts and membrane fragments. The K(s) of binding at pH 7.0 was around 4 mM in intact cells, spheroplasts and membrane fragments, but was 10.5 mM in solubilized cytochrome d. This difference between the K(s) values suggested a change in conformation, upon solubilization, leading to a decrease in the affinity of cyanide for the solubilized enzyme. The K(s) value was nearly the same at all pH investigated (pH 5-10). Cyanide was found to also bind to the reduced form of cytochrome d in membrane fragments (K(s)=18+/-3 mM, V(max)=377+/-28 pmol/min/mg prot. at pH 7) and the solubilized enzyme (K(s)=18+/-1.2 mM, V(max)=649+/-45 pmol/min/mg prot. at pH 7) with a lower affinity of cyanide for the reduced cytochrome d than for the oxidized enzyme. Pseudo-first order rate constants were 0.025 s(-1) and 0.042 s(-1) respectively for membrane fragments and solubilized enzyme. The value of V(max) for cyanide binding to the reduced cytochrome d, whether membrane-bound or solubilized, increased slightly with pH (for pH 6-10) while the K(s) value dropped significantly with increasing pH. The pH dependence observed here might be interpretable as a possible role for conformational transition associated with energy transduction. Finally, this investigation pointed to the influence of the microenvironment of a protein within the cell on its reactivity.

Cyanides↗
PubMed2003

Mechanism of superoxide anion generation in intact mitochondria in the presence of lucigenin and cyanide.

In the presence of cyanide and various respiratory substrates (succinate or pyruvate + malate) addition of high concentrations of lucigenin (400 microM; Luc2+) to rat liver mitochondria can induce a short-term flash of high amplitude lucigenin-dependent chemiluminescence (LDCL). Under conditions of cytochrome oxidase inhibition by cyanide the lucigenin-induced cyanide-resistant respiration (with succinate as substrate) was not inhibited by uncouplers (FCCP) and oligomycin. Increase in transmembrane potential (Deltaphi) value by stimulating F0F1-ATPase functioning (induced by addition of MgATP to the incubation medium) caused potent stimulation of the rate of cyanide-resistant respiration. At high Deltaphi values (in the presence of MgATP) cyanide resistant respiration of mitochondria in the presence of succinate or malate with pyruvate was insensitive to tenoyltrifluoroacetone (TTFA) or rotenone, respectively. However, in both cases respiration was effectively inhibited by myxothiazol or antimycin A. Mechanisms responsible for induction of LDCL and cyanide resistant mitochondrial respiration differ. In contrast to cyanide-resistant respiration, generation of LDCL signal, that was suppressed only by combined addition of Complex III inhibitors, antimycin A and myxothiazol, is a strictly potential-dependent process. It is observed only under conditions of high Deltaphi value generated by F0F1-ATPase functioning. The data suggest lucigenin-induced intensive generation of superoxide anion in mitochondria. Based on results of inhibitor analysis of cyanide-resistant respiration and LDCL, a two-stage mechanism of autooxidizable lucigenin cation-radical (Luc*+) formation in the respiratory chain is proposed. The first stage involves two-electron Luc2+ reduction by Complexes I and II. The second stage includes one-electron oxidation of reduced lucigenin (Luc(2e)). Reactions of Luc(2e) oxidation involve coenzyme Q-binding sites of Complex III. This results in formation of autooxidizable Luc*+ and superoxide anion generation. A new scheme for lucigenin-dependent electron pathways is proposed. It includes formation of fully reduced form of lucigenin and two-electron-transferring shunts of the respiratory chain. Lucigenin-induced activation of superoxide anion formation in mitochondria is accompanied by increase in ion permeability of the inner mitochondrial membrane.

Acridines↗
PubMed1989

Cyanide toxicity in hepatocytes under aerobic and anaerobic conditions.

The effect of cyanide on cell viability and mitochondrial function was studied in hepatocytes exposed to air or argon. Cells were more susceptible to cyanide toxicity under air than under argon. Analysis of the disposition of cyanide showed that the difference in susceptibility to KCN was not due to O2-dependent differences in cyanide metabolism or elimination. Studies of mitochondrial function revealed that cyanide under aerobic conditions resulted in substantial swelling of the mitochondria, which corresponded to a matrix loading of phosphate. In addition, cyanide caused a loss of the mitochondrial protonmotive force. This was in contrast to the results for cells exposed to 30 min of anoxia alone in which there was no loss of mitochondrial delta pH, no detectable change in mitochondrial volume, and little matrix loading of phosphate. These results show that at least some of the protective mechanisms elicited by anoxia (B. S. Andersson, T. Y. Aw, and D. P. Jones. Am. J. Physiol. 252 (Cell Physiol. 21): C349-C355, 1987) are not elicited by cyanide alone. Thus cyanide under aerobic conditions does not provide a completely valid model for simple anoxia. Moreover, the results suggest that the molecular sensor necessary to signal suppression of metabolic and transport functions during neahypoxia is dependent on O2 and is neither stimulated nor antagonized by KCN.

Adenosine Triphosphate↗
PubMed1985

Cyanide and sulfide interact with nitrogenous compounds to influence the relaxation of various smooth muscles.

Sodium nitroprusside relaxed guinea pig ileum after the segment had been submaximally contracted by either histamine or acetylcholine, intact isolated rabbit gall bladder after submaximal contraction by either acetylcholine or cholecystokinin octapeptide, and rat pulmonary artery helical strips after submaximal contraction with norepinephrine. In each of these cases the relaxation produced by nitroprusside was at least partially reversed by the subsequent addition of excess sodium cyanide. Cyanide, however, in nontoxic concentrations did not reverse the spasmolytic effects of hydroxylamine hydrochloride, sodium azide, nitroglycerin, sodium nitrite, or nitric oxide hemoglobin on guinea pig ileum, nor did cyanide alone in the same concentrations have any effect. The similar interaction between nitroprusside and cyanide on rabbit aortic strips is not dependent on the presence of an intact endothelial cell layer. Also, on rabbit aortic strips and like cyanide, sodium sulfide reversed the spasmolytic effects of azide and hydroxylamine, but it had little or no effect on the relaxation induced by papaverine. Unlike cyanide, however, sulfide augmented the relaxation induced by nitroprusside, and it reversed the effects of nitric oxide hemoglobin, nitroglycerin, and nitrite. A direct chemical reaction between sulfide and nitroprusside may account for the difference between it and cyanide. Although evidence was obtained also for a direct chemical reaction between sulfide and norepinephrine, that reaction does not seem to have played a role in these results. These observations suggest the existence of at least three distinct subclasses of so-called nitric oxide vasodilators. At least in some cases cyanide and sulfide cannot be acting by the same mechanism in their modifications of the responses to the agonists.

Acetylcholine↗
PubMed1989

The effects of cyanide on neural and synaptic function in hippocampal slices.

Transverse slices from guinea pig hippocampi were exposed to micromolar concentrations of sodium cyanide while neural and synaptic function were monitored in the CA1 region. Cyanide concentrations between 10 and 200 microM rapidly depressed synaptic transmission between Schaffer collateral-commissural fibers and CA1 pyramidal cells. Analysis of input/output curves revealed that the suppression had two components, a decrease in EPSP generation and an increase in action potential threshold. Direct electrical excitability of axons was not affected. At concentrations to 500 microM, cyanide had no effect on antidromic activation of pyramidal cells. At 1000 microM, cyanide caused a moderate depression of the antidromic response in one slice while having no effect in one other. In some experiments, postsynaptic responses in the gyrus dentatus (GD), evoked by perforant path stimulation, were recorded simultaneously with CA1 responses during cyanide application. GD was found to be less sensitive to cyanide than CA1. All cyanide effects reversed rapidly and completely upon washout. These findings suggest that cyanide has a direct effect on neurons not mediated by its inhibition of metabolism.

Action Potentials↗
PubMed1997

Electrophoretic analysis of cyanide depletion by Pseudomonas alcaligenes.

Bacterial-facilitated depletion of cyanide is under development for remediation of heap leach operations in the gold mining industry. Capillary electrophoresis was found to be a powerful tool for quantifying cyanide depletion. Changes in cyanide concentration in aqueous suspensions of Pseudomonas alcaligenes bacteria and cyanide at elevated pH were easily monitored by capillary electrophoresis. The resulting data can be used to study rates of cyanide depletion by this strain of bacteria. Concentrations of these bacteria at 10(5) cells/mL were found to reduce cyanide from 100 ppm to less than 8 ppm in four days. In addition, other ions of interest in cyanide metabolism, such as formate, can be simultaneously analyzed. Direct UV detection of cyanide at 192 nm further simplifies the analytical method for these ions.

Culture Media↗
PubMed2002

Fragmentation of uric acid calculi with the holmium: YAG laser produces cyanide.

BACKGROUND AND OBJECTIVES: To independently test previously reported findings of cyanide evolution under holmium:yttrium aluminum garnet (Ho:YAG) (holmium) lithotripsy of uric acid calculi, determine if this occurs with other forms of intracorporeal lithotripsy, and establish if this occurs due to a photothermal, photochemical, or photoacoustic reaction. STUDY DESIGN/MATERIALS AND METHODS: Human uric acid calculi were fragmented in vitro through exposure to holmium, ultrasound, and electrohydraulic (EHL) energy sources. The following parameters were varied: total laser energy, individual laser pulse energy, ultrasonic energies, and EHL energies. Uric acid powder was suspended in solution and exposed to holmium laser energy in vitro. Serum and irrigant samples from a human patient were collected following intrarenal holmium lithotripsy of a uric acid calculus. All samples were analyzed for hydrogen cyanide (HCN) content. RESULTS: Holmium lithotripsy of solid uric acid calculi produces cyanide. The yield is linearly dependent upon total laser energy delivered. Pulse energy does not affect cyanide yield. Photothermal mechanisms coupling laser energy to the solid crystal lattice are responsible for the production of cyanide. Ultrasound and EHL lithotripsy do not produce cyanide. A clinically insignificant level of cyanide was detected in the blood of a single patient following laser lithotripsy of a uric acid calculus. CONCLUSIONS: Our study confirms that cyanide is produced by a photothermal mechanism during holmium laser lithotripsy of uric acid calculi, and that the amount produced is clinically insignificant.

Holmium↗
PubMed1995

Oxidative conversion of thiocyanate to cyanide by oxyhemoglobin during acid denaturation.

Human oxyhemoglobin (Hb-O2) converts thiocyanate to cyanide under acidic conditions, in a hemoglobin and thiocyanate concentration-dependent manner. Other naturally occurring hemoglobin derivatives and hematin did not result in cyanide-producing activity. Pre-denaturation completely destroyed cyanide production. In the presence of 10% phosphoric acid, 12 microM cyanide was produced by 1 mM Hb-O2 (per heme) and 1 mM thiocyanate. This conversion was observed over a wide range of acidic pH levels at 50 degrees C, with an optimal pH of 4. The production of cyanide under strong acidic conditions was completed within 1 s, while under weak acidic conditions (pH approximately 5) the production gradually increased for half an hour. Under both conditions, the time course for cyanide production coincided with the disappearance of this converting activity. Thiocyanate conversion by acidified Hb-O2 was completely suppressed by the addition of ascorbic acid, significantly suppressed by superoxide anion radical (O2-) scavengers or thiourea, but not effected by scavengers of hydroxyl radical, singlet oxygen, and protein radical. In addition to acidification, other processes for denaturation of Hb-O2 resulted in detectable production of cyanide, e.g., heating, extraction by organic solvents, and incubation with denaturating or oxidative reagents. These data suggest that O2- generated during Hb-O2 denaturation and also a hydroperoxyl radical converted under acidic conditions are the oxidizing species that convert thiocyanate to cyanide.

Biotransformation↗
PubMed1994

Prevention of cyanide-induced cytotoxicity by nutrients in isolated rat hepatocytes.

The effects of various glycolytic substrates and keto acid metabolites on the cytotoxic effects of cyanide have been studied with isolated rat hepatocytes. The sequence of cytotoxic events with 2 mM cyanide was an immediate inhibition of respiration followed by ATP depletion. Disruption of the plasma membrane occurred when 85-90% of ATP levels had been depleted. Fructose, dihydroxyacetone, glyceraldehyde, pyruvate, and alpha-ketoglutarate prevented cyanide-induced cytotoxicity and ATP depletion. Hepatocyte respiration was also restored by all except fructose. Fructose, unlike the others, also did not prevent cytotoxicity if added 30-60 min after cyanide. Fluoride, an inhibitor of the glycolytic enzyme enolase, prevented protection by fructose but not dihydroxyacetone or glyceraldehyde, suggesting that dihydroxyacetone and glyceraldehyde are cytoprotective by trapping cyanide, thereby restoring cytochrome oxidase activity and cellular ATP levels. Fructose, on the other hand, may be cytoprotective by supplying ATP through glycolysis. Hepatocytes isolated from fasted rats were five- to sevenfold more susceptible to cyanide-induced cytotoxicity. Furthermore, all glycogenic and gluconeogenic amino acids and carbohydrates were cytoprotective against cyanide toxicity toward fasted hepatocytes, suggesting that cellular energy stores determine their resistance to cyanide.

Acetaldehyde↗
PubMed1996

Paradoxical increase in peroxisomal cyanide-insensitive respiration following dietary exposure to WY-14,643 in the perfused liver.

WY-14,643, a lipid-lowering drug, increases basal rates of oxygen uptake in perfused livers. Because peroxisomes consume oxygen for H2O2 production and are induced by WY-14,643 treatment, it is possible that peroxisomal beta-oxidation can account for some of this increase in cellular respiration. Therefore, cyanide, an inhibitor of mitochondrial cytochrome oxidase, was infused into livers of WY-14,643-fed rats (0.1% WY-14,643 in laboratory rat chow for 1, 21, and 105 days) to assess peroxisomal cyanide-insensitive respiration. As expected, the addition of cyanide abolished oxygen uptake nearly completely; however, after approximately 20 min oxygen consumption unexpectedly returned to basal levels in 105-day WY-14,643-treated animals but not in untreated controls. Urea synthesis, a process dependent upon ATP, was decreased and remained low during cyanide infusion in livers from both groups, indicating that mitochondria were not responsible for this unusual increase in oxygen uptake in the presence of cyanide. Methanol metabolism, which requires oxygen to form H2O2, was decreased from 37 +/- 5 to 6 +/- 1 micromol/g/hr in all groups treated with cyanide; however, it was increased significantly about 20 min later to 25 micromol/g/hr in livers from WY-14,643-treated rats, indicating that oxygen for peroxisomal H2O2 production is involved in cellular respiration in the presence of cyanide. Fasting abolished the recovery of both oxygen uptake and methanol metabolism in WY-14,643-fed rats, suggesting that ATP for acyl CoA synthetase, an enzyme which metabolizes fatty acids to acyl CoA compounds, is provided by glycolysis. Indeed, oleate significantly increased methanol metabolism in fed control rats from 8 +/- 4 to 26 +/- 3 micromol/g/hr in the presence of cyanide, indicating that fatty acid supply is necessary for peroxisomal respiration. Taken together, these experiments demonstrate that when mitochondrial respiration is inhibited, livers from rats fed WY-14,643 chronically have the unique ability of metabolizing fatty acids through the peroxisome using glycolytic ATP.

Animals↗
PubMed1997

Tissue-specific bioenergetic effects and increased enzymatic activities following acute sublethal peroral exposure to cyanide in the mallard duck.

Protection of wildlife and in particular migratory birds, which are protected by the Migratory Bird Treaty Act, from cyanide waste in and around gold mining operations is an important environmental issue. We have investigated the bioenergetic effects of sublethal peroral cyanide exposure using the mallard duck (Anus platyrhynchos) as a model migratory bird. At cyanide concentrations well below levels considered safe by the mining industry and some regulatory agencies (50 ppm weak acid dissociable (WAD) cyanide) significant depletions of heart, liver, and brain tissue ATP levels were observed. Tissue ATP levels were restored to normal by 24 hr postexposure. Rhodanese and 3-mercaptopyruvate sulfurtransferase activities were determined in these tissues both for basal activity and post-cyanide exposure. Only brain tissue showed increased enzymatic activity following cyanide exposure, suggesting tissue-specific regulation of these enzymatic activities. These studies suggest that 50 ppm WAD cyanide is not a safe level of cyanide in water where avian wildlife exposure can occur.

Adenosine Triphosphate↗
PubMed1981

Chronic cyanide poisoning of rainbow trout and its effects on growth, respiration, and liver histopathology.

Cyanide markedly affected growth and resting metabolic rate while causing degenerative hepatic necrosis in juvenile rainbow trout (Salmo gairdneri, Richardson). This was revealed during two experiments performed in continuously renewed water at 12.5 degree C with fish fed a restricted artificial diet and exposed to assayed cyanide concentrations of 0.00, 0.01, 0.02, or 0.03 mg/L hydrogen cyanide (HCN) for 18 days. At 0.02 and 0.03 mg/L, HCN growth was reduced by 40 to 95% after 18 days. At all concentrations, cyanide caused a severe initial repression of specific growth rate, followed by a highly significant increase which was insufficient to compensate for the original repression. Previous exposure to cyanide promoted a higher resting metabolic rate during the six days following exposure, the effect increasing with cyanide concentration. At all concentrations tested, widespread cyanide-induced degenerative necrosis of hepatocytes was observed; it was more intense at higher cyanide concentrations and well established even at 0.01 mg/L HCN.

Animals↗
PubMed2006

Non-cancer health risk assessment from exposure to cyanide by resident adults from the mining operations of Bogoso Gold Limited in Ghana.

Cyanide is a very toxic chemical that is used to extract gold from its ores. Wastewaters from gold mining companies such as Bogoso Gold Limited (BGL) contain cyanide and other potentially toxic chemicals that have adverse effects on human beings and aquatic organisms. This study was conducted to evaluate the human health risk assessment from exposure to free cyanide via oral and dermal contact of surface/underground water by resident adults within the concession of Bogoso Gold Limited. The chronic non-cancer health risk from exposure to cyanide in River Bogo Upstream is 230 and 43 (by Central Tendency Exposure (CTE) parameters respectively). This means that approximately 230 and 43 resident adults are likely to suffer diseases related to cyanide intoxication via oral and dermal contact respectively. For chronic exposure to River Bogo Downstream by resident adults, the non-cancer health risks are: 0.031 and 0.57 via oral and dermal contact for CTE parameters respectively, which also means that, the non-cancer health risks associated with cyanide intoxication is negligible as the hazard index is less than 1.0 via oral and dermal contacts respectively. The results showed that health risk for acute exposure to cyanide by the resident adults is very high. Hence the residents attribute most of the unexplained deaths in the communities to accidental ingestion and dermal contact of cyanide water.

Adult↗
PubMed1984

Effects of oxygen on the antagonism of cyanide intoxication: cytochrome oxidase, in vitro.

Since oxygen was reported to be an effective cyanide antagonist in vivo, particularly in the presence of the classic antidotal combination of sodium nitrite and sodium thiosulfate, in vitro studies were initiated in an attempt to investigate the mechanism of oxygen-mediated cyanide antagonism. The effect of oxygen on cyanide-inhibited cytochrome oxidase with and without cyanide antagonist(s) was investigated in a purified membraneous enzyme system prepared from rat liver mitochondria. Cyanide produced a concentration dependent inhibition of cytochrome oxidase, and 100% oxygen did not alter the inhibition produced by KCN either in the presence or absence of sodium thiosulfate. However, the addition of sodium thiosulfate and rhodanese to the assay reactivated the cyanide-inhibited cytochrome oxidase. Kinetic analysis indicated rhodanese competes with cytochrome oxidase for cyanide, and oxygen had no effect on this coupled reaction. In conclusion, the in vivo antidotal properties of oxygen cannot be attributed to oxygen-mediated reactivation of cyanide-inhibited cytochrome oxidase or an oxygen-mediated acceleration of rhodanese detoxification.

Animals↗
PubMed1991

The cyanide-metabolizing enzyme rhodanese in human nasal respiratory mucosa.

The cyanide-metabolizing enzyme rhodanese is present in rat nasal epithelium at high activity levels. Cyanide is a common environmental pollutant. It is both toxic and an odorant. The high rhodanese activity in rat nasal epithelium may provide a mechanism for detoxicating inhaled hydrogen cyanide and may also play a role in olfaction by limiting the concentrations of cyanide in the nasal epithelium. The objective of this study was to determine whether high levels of rhodanese activity are also present in human nasal epithelium. On a per milligram mitochondrial protein basis, the rhodanese in human nasal tissue exhibited both a lower affinity (higher Km) for cyanide and a lower maximum velocity (Vmax) for cyanide metabolism than did rhodanese from rat nasal tissue. As in human liver, the human nasal enzyme appeared to exhibit substrate activation by cyanide. Rhodanese activity in the maxilloturbinates of nonsmokers was statistically higher than in smokers although only three samples per group were available. The Vmax/Km ratios for rhodanese from the nasal tissue of nonsmokers were consistently greater, thus suggesting the possibility of higher rates of cyanide metabolism in nonsmokers than in smokers.

Cyanides↗
PubMedDate not supplied

Effects of low cobalamin diet and chronic cyanide toxicity in baboons.

The effects of a low cobalamin (Cbl) diet, together with chronic cyanide or thiocyanate administration in some animals have been investigated in baboons over a period of 42 months. All animals remained healthy throughout the study and gained weight at a similar rate. None became anaemic or showed major haematological changes and there were no major neurological changes. Plasma total Cbl in the animals on the low Cbl diet fell within 9 months to values below the lower limit in man and were lowest at 24 months in baboons not receiving cyanide or thiocyanate. A striking feature in all animals, however, was an apparently seasonal increase in the plasma total Cbl each autumn with a corresponding decrease the following spring. This fluctuation was detected by radioisotopic assay but not by Euglena. Methylmalonic (MMA) excretion after oral valine ranged from 0.1--8.4 mg/24 h and was greatest in animals on the low Cbl diet and not receiving cyanide or thiocyanate. The results suggested an inverse relationship between MMA excretion and plasma total Cbl. Plasma thiocyanate was consistently higher in animals receiving cyanide or thiocyanate and at the end of the study plasma cyanide was highest in animals on the low Cbl diet receiving cyanide. The results support the suggestions that cyanide affects bodily handling of Cbl and that hydroxo-cobalamin plays a part in detoxication of cyanide.

Animals↗
PubMed1995

Antagonism of cyanide toxicity by isosorbide dinitrate: possible role of nitric oxide.

In a search for improved cyanide antidotes, the efficacy of isosorbide dinitrate (ISDN), was compared with that of the known cyanide antidote, NaNO2. ISDN was as effective as an optimal dose of NaNO2 in protecting mice against cyanide lethality. To study the mechanism involved, the extent of formation of the cyanide scavenger, methemoglobin, in the action of ISDN was determined. ISDN (300 mg/kg, p.o.) increased methemoglobin from 5 to 10% of total hemoglobin, while, in contrast, NaNO2 (100 mg/kg, i.p.) increased methemoglobin levels to 50% of total hemoglobin. Lowering the dose of NaNO2 to 30 mg/kg reduced methemoglobin levels to approximately 10% of total hemoglobin and in turn nearly abolished its antidotal effect. Decreasing methemoglobin to less than control levels using methylene blue failed to abolish cyanide antagonism by ISDN. Thus, methemoglobin formation by ISDN does not account for its antidotal action. Further studies comparing the respiratory depressant effects of cyanide in the presence of ISDN or NaNO2 also indicated that these two antidotes have different mechanisms of action. Efforts to produce tolerance to the antidotal effect of ISDN against cyanide toxicity were unsuccessful. It is suggested that the well-known ability of ISDN to generate nitric oxide may account for the noted cyanide antagonism.

Administration, Oral↗