Administration Of Sodium Nitrite Research Articles

Effect of sodium nitrite on the execution of defensive and inhibitory conditioned reflexes.

Administration of sodium nitrite (an NO-generating preparation) doses of 11 mg/kg to rabbits was followed by motor disinhibition, with increases in myogram amplitudes in responses to nonreinforced flashes presented on a background of continuous illumination which served as a conditioned inhibitory stimulus; these changes appeared 1-1.5 h after administration and lasted throughout the 4-h observation period. After sodium nitrite doses of 5.5 mg/kg, responses to conditioned inhibition showed only a tendency to motor disinhibition. These results can be explained in terms of the ability of sodium nitrite to inhibit the function of GABAergic receptors, as development of internal inhibition is accompanied by increased inhibitory hyperpolarization processes in which the GABAergic mediator system is involved. The lower and higher sodium nitrite doses produced no increases in myogram amplitudes in responses to combinations of flashes of light and pain reinforcement, as occurred when these stimuli were presented to controls.

Comparative Efficacy of three Methemoglobin Formers in Delaying Effects of Infused Sodium Cyanide

A prophylactic treatment is needed to circumvent constraints of the current therapy for cyanide (CN-) intoxication: intravenous administration of sodium nitrite and sodium thiosulfate. Experiments were conducted to compare the anticyanide effects of three candidate pretreatment methemoglobin (MHb)-forming compounds in an anesthetized animal model. The experiment was conducted in 5 periods, with each of 9 animals receiving the vehicle control in period 1, 0.2 mg/kg p-aminopropiophenone (PA PP) in period 2, and 2.5 mg/kg WR242511 in period 3. Four of the animals received the vehicle control in period 4 followed by 7 mg/kg p-aminoheptanophenone (PA HP) in period 5, and 5 animals received 7 mg/kg PA HP in period 4 followed by the vehicle control in period 5. Sodium cyanide (Na CN) infusions for PAPP, PAHP, and WR242511 experiments were initiated when the predicted MHb level was approximately 5%. Infusions were stopped 10 s after no functional breaths (respiratory arrest) were observed. Blood samples were collected for hemoglobin (Hb), MHb, and total blood CN levels at scheduled time points. Time to respiratory arrest, percent MHb, and Na CN dose were the primary response parameters. A 11 pretreatment regimens effectively mitigated the effects of Na CN poisoning compared to the vehicle control (p <.05). No discernable differences in protection were provided by the three compounds. The results indicated that the protective effect is related to the MHb level rather than the specific pretreatment drug.

Elevation of blood cyanide values after sodium nitrite administration: Implications regarding the mechanism of detoxification

Elevation of blood cyanide values after sodium nitrite administration: Implications regarding the mechanism of detoxification

Elevation of blood cyanide values after sodium nitrite administration: implications regarding the mechanism of detoxification

Elevation of blood cyanide values after sodium nitrite administration: implications regarding the mechanism of detoxification

Effects of age on endometrial carcinogenesis induced by concurrent oral administration of ethylenethiourea and sodium nitrite in mice

Aging effects on the susceptibility to chemical endometrial carcinogenesis were investigated in ICR female mice. The animals were divided into 3 groups of different ages: 1 month (young), 6 months (middle), and 12 months (old) at initiation of treatment. They received weekly oral administration of mixture of ETU (100 mg/kg body weight) and sodium nitrite (70 mg/kg body weight) for 6 months followed by a withdrawal period of 3 months. All animals were subjected to histopathology. The incidence of endometrial adenocarcinomas was highest in the middle age group (8/20), secondary in the old age group (4/20), and lowest in the young group (1/20). The incidence of atypical glandular hyperplasia, a precursor lesion of the tumor, was also higher in the middle age group. The endometrial adenocarcinomas showed morphological similarities among all age groups and the nuclei of tumor cells lost almost all staining reactivity to estrogen receptors. The labeling indices with bromodeoxyuridine (BrdU) were notably higher in the old age group than in the young and middle age groups. A further investigation on the aging process of female genital organs in control mice revealed that their senility seemed to be preceded by the formation of ovarian cysts which first appeared at 6 months of age with a concomitant elevation of plasma 17 beta-estradiol level. These results indicate that the susceptibility of the mouse endometrium to the carcinogenic effects of N-nitroso ETU could be closely linked with the stage of aging process of the genital organs and it appears to be most susceptible when initiated at around 6 months of age. However, the mitotic activity of neoplastic endometrial glandular cells seems to be higher in older mice than younger ones.

The functional state of the xenobiotic metabolizing system in rat liver following chronic administration of diethylnitrosamine or its precursors.

The effect of chronic administration of 0.002% N-nitrosodiethylamine (DENA), 0.002% diethylamine (DEA) and 0.0005% sodium nitrite (SN) on the functional state of the xenobiotic metabolizing system in rat liver was investigated. Administration of DEA and DENA increased concentration of cytochromes P-450 and b5. SN did not affect the enzymes of the monooxygenase system. Coadministration of DEA and SN maximally increased the concentration of cytochrome P-450. It is not possible to explain the phenomenon of combined administration of SN and DEA by simple summation of the effects caused by them separately. The activity of microsomal glutathione S-transferase did not change when DEA and SN were given together, yet increased when they were administered separately. The maximum increase of the total activity of cytosol glutathione S-transferases was observed following DENA. In all four experimental groups a decrease of isoenzyme 5-5 activity was observed. Investigation of Se-independent glutathione peroxidase activity showed the multivariance of response of the glutathione S-transferase family to the compounds studied. The concentration of hepatic free SH-groups increased following administration of DENA and decreased dramatically when SN and DEA were coadministered. When they were given separately the concentration remained at control level.

Nitrate and nitrite kinetics after single intravenous dosage in sheep

Nitrite was quickly eliminated from blood plasma of sheep ( T 1 2 = 0.49 h ). Three hours after its administration, nitrite ion disappeared from blood plasma. Simultaneously the appearance of nitrate was observed. After sodium nitrite or nitrate intravenous administration, the kinetic parameters for nitrate were similar ( K el = 0.150 h −1 and 0.154 h −1, respectively). Urine excretion of nitrite amounted to only 0.29% ± 0.22 of the administered dose. Urine excretion of nitrate was 13.80% ± 5.78 of the administered dose of nitrite and was slightly lower than that observed after the administration of nitrate (16.12% ± 6.95). The quick elimination of nitrite appears to be mainly from its conversion into nitrate, because the nitrate elimination in urine, as well as the values of its kinetic parameters, were similar after the administration of nitrite or nitrate. Elimination of nitrate from blood plasma of sheep over 80% was different than its excretion in urine in the unchanged form.

Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit

To evaluate serial cyanide, methemoglobin, and carbon monoxide levels in smoke inhalation patients. Regional poison center and regional toxicology treatment center. Seven critically ill smoke inhalation patients referred to the regional poison center. Peak level and half-life were determined by obtaining serial carboxyhemoglobin, cyanide, and methemoglobin levels. The mean observed half-life of cyanide was 3.0 +/- 0.6 hours. Methemoglobinemia was evaluated in four patients after sodium nitrite administration. The peak measured methemoglobin levels (mean, 10.5% +/- 2%; range, 7.9% to 13.4%) did not occur until a mean of 50 minutes (range, 35 to 70 minutes) following administration of sodium nitrite. The total oxygen-carrying capacity reduced by the combination of carboxyhemoglobin and methemoglobin was never more than 21% (range, 10% to 21%) in this series. The administration of sodium nitrite to smoke inhalation patients in the presence of concomitant carbon monoxide poisoning may be relatively safe.

Modulation of neuroeffector transmission by endogenous nitric oxide: a role for acetylcholine receptor-activated nitric oxide formation, as indicated by measurements of nitric oxide/ nitrite release

Nitric oxide (NO) synthase inhibitors enhanced nerve-mediated contractile responses in guinea pig ileum longitudinal muscle, likely via a prejunctional effect on substance P-like neuroeffector transmission. Supporting a modulatory role for NO, application of NO through administration of acid sodium nitrite evoked marked inhibitory effects on responses to transmural nerve stimulation. Substance P-like responses to nerve stimulation were abolished by substance P receptor antagonists and were enhanced by atropine, indicating a cholinergic influence on substance P-like neuroeffector transmission. Since acetylcholine can evoke release of NO from endothelium, the possible role of acetylcholine in NO release in ileum was examined. The release of NO/nitrite, determined by chemiluminescence, was inhibited by N G-monomethyl-L-arginine (L-NMMA), by calcium removal, by tetrodotoxin or by atropine, indicating a nerve-mediated control of NO production. A basis for the NO release is likely to be spontaneous neuronal activity, where release of acetylcholine, with subsequent muscarinic receptor activation, contributes to stimulation of NO formation.

Tumor induction by concurrent oral administration of ethylenethiourea and sodium nitrite in mice.

Carcinogenic potential of ethylenethiourea (ETU) in combination with sodium nitrite was investigated in ICR mice of both sexes. Groups of 30 males and 30 females each were given 10 weekly oral administrations of ETU and sodium nitrite with the following combinations of dosing (ETU vs sodium nitrite, mg/kg/wk): 0 vs 0, 100 vs 0, 0 vs 70, 25 vs 17.5, 50 vs 35, and 100 vs 70. Thereafter, the animals were allowed to live without treatment up to 18 mo after the first administration. Concurrent administration of ETU and sodium nitrite caused earlier development of tumors and/or dose-dependent increases in the incidences of tumors in the lymphatic tissue, lung, forestomach, Harderian gland, and uterus, whereas treatment with either ETU or sodium nitrite failed to show carcinogenic activity. In addition, carcinomas in the forestomach and uterine horn were limited to mice receiving concurrent administrations of ETU and sodium nitrite. These results indicate that ETU is most probably converted in vivo into N-nitroso ETU and that the N-nitroso ETU has a greater carcinogenic potential in mice than ETU alone.

The effect of subchronic poisoning with potassium nitrate and sodium nitrite on the processes of intestinal absorption of D-xylose in rats.

The intestinal transport of D-xylose was studied during subchronic poisoning of male Wistar rats with the oral administration of potassium nitrate and sodium nitrite. The metabolic parameters of small intestine mucosa were determined one hour after xylose administration, i.e., Na+/K(+)-ATPase, alkaline phosphatase, oxygen consumption, and lactic acid level. Nitrite reduced the absorption of xylose and decreased the activity of Na+/K(+)-ATPase and alkaline phosphatase. No effect of sodium nitrite was demonstrated on the aerobic metabolism of intestinal mucosa with an increased lactic acid level. Potassium nitrate did not effect the processes of intestinal absorption of xylose nor the metabolic parameters of small intestine mucosa.

Severe cyanide poisoning from the ingestion of an acetonitrile-containing cosmetic

A 39-year-old woman ingested 59 mL of Super Nail Nail Off (American International Industries, Hollywood, CA) (containing 99% acetonitrile) in a suicide attempt. Following a latent period of approximately 12 hours, the patient developed cyanide poisoning with severe metabolic acidosis, seizures, and shallow respirations. She responded to the administration of sodium nitrite and sodium thiosulfate, although the administration of nitrite produced bradycardia and hypotension. She developed several relapses over the course of her hospitalization and each time responded to sodium thiosulfate administration. The patient developed hypernatremia from the sodium load given to her; hemodialysis and charcoal hemoperfusion were initiated to correct the hypernatremia and to attempt to remove cyanide, thiocyanate, and acetonitrile. On the fifth hospital day, the patient was fully recovered and was discharged.

Exogenous GTP Enhances the Effects of Sodium Nitrite on Cyclic GMP Accumulation, Vascular Smooth Muscle Relaxation and Platelet Aggregation

Exogenous guanosine triphosphate (GTP) (1-2 x 10(-4)M) resulted in increased concentrations of cyclic GMP both in endothelium denuded rat mesenteric artery (RMA) and in human ADP-stimulated platelets. Sodium nitrite (3.3 x 10(-4)M) relaxed precontracted RMA by 34%. When the arteries were preincubated with GTP (2 x 10(-4)M) sodium nitrite administration resulted in a significantly greater relaxation (58%) of the RMA with concomitant 2-fold increase in cGMP. Sodium nitrite (1 x 10(-4)M) had an inhibitory effect on ADP-induced platelet aggregation. Preincubation with GTP enhanced significantly the sodium nitrite-induced inhibition of ADP-induced platelet aggregation with a simultaneous 5-fold increase in cGMP. These results indicate that exogenous GTP enhances the sodium nitrite-induced stimulation of guanylate cyclase and thus enhances the effects of sodium nitrite on arterial smooth muscle and platelets.

Pretreatment effects on nitrite-induced methemoglobinemia: Saline and calcium channel antagonists

This study was undertaken to evaluate the effects of pretreatment with calcium channel antagonists (nimodipine or verapamil) on the formation of methemoglobin produced by sodium nitrite. Unexpectedly, the pretreatment of animals with control injections of physiological saline 2 hours before the nitrite administration reduced the amount of methemoglobin found in the blood 25 minutes later. When either of the calcium channel antagonists was given 2 hours before the administration of sodium nitrite, the saline effect was eliminated. When the injections of physiological saline or either of the calcium channel blockers were divided 24 hours before the nitrite administration, all reduced the amount of methemoglobin formed relative to rats that received no pretreatment. A tentative hypothesis is that the reduction of the nitrite-induced methemoglobin can be induced by the stress of handling and intraperitoneal injection and that this stress effect can last at least 24 hours. It is likely that whatever stress-related mechanism is involved in reducing methemoglobin levels, this effect can be reduced by the presence of “L channel” voltage-sensitive calcium antagonists or their active metabolites.

Oral administration of chlordiazepoxide plus sodium nitrite investigated for tumor initiating activity in the rat liver

Chlordiazepoxide (CDE) reacts with sodium nitrite at acid pH yielding the genotoxic derivative N-nitrosochlordiazepoxide (NO-CDE). In the present study oral administration of CDE plus NANO 2, previously found to produce DNA fragmentation in the rat liver, was examined for its ability to initiate hepatocarcinogenesis. The oral treatment for 6 successive weeks with CDE + NaNO 2, added to the diet at the levels of 290 + 270 and 870 + 800 ppm, did not significantly increase the number or volume of γ-glutamyltranspeptidase-positive foci (putative preneoplastic lesions). These findings are in agreement with the negative results previously obtained in rodent carcinogenesis assays and indicate that NO-CDE belongs to the progressively expanding list of genotoxic non-carcinogens.

Inhibition by coffee of nitrosourea-mediated DNA damage in mice

Oral administration of coffee at doses ranging from 150 mg to 1 g per kg body weight significantly decreased endogenously formed nitrosourea-mediated DNA damage in bone marrow as well as in colon epithelial cells in mice that had simultaneously received oral administration of methylurea and sodium nitrite. Since coffee (1 g/kg body weight) did not decrease DNA damage when administered orally together with preformed methylnitrosourea, it was hypothesized that coffee inhibits nitrosation in the stomach of mice. The lowest effective level of coffee, when compared on the basis of body weight, corresponds to a human intake of about 5 cups of coffee. Both chlorogenic acid (150 mg/kg body weight) and premelanoidins (1 g/kg body weight), which occur as ingredients in, or are formed during roasting of, coffee, were shown to inhibit nitrosourea-induced DNA damage in mice.

DNA damage induced in rats by oral administration of chlordiazepoxide plus sodium nitrite or of N-nitrosochlordiazepoxide

Chlordiazepoxide (CDE) reacts in acidic conditions with NaNO 2 yielding N-nitrosochlordiazepoxide (NO-CDE), previously shown to exert genotoxic effects in some in vitro systems. The possible intragastric nitrosation of CDE to NO-CDE has been investigated in rats given by gavage high single doses of this benzodiazepine along with NaNO 2. Liver DNA fragmentation, as revealed by both DNA alkaline elution and a more sensitive viscometric method, was found to occur consistently and to be essentially independent of the molar ratio drug/nitrite or of gastric pH. The significant increase in the frequency of DNA lesions observed in rats treated for 15 successive days indicates that DNA repair did not keep pace with the accumulation of the damage. Oral administration of single doses of NO-CDE induced similar dose-dependent amounts of DNA fragmentation in liver, gastric mucosa, and brain. Due to the demonstrated absence of carcinogenic activity in rodents, the present results should be interpreted solely as indicating that NO-CDE is intrinsically capable of producing DNA lesions in vivo, an effect by itself not sufficient to induce tumor growth.

Cyanide poisoning successfully treated without ‘therapeutic methemoglobin levels’

A 24-year-old woman ingested an unknown amount of potassium cyanide in a suicide attempt. Coma and metabolic acidosis developed. Administration of the Lilly Cyanide Antidote kit (Eli Lilly and Co, Indlanapolis) resulted in prompt resolution of symptoms and full recovery. Whole blood cyanide level was 13 μg/mL approximately one hour after ingestion. The highest measured methemoglobin level after sodium nitrite administration was 9.2%, demonstrating that attaining a “therapeutic methemoglobin level” of 25% is unnecessary to insure a satisfactory clinical outcome. Because severe hypotension or excessive methemoglobinemia can be caused by the sodium nitrite component of the Lilly kit, only enough to produce an acceptable clinical response should be administered.

Mutagenicity of urine from mice exposed orally to nitrite and various aminated antiparasitic drugs

Mutagenic N-nitroso compound formation from the in vitro reaction of amebicides and anthelmintic drugs, which are pyrimidine derivatives or contain secondary aliphatic amines or heterocyclic nitrogens, has been previously described (Arriaga Alba et al.: Environmental and Molecular Mutagenesis 12:65-73, 1988). Under similar conditions, antiparasitic drugs containing halogenated derivatives of tertiary amines or quaternary ammonium salts do not form mutagenic nitrosated compounds. In the present study the mutagenic activity of mouse urine was determined after oral administration of sodium nitrite and the two above-mentioned groups of drugs (pyrantel pamoate, chloroquine, piperazine and dehydroemetine/iodochlorhydroxyquin and bephenium hydroxynaphthoate, respectively). Results show that the simultaneous administration of piperazine or chloroquine with sodium nitrite produced urinary mutagens that appeared conjugated as glucuronides, whereas pyrantel pamoate and dehydroemetine in the presence of nitrite caused only slightly mutagenic urine. No mutagenic activity was detected in the urine of mice to which halogenated derivatives of tertiary amines (iodochlorhydroxyquin) or quaternary ammonium salts (bephenium hydroxynaphthoate) were administered together with nitrite.

Interaction of nitrite with catalase in the perfused rat liver

The interaction of nitrite with catalase was investigated spectrophotometrically in the perfused rat liver. Real-time spectral changes were obtained using a reflectance scanning spectrophotometer in the liver perfused with a haemoglobin-free medium in a non-recirculating system. Administration of sodium nitrite caused a specific pattern of spectral change indicating the decomposition of catalase compound I to free catalase. The spectral change due to the interaction with nitrite did not occur during potassium cyanide or ethanol infusion, nor in the aminotriazole-pretreated rat liver. The spectral change was observed at concentrations of nitrite in the perfusate over 0.01 m m, and the K 0.5 value (the concentration producing half the maximum spectral change) was 0.06 m m. It was concluded that relatively low concentrations of nitrite caused decomposition of catalase compound I in the physiologically functioning liver cell.