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PubMed1978

Characterization of intermediate hemoglobin produced during methemoglobin reduction by ascorbic acid.

Methemoglobin reduction by ascorbic acid was found apparently to cease halfway without further reduction. Studies by isoelectric focusing on Ampholine plate gel revealed that the solutions of the halfway reduced methemoglobin are composed of about 6% oxyhemoglobin, 59% intermediate hemoglobin, and 35% methemoglobin. The intermediate hemoglobin was isolated by CM Sephadex C-50 column chromatography and identified as alpha3+beta2+ valency hybrid by studies using the pattern of isoelectric focusing of p-chloromercuribenzoate-treated intermediate hemoglobin on Ampholine plate gel, absorption spectra, and difference spectra induced by the addition of inositol hexaphosphate in comparison with the reconstituted valency hybrids, alpha3+beta2+ and alpha2+beta3+. Essentially no alpha2+beta3+ valency hybrid was included in the intermediate hemoglobin solutions. These results suggest that methemoglobin reduction by ascorbic acid is mainly initiated by the attack of beta-methemoglobin chains accompanied by the following scheme. Methemoglobin leads to alpha3+beta2+ valency hybrid leads to oxyhemoglobin. The course of methemoglobin reduction by ascorbic acid through alpha2+beta3+ is likely to be small.

Ascorbic Acid↗
PubMed2001

Changes in rodent-erythrocyte methemoglobin reductase system produced by two malaria parasites, viz. Plasmodium yoelii nigeriensis and Plasmodium berghei.

The methemoglobin reductase system plays a vital role in maintaining the equilibrium between hemoglobin and methemoglobin in blood. Exposure of red blood cells to oxidative stress (pathological/physiological) may cause impairment to this equilibrium. We studied the status of erythrocytic methemoglobin and the related reductase system during Plasmodium yoelii nigeriensis infection in mice and P. berghei infection in mastomys. Malaria infection was induced by intraperitoneal inoculation with 10(6) infected erythrocytes. The present investigation revealed a significant decrease in the activity of methemoglobin reductase, with a concomitant rise in methemoglobin content during P. yoelii nigeriensis infection in mice erythrocytes. This was accompanied with a significant increase in reduced glutathione and ascorbate levels. The activity of lactate dehydrogenase, glucose 6-phosphate dehydrogenase and glutathione reductase increased with a progressive rise in parasitemia. However, no methemoglobin or associated reductase activity was detected in normal and P. berghei-infected mastomys. P. berghei infection in mastomys resulted in an increase in the level of reduced glutathione and ascorbate in erythrocytes, and also in the activity of lactate dehydrogenase, glucose 6-phosphate dehydrogenase and glutathione reductase. These results suggest that antioxidants/antioxidant enzymes may prevent or reduce the formation of methemoglobin in the host and thereby protect the host from methemoglobinemia.

Animals↗
PubMed1997

Circulating methemoglobin and nitrite/nitrate concentrations as indicators of nitric oxide overproduction in critically ill children with septic shock.

OBJECTIVES: To examine the relationship between circulating methemoglobin and nitrite/nitrate concentrations and to compare these markers of nitric oxide overproduction with clinical variables in children diagnosed with septic shock. DESIGN: Prospective, controlled, clinical study. SETTING: Pediatric intensive care unit and outpatient clinic in a children's hospital. PATIENTS: Twenty-two children diagnosed with septic shock and ten age-matched healthy control patients. INTERVENTIONS: Patients diagnosed with septic shock had blood specimens taken on study entry and every 6 hrs for 72 hrs for methemoglobin and nitrite/nitrate determinations. Single blood specimens were obtained from controls. MEASUREMENTS AND MAIN RESULTS: Circulating methemoglobin and nitrite/nitrate concentrations were significantly higher in children diagnosed with septic shock in comparison with healthy control children (p = .01 and .05, respectively). Peak nitrite/nitrate concentrations correlated with serum creatinine (r2 = .19; p = .04) and were inversely correlated with arterial pH (r2 = .28; p = .01) and urine output (r2 = .21; p = .03) when analyzed by log-linear regression. There were no significant relationships between methemoglobin and nitrite/nitrate or between methemoglobin and any other clinical variable. CONCLUSIONS: Circulating methemoglobin and nitrite/nitrate concentrations are increased in children diagnosed with septic shock. Plasma nitrite/nitrate values correlate with selected clinical variables in these children. Circulating methemoglobin measurements are not superior to plasma nitrite/nitrate concentrations as an indicator of endogenous overproduction of nitric oxide in children diagnosed with septic shock. A need remains to develop markers of endogenous nitric oxide activity that have greater accuracy and reliability.

Adolescent↗
PubMed1972

Unstable variant of NADH methemoglobin reductase in Puerto Ricans with hereditary methemoglobinemia.

The electrophoretic mobility of erythrocyte NADH methemoglobin reductase in five hereditary methemoglobinemia patients from three Puerto Rican kindreds was 118% of normal at pH 8.6. The methemoglobin ferrocyanide reductase activity of the enzyme in erythrocyte hemolysates was 3.2-6.4% of normal. Electrophoresis of hemolysates prepared from the blood of patients from two different families at six pH values between 4.6 and 9.3 did not differentiate between the variant enzymes. Examination of the deficient enzymes extracted from the erythrocytes of one patient from each kindred revealed altered affinity for NADH and dichloroindophenol dye and decreased thermal stability. The quantitative similarity of the abnormal findings, together with the Puerto Rican origin of the kindreds, suggested that the cyanotic patients possessed the same abnormal enzyme and were thus homozygous for the same rare mutant gene. Consanguinity of the kindreds could not be established. The rates of decline of the normal and variant NADH methemoglobin reductase enzymes in vivo were measured in erythrocyte fractions of increasing cell age. The rate of decline of the variant enzyme was increased 20-fold by comparison with the normal enzyme. The methemoglobin percentage in erythrocyte fractions of increasing cell age correlated inversely with the activity of the variant. The variant enzyme averaged 37% of normal mean activity in young cells and 1% in old cells. The normal enzyme, on the other hand, lost only one-sixth of its activity as the cells aged, and the methemoglobin content in old normal cells did not rise. These observations support the hypothesis that the deficient activity and the heterogeneous pattern of methemoglobin accumulation in vivo arise principally from the accelerated inactivation of variant NADH methemoglobin reductase during the life-span of the red blood cell.

Adolescent↗
PubMedDate not supplied

Effectiveness of intramuscularly administered cyanide antidotes on methemoglobin formation and survival.

Successful first aid therapy for cyanide intoxication is dependent upon immediate administration of antidotes which directly or indirectly interact with the cyanide ion to remove it from circulation. Owing to the severe respiratory, cardiovascular and convulsive episodes following acute cyanide intoxication, the most practical approach is to administer antidotes by intramuscular injection. Exceptionally rapid methemoglobin formers-hydroxylamine hydrochloride (HH) and dimethylaminophenol (DMAP)-are usually able to prevent the lethal effect of cyanide following intramuscular injections in doses sufficient to induce 20% methemoglobin (HH = 20 mg kg-1 and DMAP = 2 mg kg-1). Sodium nitrite, the methemoglobin inducer approved for military use, must be administered by intravenous infusion because it is not an effective cyanide antidote by the intramuscular route. In the normal unintoxicated animal an intramuscular injection of 20 mg kg-1 sodium nitrite will form 20% methemoglobin; however, in acute cyanide intoxication the associated severe bradycardia appears to limit the rate of absorption and thus the rapid formation of methemoglobin. If the bradycardia is prevented or reversed by atropine, the rate of absorption of sodium nitrite and the formation of methemoglobin is able to reverse the otherwise lethal effects of cyanide. Thus, an intramuscularly administered combination of 20 mg kg-1 sodium nitrite and 1 mg kg-1 atropine sulfate, rapidly absorbed from the intramuscular site, appears to achieve the same degree of effectiveness against acute cyanide intoxication as intramuscularly administered HH or DMAP. It would appear from these studies that HH, DMAP and sodium nitrite with atropine are all potentially effective intramuscular antidotes for acute cyanide poisoning.

Aminophenols↗
PubMed1984

Methemoglobin levels produced by organic nitrates in patients with coronary artery disease.

To determine if ordinary doses of nitrates produce a significant increase in methemoglobin, methemoglobin levels were measured in 59 randomly selected patients with coronary artery disease and unstable angina pectoris who were receiving organic nitrate therapy. Patients were taking isosorbide dinitrate, 2% nitroglycerin ointment, or a combination of the two. Patients were subdivided according to whether they were using one (group A) or more than one (group B) organic nitrate preparations. These results were compared with 17 control patients. Mean methemoglobin levels in group B were 1.78 +/- 1.29%, and this differed significantly (P less than 0.05) from both group A mean methemoglobin, 1.13 +/- 0.92%, and controls, 0.99 +/- 0.55%. The proportion of patients with elevated methemoglobin concentration increased from the control to group A to group B. It is concluded that commonly used dosages of nitrates are capable of causing elevations of methemoglobin which are probably not of routine clinical significance. However, these elevations may be of import in certain patient populations such as those with coronary insufficiency or anemia.

Aged↗
PubMed2004

Methemoglobin formation during laser induced photothermolysis of vascular skin lesions.

BACKGROUND AND OBJECTIVE: Monitoring dynamic changes during laser induced photothermolysis of vascular skin lesions is essential for obtaining an optimal therapeutic result. Rapid photoinduced thermal damage occurs at a threshold temperature of about 70 degrees C. It is therefore, relevant to identify markers to indicate if this threshold temperature has been reached. Methemoglobin, which is formed by a photo-induced oxidation of hemoglobin, indicates that the temperature has reached this threshold value. This study presents a proof of concept of a method for monitoring the in vivo presence of methemoglobin immediately after laser exposure. STUDY DESIGN/MATERIALS AND METHODS: The present study was designed to investigate the in vivo temperature dependence of hemoglobin absorption in the 450-800 nm spectrum range. In vivo diffuse reflectance measurements of port-wine stain (PWS) and telangiectasia were performed prior to, and immediately after, laser treatment with a pulsed dye laser (PDL) at 585 nm wavelength. RESULTS: In vivo measurements following laser treatment of vascular skin lesions showed an immediate increase in the optical absorption of blood. This effect, caused by thermal stress, is a result of an increased dermal blood volume fraction and methemoglobin formation. The effect is light dose dependent, and reflectance spectra revealed methemoglobin formation in patients treated with fluences above 5 J/cm2 at 585 nm wavelength. CONCLUSIONS: It was proved that methemoglobin can be measured in vivo by reflectance spectroscopy. Measurements of the average methemoglobin concentrations immediately after laser exposure may be a valuable diagnostic tool to verify that the blood temperature has been sufficiently high to induce thermal damage to the vessel wall.

Adolescent↗
PubMed1984

The special behavior of equine erythrocytes connected with the methemoglobin regulation.

Erythrocytes from thoroughbred horses were submitted to total (80-90%) and partial (25-40%) oxidation of hemoglobin by sodium nitrite. The ability of these cells to reduce methemoglobin to hemoglobin in the presence of either glucose, glucose plus methylene blue or lactate was investigated. The results were compared with those ones obtained for human erythrocytes. Under total oxidation: the horse erythrocytes need longer incubation time with glucose or glucose plus methylene blue than human erythrocytes for reducing the methemoglobin; methylene blue did not enhance methemoglobin reduction in the equine erythrocytes, as occurred in human erythrocytes; for horses, lactate was a more efficient substrate in promoting methemoglobin reduction. The reduction of methemoglobin by equine erythrocytes under partial oxidation was very quick in any of the incubation media. The results can explain the incongruity between the previously reported inability of equine erythrocytes to reduce methemoglobin and the lack of methemoglobinemias in equine veterinary practice.

Animals↗
PubMed1981

A comparison of the binding of imidazole to valence hybrid and methemoglobin: an assignment of individual heme reactivity.

The ferric hemes of valence hybrid hemoglobins combine with imidazole in a manner analogous with the hemes of methemoglobin. Equilibrium studies show that imidazole binding to methemoglobin is minimally described by the sum of two independent processes (k1 = 200 M-1 an K2 = 37 M-1), both of which contribute equally to the observed difference spectrum. Using valance hybrid hemoglobins, which show single binding processes under similar conditions, it is possible to identify the high affinity sites in methemoglobin with the alpha chains and the low affinity sites with the beta chains. Kinetic studies show that the valance hybrid hemoglobins react in a single exponential fashion with imidazole in contrast with methemoglobin which shows a biphasic reaction (k1 = 85 M-1 sec-1 k2 = 25 M-1 sec-1). A comparison of the rates of reaction of the hybrids allows the assignment of the fast phase in methemoglobin to the beta chains and the slow phase to the alpha chains. The heterogeneity of the imidazole reaction with methemoglobin occurs over the pH range 5.5-9.5 within which two ionization processes are discernable at pH 6.9 an 7.5.

Adult↗
PubMed1987

Methemoglobin levels following intravenous lidocaine administration.

Methemoglobin levels were obtained before and after administration of IV lidocaine in 40 cardiac patients. Patients were given a 1-mg/kg bolus of IV lidocaine hydrochloride, started on a maintenance infusion at 2.0 mg/min, and given a second bolus of lidocaine of 0.5 mg/kg 15 minutes after the initial bolus. The maintenance infusion was adjusted from 1 to 4 mg/min according to clinical needs. Methemoglobin levels were drawn at zero, one, and six hours, and lidocaine levels were drawn at one and six hours after the initial bolus. Elevation of methemoglobin levels after lidocaine administration was statistically significant (P less than .05), but not clinically significant. The highest methemoglobin level obtained was 1.2%. Only one other patient had a level above 1%. No patient developed either signs of lidocaine toxicity or toxic levels of methemoglobin. Routine determination of methemoglobin levels is not clinically indicated following routine lidocaine administration. It may have some as-yet-undetermined value in lidocaine-toxic patients.

Adult↗
PubMed2006

Measurement of carboxyhemoglobin and methemoglobin by pulse oximetry: a human volunteer study.

BACKGROUND: A new eight-wavelength pulse oximeter is designed to measure methemoglobin and carboxyhemoglobin, in addition to the usual measurements of hemoglobin oxygen saturation and pulse rate. This study examines this device's ability to measure dyshemoglobins in human volunteers in whom controlled levels of methemoglobin and carboxyhemoglobin are induced. METHODS: Ten volunteers breathed 500 ppm carbon monoxide until their carboxyhemoglobin levels reached 15%, and 10 different volunteers received intravenous sodium nitrite, 300 mg, to induce methemoglobin. All were instrumented with arterial cannulas and six Masimo Rad-57 (Masimo Inc., Irvine, CA) pulse oximeter sensors. Arterial blood was analyzed by three laboratory CO-oximeters, and the resulting carboxyhemoglobin and methemoglobin measurements were compared with the corresponding pulse oximeter readings. RESULTS: The Rad-57 measured carboxyhemoglobin with an uncertainty of +/-2% within the range of 0-15%, and it measured methemoglobin with an uncertainty of 0.5% within the range of 0-12%. CONCLUSION: The Masimo Rad-57 is the first commercially available pulse oximeter that can measure methemoglobin and carboxyhemoglobin, and it therefore represents an expansion of our oxygenation monitoring capability.

Bias↗
PubMed1995

Near-patient measurements of methemoglobin, oxygen saturation, and total hemoglobin: evaluation of a new instrument for adult and neonatal intensive care.

OBJECTIVES: a) To evaluate the performance of a compact, new instrument that uses disposable cuvettes to measure total hemoglobin concentration, oxygen content, and the relative concentrations of oxy- and methemoglobin in 50-microL blood samples; b) to determine whether the instrument can be used for near-patient assessment of methemoglobinemia; and c) to ascertain whether problems commonly encountered in neonatal blood samples affect the instrument's performance. DESIGN: Prospective study, in which the test instrument was compared with a standard method. Samples of whole blood with and without bilirubin, fetal hemoglobin, and hemolysis were analyzed on the new (test) instrument and on a widely used cooximeter (OSM3 hemoximeter, Radiometer; reference instrument). SETTING: In vitro analyses of blood samples in clinical and university laboratories. MEASUREMENTS AND MAIN RESULTS: There was a close linear correlation between the methomoglobin measurements of the test instrument and those measurements of the reference instrument (slope = 0.989; r2 = .989). The average difference in mean assay values between the reference instrument and the test instrument was -0.59%, i.e., < 1% methemoglobin. Repeated measurements indicated the precision was 0.5% methemoglobin. Complete hemolysis of the sample reduced the methemoglobin reading by only 0.40%. Adding bilirubin (10 to 11 mg/dL [171 to 188.1 mumol/L]), increased the methemoglobin reading by 0.23%, increased the oxyhemoglobin reading by 0.45%, and increased total hemoglobin by 0.21 g/dL. Fetal hemoglobin also had minimal effects on the readings. CONCLUSIONS: The test instrument is fast and easy to operate. No sample preparation or pipetting is required. To operate the instrument, the user simply connects a syringe containing the blood sample to one of the disposable cuvettes, injects 50 microL of blood into the cuvette, and inserts the cuvette into the instrument. The test instrument automatically detects the presence of the cuvette, analyzes the sample, and displays the results in < 10 secs. The findings in this study indicate that the test instrument has sufficient accuracy for near-patient testing in intensive care units. The errors introduced by hemolysis, fetal hemoglobin, and bilirubin were too small to be of clinical importance. Thus, the test instrument is essentially unaffected by complications commonly encountered in neonatal blood. The capacity of the test instrument to measure methemoglobin makes it particularly useful if inhaled nitric oxide therapy becomes a standard clinical practice.

Adult↗
PubMed1995

Superoxide dismutase and catalase cross-linked to polyhemoglobin reduces methemoglobin formation in vitro.

Superoxide dismutase (SOD) and catalase (CAT) were evaluated for their ability to reduce methemoglobin formation in chemically cross-linked hemoglobin that was incubated in Tris-HCl buffer. Two parallel studies were carried out using identical experimental conditions with one exception only. This involved the physical state of SOD and CAT in solution such that the enzymes were either cross-linked directly to hemoglobin (hemoglobin-SOD-CAT) or simply incubated with polyhemoglobin. The concentration of SOD and CAT was subsequently varied to examine and compare the effect on the rate of methemoglobin formation between the two experiments. Overall, a comparison between the results clearly indicated that cross-linking SOD and CAT to hemoglobin was more effective at reducing methemoglobin levels than incubating polyhemoglobin with SOD and CAT. More specifically, the incubation experiment would require an enzyme concentration exceeding twice that cross-linked to hemoglobin in order to achieve a similar beneficial effect. However, it was more striking to observe that the presence of SOD and CAT during the cross-linking reaction had markedly reduced the initial formation of methemoglobin. When SOD and CAT were included during the chemical process of generating polyhemoglobin, about 7% methemoglobin was formed in the cross-linked hemoglobin-SOD-CAT product. By comparison, methemoglobin had increased about 20% after the cross-linking reaction when generating polyhemoglobin.

Animals↗
PubMedDate not supplied

Studies on erythrocytic methemoglobin reductase systems in Plasmodium yoelii nigeriensis infected mice.

BACKGROUND: The methemoglobin reductase system plays a vital role in maintaining the equilibrium between hemoglobin and methemoglobin in blood. Exposure of red blood cells to oxidative stress (pathological/physiological) causes an impairment in this equilibrium. OBJECTIVE: To study the status of methemoglobin and the related reductase system during Plasmoidum yoelii nigeriensis (P. y. nigeriensis) infection in mice. METHOD: Mice were divided into two groups viz., normal mice and P. y. nigeriensis infected mice. Malaria infection was induced by intraperitoneal inoculation of 10(6) infected erythrocytes. RESULTS: The present investigation revealed significant decrease in the activity of methemoglobin reductase, with concomitant rise in methemoglobin content during P. y. nigeriensis infection in mice erythrocytes. This was accompanied with a significant increase in reduced glutathione and ascorbic acid levels. Also the activities of the associated enzymes viz., lactate dehydrogenase, glucose-6-Phosphate dehydrogenase and glutathione reductase were found to increase with progressive rise in parasitemia. CONCLUSION: P. y. nigeriensis infection in mice results in impairment of methemoglobin reductase in the host.

Animals↗
PubMedDate not supplied

[Method of determining methemoglobin in cadaver blood].

Poisoning with methemoglobin toxins are not rare in forensic medical practice, but there is still no reliable method for measuring methemoglobin in cadaveric biological fluids and tissues. The author investigated factors affecting evaluation of natural amounts of methemoglobin in the blood, compared several methods for methemoglobin measurements, and developed qualitative characteristics indicating the presence of methemoglobin in cadaveric blood. A rational method for measuring methemoglobin in the blood, blood clots, and tissues is offered for forensic chemical and biochemical evaluations.

Cadaver↗
PubMed1990

[Permeability of 5 methemoglobin formers through red cell membrane].

By measuring the methemoglobin formation, the permeabilities of some cyanide antidotes passing through mouse erythrocyte membrane were studied. K3Fe(CN)6(0.1 mol/L) did not permeate the red cell and no methemoglobin formed. To the red cell suspension, adding PAPP 0.07 mmol/L, an useful cyanide antidote, no methemoglobin was found. On the contrary, PHAPP, the metabolite of PAPP, transported into the cell readily and reacted with hemoglobin to form methemoglobin quickly. DMAP and NaNO2 passed through the red cell membrane easily. With comparable amount of methemoglobin formation, the concentration of NaNO2 was about 200 times as much as that of DMAP. A comparison of the anticyanide potency of DMAP and NaNO2, the permeability rate constant, the half time and activation energy were measured as: 0.217 and 0.0506/min; 3.2 and 13.7 min; 17.1 and 50.2 kJ/mol, respectively. Owing to its ready permeability and formation of methemoglobin, DMAP is a better antidote than NaNO2 against cyanide poisoning.

Aminophenols↗
PubMed1986

The effect of heme-linked ionizable groups on cyanide binding to methemoglobin.

The pH dependence of the kinetics of the binding of cyanide ion to methemoglobins A and S and to guinea pig and pigeon methemoglobins appears to be not directly correlated with the net charges on the proteins. The kinetics can, however, be adequately explained in terms of three sets of heme-linked ionizable groups with pK1 ranging between 4.9 and 5.3, pK2 between 6.2 and 7.9, and pK3 between 8.0 and 8.5 at 20 degrees C. pK1 is assigned to carboxylic acid groups, pK2 to histidines and terminal amino groups, and pK3 to the acid-alkaline methemoglobin transition. Kinetic second order rate constants have also been determined for the binding of cyanide ion by the four sets of methemoglobin species present in solution. The pKi values and the rate constants of methemoglobin S are strikingly different from those of methemoglobin A. This result is explained in terms of different electrostatic contributions to the free energy of heme linkage arising from differences in the environments of ionizable groups at the surfaces of the two molecules.

Animals↗
PubMed1982

Neutrophil-mediated methemoglobin formation in the erythrocyte. The role of superoxide and hydrogen peroxide.

Human neutrophils incubated with phorbol myristate acetate oxidized hemoglobin within the intact erythrocyte by a mechanism dependent on cell-cell contact but independent of phagocytosis. Spectrophotometric examination of the erythrocyte lysates revealed that the major component formed was methemoglobin along with small amounts of a species with spectral characteristics similar to choleglobin. Methemoglobin formation was directly related to the neutrophil concentration and the time of incubation. The addition of superoxide dismutase or catalase modestly inhibited the formation of methemoglobin, while a combination of the enzymes provided the most dramatic protection. Methemoglobin of hydroxyl radical or hypochlorous acid scavengers. Apparently, either O2.- or H2O2 alone was capable of mediating methemoglobin formation in the intact erythrocyte. Maintenance of the intraerythrocytic hemoglobin in its oxygenated state or its derivatization to carbon monoxyhemoglobin markedly inhibited methemoglobin formation. Blockade of the anion channels in the intact erythrocyte with sulfonated stilbenes inhibited O2.- but not H2O2 from oxidizing intracellular hemoglobin. It appears that neutrophil-derived O2.- and H2O2 can cross the erythrocyte membrane through the anion channel or diffuse directly into the intracellular space and react with oxyhemoglobin or deoxyhemoglobin to form a mixture of hemoglobin oxidation products within the intact cell.

Carbon Monoxide↗