Nitrite and Nitrate Analyses

Clinical Biochemistry, Vol. 31, No.
4, 195220, 1998 Copyright 1998 The Canadian Society of Clinical Chemists Printed in the USA. All rights reserved 0009-9120/98 $19.00 .00
PII S0009-9120(98)00015-0
Nitrite and Nitrate Analyses: A Clinical Biochemistry Perspective

GRAHAM ELLIS,1 IAN ADATIA,2 MEHRDAD YAZDANPANAH,1,3 and SINIKKA K. MAKELA3
1
Department of Laboratory Medicine and Pathobiology, University of Toronto, 100 College Street, Toronto, ON M5G 1L5, Canada, 2Divisions of Cardiology, Critical Care Medicine and Pediatrics, University of Toronto, and 3Division of Clinical Biochemistry, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
the metabolism of NO to nitrite and nitrate and summarize methods of measuring these ions in body fluids. We shall comment on the clinical relevance of the measurements. Finally, we shall discuss possible associations between dietary intake and disease incidence. Dietary intake of nitrite and nitrate Nitrite and nitrate ions are both highly soluble in water. With few exceptions, they form water-soluble salts with almost all cations. When taken orally, they are readily absorbed from the proximal small intestine as reviewed by Walker (6). About 25% of orally ingested available nitrate is actively secreted into the saliva. This nitrate is then partially converted to nitrite by oral bacteria (7) and to NO by stomach acids, helping to reduce gastrointestinal tract infection (6,8). The transport systems of nitrates and nitrites have only recently become better understood in bacteria (9), in plants (10), and in mammalian cells (11), where a nitrate and H cotransporter seems important. Nitrites and nitrates are added as preservatives and texture enhancers to various foods, such as meat products and cheeses (12), but they are also a natural part of the diet. The concentrations in drinking water are usually 10 mg/L in the absence of bacterial contamination (13). In areas where drinking water concentrations are high, steps are taken to lower them (14) in order to avoid nitrate-induced methemoglobinemia in infants. Vegetables, especially beets, celery, and leafy vegetables like lettuce and spinach are rich in nitrates (6,15,16). Other vegetables contain nitrate at lower concentrations, but because they are consumed in greater quantity, they may contribute more nitrate to the diet. Santillana et al. (17) summarized findings from 710 commercial food samples available in Spain. Cured meats had the highest mean nitrite content (36 g/g) and canned vegetables the highest mean nitrate content (88 g/g).
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Objective: To review the assays available for measurement of nitrite and nitrate ions in body fluids and their clinical applications. Design and Methods: Literature searches were done of Medline and Current Contents to November 1997. Results: The influence of dietary nitrite and nitrate on the concentrations of these ions in various body fluids is reviewed. An overview is presented of the metabolism of nitric oxide (which is converted to nitrite and nitrate). Methods for measurement of the ions are reviewed. Reference values are summarized and the changes reported in various clinical conditions. These include: infection, gastroenterological conditions, hypertension, renal and cardiac disease, inflammatory diseases, transplant rejection, diseases of the central nervous system, and others. Possible effects of environmental nitrite and nitrate on disease incidence are reviewed. Conclusions: Most studies of changes in human disease have been descriptive. Diagnostic utility is limited because the concentrations in a significant proportion of affected individuals overlap with those in controls. Changes in concentration may also be caused by diet, outside the clinical investigational setting. The role of nitrite and nitrate assays (alongside direct measurements of nitric oxide in breath) may be restricted to the monitoring of disease progression, or response to therapy in individual patients or subgroups. Associations between disease incidence and drinking water nitrate content are controversial (except for methemoglobinemia in infants). Copyright 1998 The Canadian Society of Clinical Chemists
KEY WORDS: nitrates, nitrites, nitric oxide, nitricoxide synthase, arginine, human disease
Introduction nterest in the measurement of nitrite and nitrate in various body fluids has increased in recent years (15). These ions are ingested as part of the diet and are also produced endogenously from nitric oxide (NO). In this article, we shall review the effects of dietary intake on nitrite and nitrate concentrations in plasma and urine. We shall discuss
Correspondence: Dr. Graham Ellis, Department of Clinical Biochemistry, St. Johns Hospital at Howden, Howden Road West, Livingston, West Lothian, EH54 6PP, United Kingdom. Manuscript received January 6, 1998; accepted March 24, 1998.
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Improper storage and bacterial contamination may increase nitrite (18). In Western diets, assessed by dietary survey, the mean adult daily dietary intake of nitrite (0.1 mg) is much lower than that of nitrate (80 mg) (19). Others have found corresponding values of 1.4 mg and 54 mg in a 9 to 24-year-old Finnish population (20). In some European countries, mean daily intake may be as high as 8.7 mg of nitrite and (in vegetarians) as high as 194 mg of nitrate (6). Excessive nitrite or nitrate intake could potentially generate N-nitroso compounds, that are carcinogenic (21,22), but this is still controversial (6). Nitrite and nitrate are excreted in the kidneys. The nitrate is excreted in the urine as such or after conversion to urea (23). Clearance of nitrate from blood to urine approximates 20 mL/min in adults (24), indicating considerable renal tubular reabsorption of this ion. Tubular reabsorption is also supported by studies of the urinary excretion of total nitrate plus nitrite (NOx) concentrations in response to diuretics (25). There is little detectable nitrite or nitrate in feces (26). There is some loss of nitrate (40 mol/L) or nitrite (3 mol/L) in sweat, but this is not a major route of excretion (27). (These values represent means for 6 subjects after a 40 min sauna.) Patients on antibiotics had much lower sweat nitrite, implying a role for skin bacteria in nitrite synthesis. Variability in dietary intake (28) may contribute greatly to the variability of plasma nitrate and to urinary excretion. As would be expected, in controlled studies, the daily urine output increased with higher intake (26). Plasma nitrate increased from about 30 mol/L to about 200 mol/L in response to a high-nitrate diet and to about 300 mol/L after 500 mg of oral potassium nitrate (29). The ions disperse widely into body fluid spaces, giving a large volume of distribution: 0.28 L/kg (30), similar to that of the dog at 0.21 L/kg, equivalent to the extracellular volume (31). A diet high in nitrate may still elevate urinary excretion during the next day (29,32). There was a wide variability in plasma NOx over the course of 1 day in five individuals taking their normal Japanese diet, as measured by 4 hourly samples (33). Between-day variation was also observed by Wang et al. (34). Some authors have recommended that random urines should be taken immediately after getting up in the morning (35), as the second fasting sample of the morning (36), or just prior to dinner (32) to reduce this variability. Excretion is then related to urine creatinine. One group has recommended that there should be dietary restriction of nitrates and nitrites for at least 48 h prior to collection, if excretion is to be regarded as a measure of NO metabolism (29). Others have used a 15 h fast, with distilled water as the only fluid permitted (37,38). If a diet low in nitrite and nitrate is needed, Westfelt et al. (39) recommends the exclusion of alcoholic beverages, caviar, charcuteries (cooked or cured delicatessen-style meats), cheese, herbs, pickled fish, roots and vegetables during the study and
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for 2 days before the studies are undertaken. Viinikka (2) noted that many foodstuffs contain considerable amounts of nitrate and listed meat, vegetables, fish, melon, herb and black teas, malt beverages and wine as examples. Others have used low-nitrate diets containing approximately 210 mol/d (40) or 180 mol/d (41); the latter reference lists both permitted and avoidance food groups. A low nitrate diet for at least 3 to 4 days was found by Wang et al. (34) to minimize the influences of the Japanese diet on plasma NOx concentrations and 24 h urinary excretion, expressed in relation to creatinine excretion. However, these authors collected samples only between the third to the sixth day of the low nitrite and nitrate diet. Plasma levels taken at 0600 h were found to be consistent after 4 days of a well-balanced Japanese hospital diet (33). In contrast, morning urines (the second fasting sample of the morning in 12 healthy volunteers, expressed in relation to creatinine) seemed little affected by two days of low nitrate (180 mol/d) diet, compared to the normal Scottish diet or a nitrate-supplemented diet (36). Nitrate-containing drugs have been used for many years for the treatment of angina. They produce NO (42,43) and give rise to urine nitrate. Because the therapeutic doses are relatively small compared with normal dietary intake, their contribution to excretion is generally quite small. Nitric oxide (NO) In humans, NO is produced endogenously from various sources, the most important of which is L-arginine (4,5,29,39,44 48). Arginine is oxidized by NO synthase(s) (NOS, EC 1.14.13.39) to produce citrulline and NO. There are at least three isoenzymes of NOS (49 53); one is located almost exclusively in vascular endothelium. The NO that it produces acts as a relaxing factor on smooth muscle cells of the blood vessel wall, causing vasodilatation (44,54). By so doing, it is an important determinant of blood pressure (55). It is constitutively expressed. A second (inducible) NOS is produced in macrophages and many other cell types in response to inflammation or infection (52,56 63). The NO produced by the macrophage NOS not only damages the agent under attack but also causes apoptosis of the macrophage (64). NO may also induce apoptosis in other cell types (65 67). A third isoenzyme (neuronal NOS) is found constitutively in brain, neuronal tissue, neuroblastomas, skeletal muscle, -cells of the pancreatic islets, and also epithelial cells of bronchioli uterus, and stomach (52). All three isozymes are found in kidney (68). The activities of the two constitutively expressed NOS isozymes are not constant. They are calcium and calmodulindependent enzymes. Transient increases in intracellular calcium concentrations result in short-lived bursts of activity. This enables NO to act as a neurotransmitter/neuromodulator by diffusion (62, 69 71) or by S-nitrosylation, nitrosothiol exchange,
NITRITE AND NITRATE ANALYSES
and related mechanisms (72). Inducible NOS contains tightly bound calcium and calmodulin and it is generally insensitive to ambient calcium concentration (49,73) Hormones, such as estradiol, may upregulate NO synthesis (74). As much as 90% of circulating nitrite is derived from the L-arginine:NO pathway (38). On a low-nitrate controlled diet (210 mol/d) about one-half the urine nitrate originated from plasma arginine (40). NO can also be produced from recycled nitrite or nitrate in various ways. Acidification of nitrite may release NO in the stomach (8). NO may be derived from urine nitrate in infected urine (75). NO production has been described in infarcted heart tissue (76). The process is independent of NOS because it is unaffected by specific NOS inhibitors. NO is also produced in the mouth of both the rat (77) and humans (78), or in human sweat (27). In these instances, commensal bacteria may play a role in synthesis and the NO that is produced may serve as a defense mechanism against pathogens. NO is used therapeutically in patients with pulmonary hypertension and other conditions (79,80). Serum nitrates and nitrites (measured as a combined total) or plasma nitrate by high-performance liquid chromatography (HPLC) increase with NO inhalation (24,81). Most (90%) of the 15NO that is inhaled is retained and at least 70% is recovered in urine as 15N nitrate (39). NO has an unpaired electron and this makes its chemistry and biochemistry (82) and its pharmacology (83) complex. Its biological half-life is 5 s or less (84,85). Some of the NO produced by various tissues rapidly binds to heme groups in enzymes such as guanylyl cyclase, in effector cells such as the smooth muscle cells of the blood vessel wall (86) or platelets (87). This increases cGMP and in this way NO acts as an intermediate or second messenger of hormone action (88). In some cells, NO action is effected through intracellular calcium cycling (89). Residual amounts of NO react with water to form nitrite, which in the presence of heme groups in proteins such as myoglobin, hemoglobin, or enzymes, rapidly oxidizes to nitrate and the corresponding met-heme protein (85). For example, when NO diffuses into the red cell, it reacts rapidly with oxyhemoglobin to form methemoglobin and nitrite (90). In the presence of oxygen and methemoglobin reductase, these are rapidly converted back to hemoglobin and to nitrate. NO also reacts with thiol groups to form nitrosothiols, such as nitrosocysteine or nitrosoalbumin (91, 92) or nitrosohemoglobin (93,94). The association between thiols and NO is relatively weak and nitrosothiols can exert long-acting endothelium-derivedreleasing-factor-like effects by slowly releasing NO. As nitrosohemoglobin becomes deoxygenated, conformational changes take place and NO is released; this may act on the endothelium to cause vasodilatation where it may be most needed (94). Because albumin is so abundant and it has one free cysteine residue, much of the protein-bound releasable NO circulates as the albumin-adduct. Advanced glycaCLINICAL BIOCHEMISTRY, VOLUME 31, JUNE 1998
tion adducts may quench NO release from nitrosothiols, reducing their effectiveness as NO donors (91). The exact role has not been determined for a group of proteins described in insect salivary glands that bind and readily release NOnitrophorins (95), though they may act to increase blood supply to the bite area. Their mammalian counterparts (dedicated high capacity NO carriers) have not been described. NO has important effects as a bactericidal agent when it is released by macrophages during infection (58,59,96). This defense mechanism seems to have been conserved through evolution (97). Peroxynitrite (ONOO) is formed from NO and superoxide (O2) (98) and may be responsible for some of the cytotoxic effects of these molecules (57,99). When protonated, ONOO gives rise to hydroxyl (OH) and nitrogen dioxide (NO2) radicals, which can induce tissue damage (100 105). Nitrite may also produce the nitrogen dioxide radical when oxidized by hydrogen peroxide, catalyzed by heme peroxidases (106). Tissue damage may result from tyrosine nitration (107,108). In mammalian smooth muscle cells, NO may inhibit proliferation by influencing cyclin-dependent kinases that are critical to the cell cycle (109). Methods of measuring nitrite and nitrate in plasma and urine Methods for these analyses have been reviewed (2,110,111). Nitrite is difficult to measure reliably in blood because it is unstable, being rapidly oxidized to nitrate. When added to blood, 16% of added nitrite remained after 30 min at room temperature; at 60 min, the corresponding fraction was 5%. At 4C, the percentages were 69% and 55%. Once plasma is separated from blood (avoiding hemolysis), both nitrite and nitrate are stable at 20 C for at least 1 year (3). Urine nitrate and nitrite are stable in the absence of microbial contamination. Acid pH destroys nitrite, so acid preservatives should be avoided. Samples should be collected on ice, possibly with the addition of antibiotics or isopropanol to the urine during the collection (4). After collection, freezing is recommended for long-term storage. Nitrite concentrations in plasma and urine are usually only a small fraction (5%) of the nitrate concentrations, reflecting in part the dietary intakes of these ions and also their bioreactivity. A combined measurement of nitrate plus nitrite (termed NOx) is often used with colorimetric assays because the procedures can be simplified and the stringent sample preparation requirements for nitrite analysis can be avoided. If investigators have no interest in nitrite, serum can be used for NOx determinations. Because nitrite is usually present at much lower concentration than nitrate in body fluids, NOx is almost synonymous with nitrate in most instances. There is some confusion in the literature over nomenclature. Some authors have used nitrite to mean NOx because nitrite is the component mea197
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sured after reduction of nitrate (112116). This error has been noted by others (117). In this review, when authors have used the abbreviation NOx to denote something other than a combined total concentration of nitrite plus nitrate, e.g., nitrite plus nitroso compounds, then we have explained their usage and we have used quotes (NOx) to denote this. Proposals to standardize nomenclature in NO research have recently been published (118). COLORIMETRIC
METHODS
FLUORIMETRIC
ASSAYS
Nitrite is reactive and used extensively in dye manufacturing. Over 50 colorimetric methods were proposed for its determination; many based on the formation of azo dyes (119). Currently, there are occasional references to the use of the Brucine method, in which nitrite is oxidized to nitrate by permanganate and boiled with strychnine to produce a yellow color (35). However, most recent clinical papers use colorimetric methods based on the Griess reaction. Nitrite is reacted with sulfanilamide and N-(1-naphthyl)ethylenediamine (3) to produce an azo dye. Nitrate may also be measured if it is first converted to nitrite with the enzyme nitrate reductase from bacteria (Escherichia coli, Pseudomonas oleovorans) (111) or fungi (Aspergillus) (120). Alternatively, metallic reduction over copper-plated cadmium (121,122) or granulated cadmium (123) can be used. There are a number of variants of the Griess reaction, designed to eliminate interference from both reagents (120,124) and the material assayed. Plasma assays require protein removal, e.g., by precipitation with zinc hydroxide (125), zinc sulfate (3), or by ultrafiltration (61). When the methods are compared against gas chromatography-mass spectrometry, other sources of interference become evident, such as free reduced thiols and other poorly characterized plasma constituents (126). Drugs, such as L-arginine analogs, may interfere also (127,128). Recoveries have been reported to be 91.5%, compared with copper-cadmium reduction (120) or 95% for nitrate and 100% for nitrite in serum (124). However, when compared with mass spectrometry, the variant of the Griess reaction that was used for urine gave recoveries varying between 30 80% (126). There are several automated methods based on the Griess reaction and flow injection analysis (121) or HPLC. Methods based on HPLC are discussed subsequently. Variants of the method have used alternate coupling reagents for nitrite determination (129). ULTRAVIOLET
SPECTROPHOTOMETRIC METHOD
Nitrite (and nitrate after reduction) have also been measured fluorimetrically. In one method, nitrite enables the acid-catalyzed ring closure of 2,3diaminonaphthalene to form highly fluorescent 2,3diaminonaphthotriazole (132,133). The method is 50 100 times more sensitive than the Griess reaction and was used on serum or plasma and tissue culture media. With minor adaptation, these methods may be used for determination of S-nitrosothiols (134). A simple and highly selective fluorimetric method for determining nitrite with Rhodamine 6G has been described in which Rhodamine 6G is oxidized in sulfuric acid medium. The assay has been applied to the analysis of milk (135). METHODS
ELEMENTS USING ELECTRODES OR BIOANALYTICAL
Several nitrate or nitrite-specific electrodes and bioanalytical elements have been designed. They have usually been shown to work with aqueous samples (136 143). One has been used with saliva (144) and another with milk (145). Electrochemical detection of nitrite has been used with HPLC (described subsequently). METHODS
USING
NO
ANALYZERS
A direct continuous kinetic spectrophotometric method has been described for urine and serum nitrate (130). The nitrate is reduced by NADPH using nitrate reductase from Aspergillus. A similar one-step assay used the method of standard additions to adjust for possible reaction interferents in serum (131).
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NO analyzers have been designed to measure NO in air samples by chemiluminescence in the presence of ozone. The ozone is produced by an electrical discharge acting on oxygen supplied from a cylinder. The first product from NO is excited nitrogen dioxide, which emits chemiluminescence as it returns to its ground state (146). The analyzers have been refined and are used in clinical investigation to monitor both NO and NO2 when NO is used in the therapy of pulmonary vascular disease (79,80), and NO production in exhaled breath in asthma and other conditions (147149). With this instrumentation, exhaled NO is easier to measure than nitrite and nitrate. It has also been applied to the study of NO metabolism in various conditions. However, the apparent production rate of exhaled NO varies with exhalation technique. Moreover, the site of origin of the exhaled NO is unclear. Much of the measured exhaled NO may be produced in the nasopharynx, unless stringent precautions are used (147), or in the airways, rather than at the level of the alveolus (150). In order to measure nitrite or nitrate, the NO analyzers are coupled to an enclosed vessel through which an inert gas, such as nitrogen or helium, is purged (151). Then selective chemical reduction of either nitrite or nitrate to nitric oxide can be monitored directly as sequential samples are added to excess of the appropriate reagent. Acetic acid/iodide are often used for nitrite or vanadium III/NaOH for nitrate. Various oxidants have been tested and compared (152). It is subject to interference by a number
of arginine analogs currently investigated as potential pharmacological agents (127). The method has also been applied to saliva (153). In a modification of the method to include a photolysis step (154), or thermolysis, followed by nitrate reductase (155), S-nitrosothiols can be quantified. CAPILLARY
ELECTROPHORESIS
Capillary electrophoresis (CE) methods have been applied to a wide range of analyses and they show promise for the future (156). CE procedures have been described for assay of nitrite and nitrate in serum or plasma (37,157160) and urine (158 161). Nitrite and nitrate show good resolution with a short run-time of 4 22 min. Both anions may be quantified with a single injection after minimal sample preparation, such as ultrafiltration. Capillary isotachyphoresis methods permit assay of Snitroso compounds in addition to nitrite and nitrate (162). Micellar electrokinetic capillary chromatography has also been used for determination of nitrite and nitrate in extracts prepared from milk and blood (163). In this technique, migration of the ions is modified by inclusion of a positively charged surfactant, such as dodecyltrimethylammonium bromide. CE is a microtechnique, suitable for small volumes of fluid. It has been used experimentally for measurement of airway surface fluid from rats (164) and to assess nitrite and nitrate content of single neurons (165). Despite the availability of alternative approaches for nitrate and nitrite analysis using capillary electrophoresis, CE equipment and expertise are not yet widely available in clinical laboratories. GAS
CHROMATOGRAPHY AND GAS CHROMATOGRAPHY-MASS
173176). The methods are generally based on separation by ion-exchange HPLC, although some have been described for nonbiological matrices that use reversed phase chromatography on C18 with ionpairing reagents such as cetyltrimethylammonium (177). The binding of ion-pairing reagents to C18 columns is often difficult to predict (178) and HPLC columns with intrinsic ion-exchange functionality are probably more reliable. Plasma assays require ultrafiltration or protein precipitation and additional sample preparation by some form of chromatography. Similar preparation (without protein precipitation) is used for urine (24,173). Not all methods have been fully described and validated. Dedicated ion chromatographs (with conductimetric or spectrophotometric detection) can also be used for these ions (179 181). Chloride ion has to be removed to prevent interference when conductimetric detection is used because of its high concentration in biological samples. Sensitive HPLC assays for nitrite in foods (182) and tissues (183,184) have been developed using electrochemical detection. A method has also been described for whole blood, in which nitrite is detected electrochemically and nitrate by spectrophotometry (185). It is unclear whether there would be significant interference from nitrosohemoglobin when whole blood is analyzed. Ion-exchange HPLC has also been used followed by copper-cadmium reduction and the colorimetric Griess reaction to measure plasma, urine and cell culture nitrite and nitrate (173,186). CONTAMINATION
AVOIDANCE
SPECTROMETRY
Gas chromatography has been used for the analysis of nitrite in water (166) and saliva (167) and for nitrate analysis in rat urine (168). GC-MS methods use 15N labeled internal standards or isotope dilution techniques and derivatization with pentafluorobenzyl bromide (169), benzene (168), or toluene (24). They form the basis of reference methods for nitrite and nitrate in plasma and urine (126) and water (170). The specificity of a commonly used GC-MS method for nitrite in plasma (171) has been questioned on the basis of 15N enrichment studies (38). Nitrate recovery from rat serum was as low as 67%, with one method (168). HIGH-PERFORMANCE
LIQUID CHROMATOGRAPHY
It is important that clinicians and laboratory workers be ever vigilant against possible contamination of nitrite and nitrate assays (37). Glassware is often contaminated with nitrate and sometimes nitrite, unless it is sold for use in trace analysis (e.g., HPLC vials). Ultrafiltration filters are contaminated with nitrate (possibly from the azide, presumably added to preserve the cellulose or other filtermatrix) (174). We have generally found plastic disposable wares clean. Disposable glass transfer pipettes, gloves, and glove powder are potential sources of contamination (187). We have found that blood tubes containing anticoagulants such as EDTA from some manufacturers contain nitrate. Some heparinized syringes are contaminated and rubber stoppers in vacutainer tubes may leach nitrate. Others have noted nitrite contamination of blood tubes containing citrate or EDTA anticoagulants (126). Type A water (18 M) should be used for reagent preparation and final rinsing of glassware. Clinical correlates REFERENCE
VALUES
High-performance liquid chromatography (HPLC) is used for nitrite/nitrate measurement in environmental studies and a direct UV spectrophotometric method (at 215 nm) is approved by the US Environmental Protection Agency for this purpose (172). A number of similar methods are available for measurements in foods (17,28), urine and serum (24,
Sex differences In one study (188), 22 men had mean plasma nitrate (27 mol/L) approximately twice that of 18
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women (14 mol/L) and they exhaled more NO (34 vs. 20 ppb), even after correction for body weight. Diet was uncontrolled in this study and no estimates of intake were given, but samples were taken after a 12-h fast. Others have observed higher values for plasma nitrate in men and have noted increasing values with age and other factors associated with atherogenesis, such as lipids, glucose, and blood pressure (189). Giovannoni et al. (124) did not observe gender differences of this magnitude. Mean serum NOx concentrations were 39 mol/L in 12 men and 33 mol/L in 12 women. These authors also noted a two- to three-fold increase in values in plasma, compared with serum. However, they did not seem to exclude contamination from the anticoagulant as a possible reason for the observed differences. No difference was found between serum and plasma in another study (3). Men and postmenopausal women had similar serum NOx concentrations (190). Reference values have been summarized in two reports (2,126); each contains information on 12 studies. Dietary restriction in 12 German subjects reduced plasma concentrations and urinary excretion by approximately one-third to one-half (126,169). Reports on the effects of the menstrual cycle on values are conflicting. Plasma NOx values increase in adult women in association with follicular development (74). In this latter study, there was a positive correlation of plasma NOx with plasma estradiol in control women and in those undergoing hormone therapy for in vitro fertilization. Diet was uncontrolled, but most samples were fasting. Subsequent studies by these authors showed increased plasma NOx in postmenopausal women when they were treated with estrogens (191). In a similar studies, serum NOx concentrations increased in women (but not in men) following 3 days of transdermal estradiol (190) or in women following 12 months of therapy (192). In contrast, Jilma et al. (188) found no changes in breath NO or plasma nitrate over the course of the menstrual cycle in 18 women and in a small group of 5 ovulating women, Morris et al. (193) found no changes in exhaled NO and early-morning urinary nitrite/creatinine ratios over 30 days. However, amenorrheic women with hyperprolactinemia had lower serum NOx than controls and values increased after successful therapy (194). Values in children In a group of 90 normal Japanese children, those 3 years old had higher NOx/creatinine ratios than older children, values showed no gender differences, and were independent of age after about 12 years (35,195). Plasma and urine NOx were also measured in a small group of 16 healthy children (196). Values for urine NOx (not nitrite) in 17 children have also been presented (113). In groups of East Indian children and adults, mean salivary nitrate concentrations (2136 ppm) were approximately twice or
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three times those of nitrite (1217 ppm) (197). Cerebrospinal fluid (CSF) NOx is age related in children. In 35 British children with various neurological conditions in whom no disturbances of monoamine neurotransmitter metabolism or infection were suspected, values are highest in the first 2 years after birth and appear to decrease after this time to 17 years (198). GENERAL
CONSIDERATIONS
Because NO is involved in so many diverse activities in the body, one might expect that its metabolism would change in a wide variety of conditions, leading to alterations in the concentrations of its metabolites in blood and urine. While this is true to some extent, many of the physiological activities involve one of the two constitutive NOS isoenzymes that change little in disease. However, other processes are associated with the many tissues and organs that have inducible NOS isozymes. These enzymes can be massively induced by infection or inflammation. The enzyme activity of a fully-induced macrophage can be approximately 1000-fold that of an endothelial cell (45). URINE
NITRITE AS A MARKER OF URINARY TRACT
INFECTION
Nitrite is produced from urine nitrate by bacterial nitrate reductase (75) and small quantities may perhaps arise by alternate pathways, involving NOS (199). Some nitrite is converted to NO in acidified urine (75), but much remains. Elevated urine nitrite may assist in the diagnosis of urinary tract infections and test strips for this purpose have been available for many years. Some have found that strips for bacterial leukocyte esterase are more effective than those for urine nitrite (200). Nitrofurantoin may reduce the effectiveness of nitrite test strips (201). The merits of using these test strips has been the subject of much debate. Results should not be used to direct antibiotic therapy (202), they had low positive predictive value (203205), but they may be better than urinalysis (204,206) and they have merit in certain specific situations (204,206 208). Others have reported that they perform well (209). NITRITE
AND NITRATE IN OTHER INFECTIONS
In sick hospitalized patients, dietary intake, if any, is less likely to contribute to plasma or urine nitrate and nitrite. For this reason, increases in these ions may become more reliable markers of diseases, because of alterations in NO synthesis, degradation or excretion. This may apply in septic shock (210 217), in patients with endotoxemia due to severe cirrhosis (218,219), or in patients with systemic inflammatory response syndrome (220, 221), and multiple organ failure (222). There were significant differences between plasma NOx (by the
Figure 1 (A) Urinary nitrate:creatinine molar ratios and (B) serum nitrate concentrations (mol/L) in healthy volunteer controls and in patients with rheumatoid arthritis or infectious gastroenteritis. Bars show the mean SD. Broken line shows mean 2SD for controls. Group means significantly different from controls are indicated by * p 0.005 and ** p 0.001. (Reproduced with permission from Lippincott-Raven Publishing from Grabowski PS, England AJ, Dykhuizen R, et al. Elevated nitric oxide production in rheumatoid arthritis. Detection using the fasting urinary nitrate:creatinine ratio. Arthritis Rheum 1996; 39: 6437 [36].)
Griess reaction) in controls and infants with sepsis and septic shock; mean values were: 35, 126, and 582 mol/L for the respective groups (212). It is unclear whether the assessment of efficacy of the possible use of NOS inhibitors in septic shock (223) would be assisted by measurements of plasma/urine nitrite or nitrate. Plasma nitrite was increased in AIDS with pulmonary involvement (224) and was increased in other AIDS-related infection (225). Others saw no change in NO production in AIDS patients without severe infection (41). Serum NOx was increased in trypanosomiasis (226). NITRITE
AND NITRATE IN GASTROENTEROLOGY
Possible low vegetable consumption could enhance the utility and selectivity of plasma and urine nitrate in patients with gastrointestinal diseases, unmasking higher values in gastroenteritis (36,227 229) (Figure 1). The precise role of NO and other free radicals in secretory diarrhea is still to be determined (230). In inflammatory bowel disease, urine nitrate/creatinine ratios were about four-fold those of patients with non-inflammatory disorders (231). However, others found no significant differences between median serum nitrate in ulcerative colitis, Crohn disease, and healthy controls; but patients with active disease had higher values than those with inactive disease (232). Greatly increased serum NOx may help predict those patients with ulcerative colitis who require a change in medical therapy or surgery (233). Urine nitrate in 14 patients declined in parallel with their recovery in response to therapy (234). Plasma NOx was significantly increased in small groups of patients with collagenous colitis and also those with lymphocytic colitis; at colonoscopy, NO sampled from the lumen of the colon, close to the mucosal surface, was also increased in 4 of 5 patients with collagenous colitis compared with that in 10 controls (235).
Increased NO production might also be expected in these conditions from other evidence. Colon mucosa cultured from biopsy specimens showed 4 to 10-fold higher NOS activity and 4 to 8-fold higher nitrite production in areas of active Crohn disease or ulcerative colitis, compared to those from normal controls, and values were lower when biopsies were cultured in the presence of methylprednisolone or ketotifen (236). Similar increases in mucosal NOS in Crohn disease were seen by others (237). Also mucosal L-citrulline (an indirect measure of NO synthesis) is higher in biopsies from patients with active colitis (238). Topical application of L-NAME (N-omega-nitro-L-arginine methyl ester, a competitive inhibitor of NOS) reduced colonic inflammation in a rat model of ulcerative colitis, suggesting that NO synthesis was associated with the inflammation in this condition (239). In mice, oral arginine supplementation protected against bacterial translocation from the gut to other organs after lipopolysaccharide-insult (240), suggesting an important role for NO synthesis in host defense from pathogen entry via the gut. The defensive roles of NO production by the gut in gastrointestinal disease probably outweigh its potentially harmful effects (241). Increased nitrite concentrations were found in the gastric juice of patients with chronic atrophic gastritis (242). The affected group also had slightly higher gastric pH, which might be expected to increase the stability of nitrite. Nitrite production from nitrate by commensal bacteria in the mouth may serve to protect against Candida and other pathogens (78). The NO (nitrergic) nervous system plays an important role in gut motility and secretion and in other functions (243). Pyloric stenosis in infants appears linked to a neuronal NOS gene polymorphism (244), and Hirshprung disease is associated with low neuronal NOS in intestinal nerve fibers (245), but we are unaware of any studies on NOx production in these conditions.
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Mean serum NOx was 63 mol/L in 24 patients with chronic hepatitis C virus infection, compared with 33 mol/L in 8 patients with other liver disease and 25 mol/L in 12 healthy subjects. RNA transcripts for inducible NOS in biopsy specimens were also increased. It was unclear whether these effects were caused directly by the virus or through interferon- (246). In contrast, in chronic hepatitis, from various causes, serum nitrite was lower than in controls, but many values in the groups overlapped (247). Both exhaled NO and serum NOx were higher in cirrhotic patients than controls (248). The differences were more marked for mean NO (252 vs. 75 nL/min/m2) than mean NOx (48 vs. 33 mol/L) and values did not correlate. Cirrhosis also increases plasma NOx in rats (249) and in humans with ascites (250). Nitrate concentrations in urine and serum correlate with disease progression (251). These increases seem to be related more to renal impairment (250,252) than to endotoxin action on hepatic or other macrophages as was first thought (218). Plasma NOx was increased in patients with hepatocellular carcinoma and other liver diseases; values increased with increasing tumor size and were higher in those patients who developed their cancers from chronic hepatitis than from cirrhosis (253). As judged from inhibitor studies, NO seems to be involved in both exocrine and endocrine secretion by the pancreas (254). NITRITE
AND NITRATE AS MARKERS OF IMMUNE
ACTIVATION
Plasma nitrate has been proposed as an index of immune system activation (58). During an immune challenge; values increased 20-fold in experimental animals after zymosan (59) or endotoxin (255). Lipopolysaccharide increased NOx in the plasma of rats and mice (61). Values peaked approximately 20 h after injection. Nitrite and nitrate in blood, urine or culture fluids can also be used to investigate NO production and how it is affected by various drugs, cytokines (256,257) or hormones such as insulin (258), parathyroid hormone related protein (259), or atrial natriuretic peptide (260). Serum nitrite is increased in patients with rheumatoid and osteoarthritis. Concentrations in synovial fluid from affected joints are higher than corresponding serum concentrations, suggesting that much of the serum nitrite originates from the joints (261,262). The changes were more marked in rheumatoid arthritis (261) (Figure 2). Urine NOx (nitrate)/creatinine ratios but not serum NOx were increased three-fold in rheumatoid arthritis and provided a useful indicator of NO production in this disease (36) (Figure 1). Urinary nitrate values fell by 28% in rheumatoid arthritis with prednisolone therapy, but mean values remained elevated compared with controls (263). There was extensive overlap between controls and patients, even before therapy, and the test could not be used to support a diagnosis. Urine nitrate was approximately three-fold higher
202
Figure 2 Nitrite concentrations in synovial fluid (SF) and serum samples from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and from controls matched for age and sex. Bars indicate group means. (Reproduced with permission from BMJ Publishing Group, from Farrell AJ, Blake DR, Palmer RM, Moncada S. Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 1992; 51: 1219 22 [261].)
in arthritic rats compared with controls (264). In 14 patients with active spondyloarthropathy, mean serum nitrate concentrations (taken 2 4 h after breakfast, with no dietary control) were approximately two-fold those of patients with inactive disease or those of control subjects (265). Nitrate correlated with erythrocyte sedimentation rate and C-reactive protein. Serum NO (nitrite, measured as NO after ascorbate reduction) has also been measured in rheumatoid arthritis and may be a more sensitive measure than NOx; mean values (293 nmol/L) were about 10-fold higher than those of controls (36 nmol/L) and patients with osteoarthritis (33 nmol/L) (266). Serum NOx may assist in monitoring the effects of interleukin and interferon therapy of certain cancers (267). Measurements of exhaled NO have also been proposed as marker of lung inflammation (268). Mean serum NOx (not nitrite, as reported by the authors) was increased in 46 patients with systemic lupus erythematosis, compared to 5 control subjects. Overlap could not be assessed because of the small number of controls. Endothelial cell and keratinocyte expression of inducible NOS protein
were also increased in skin biopsy specimens (112). Yet in another study, plasma nitrate concentrations were similar in controls, and patients with systemic lupus erythematosis, thrombotic throbocytopenic purpura and primary antiphospholipid syndrome (269). In Kawasaki disease, a pediatric systemic panvasculitis associated with immunological abnormalities, more urinary NOx and neopterin were excreted at certain stages of the disease than in controls (270). Mean early morning urine NOx/creatinine was increased in eight patients with Kawasaki disease; values rose with initial therapy and declined to normal as the disease resolved (271). NITRITE
AND NITRATE IN HYPERTENSION AND IN RENAL
AND CARDIOVASCULAR DISEASE
The role of NO in the regulation of blood flow and arterial pressure has been reviewed (272,273). Mice lacking the gene for endothelial NOS are hypertensive (274). The blood pressure of spontaneously hypertensive rats can be lowered for several weeks (relative to controls) by (non-genomic) delivery of the gene for human NOS (275). This procedure increased urine and serum NOx, along with urine and aortic cGMP. The endothelium itself has a multifactorial role in blood pressure modulation (86), and its dysfunction is important in atherogenesis (47, 276). The interaction of the NO system with aging and atherosclerosis in general (277), and with homocysteine metabolism in relation to atherothrombosis are not fully understood (278,279). NO has multiple effects within the kidney (5,280 283) and, as previously mentioned, renal tissue contains all three isozymes of NOS and their precise role in normal physiology, hypertension and diabetes has not been fully elucidated (68). The use of selective and nonselective NOS inhibitors and NO donors may help elucidate the role of NO production within the complex physiology of the renal tubule (284,285) and its diuretic and natriuretic responses (286). In rats, chronic specific inhibition of neuronal NOS (found also in the macula densa cells of the kidney) caused an increase in blood pressure, possibly related to tubuloglomerular feedback and transiently decreased GFR (287). Because nitrate and nitrite are excreted by the kidney, renal function and clearance have to be considered if they are intended to be used as markers of NO production in various conditions. In 71 patients in an intensive therapy unit, there was a strong positive correlation between NOx and creatinine concentrations in serum (288). Mean plasma nitrate was approximately three- to four-fold higher than normal in patients with renal disease prior to dialysis and fell to below normal following the procedure (289). NO may have a role in the initiation of hypertension (290). Dubey et al. (290) showed that in the one kidney, one clip hypertensive rat model, increasing serum NOx correlated with systolic blood pressure. Corresponding human studies in renovascular hypertension do not show significant changes. In 38 children with
Figure 3 Urinary NOx (not nitrite) excretion (nmol/mg creatinine) in healthy controls (CONT), children with minimal change nephrotic syndrome (MCNS) in remission (REM) or relapse (REL), with focal segmental glomerulosclerosis (FSGS), or IgA nephropathy (IgAN). Bars indicate group means; the asterisks indicate a p value of 0.025 versus other patient groups. (Reproduced with permission from Mosby, Inc. from Trachtman H, Gauthier B, Frank R, Futterweit S, Goldstein A, Tomczak J. Increased urinary nitrite excretion in children with minimal change nephrotic syndrome. J Pediatr 1996; 128: 173 6 [113].)
hypertension, plasma NOx was increased compared with 16 normal children. Values in all but one patient with renovascular hypertension were normal, as were about one-half the remaining patients with renal parenchymal disease. Elevated plasma NOx was associated in part with the reduced GFR in the patients with parenchymal disease (196). In nephrotic syndrome, urine NOx (referred to as nitrite) was increased in children with minimal change nephrotic syndrome and normal in patients with focal segmental glomerulosclerosis or IgA nephropathy (113,114) (Figure 3). A number of endogenous inhibitors of NOS have been described: N(G)-monomethyl-L-arginine (L-NMMA), asymmetrical dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA). They are increased in patients with hypertension, especially those with low GFR and they may have physiological effects in vivo, but it is uncertain whether they are a contributory cause of the hypertension or a consequence of it and its related disease processes (291). In Bartters syndrome, a normotensive, renal potassium-wasting disease, mean NOx/creatinine ratios, in mol/mol creatinine, (0.45) were approximately twice those of controls (0.25) or patients with pseudo-Bartter syndrome (0.28), and urinary c-GMP excretion was also increased (292). The protective role of estrogens on the coronary vasculature may in part be related to their complex effects on NOS (293). Short-term oral high-dose antioxidant therapy lowers blood pressure in normotensives and hypertensives and increases nitrite excretion, implying a role for NO in this effect (294). Some of the deleterious effects of oxidized LDL also relate to interactions with the NO system (295,296).
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Figure 4 Serum nitrate concentration (mol/L) for women with preeclampsia, matched healthy pregnant and nonpregnant women. Bars indicate group means. (Reproduced with permission from Blackwell Science Ltd., from Smarason AK, Allman KG, Young D, Redman CW. Elevated levels of serum nitrate, a stable end product of nitric oxide, in women with pre-eclampsia. Br J Obstet Gynaecol 1997; 104: 538 43 [304].)
Plasma cholesterol and LDL were inversely correlated with plasma NOx, taken at 0600 h on a well-balanced hospital diet (33). The role of NO in heart failure and cardiomyopathy is not known (297), but cardiomyopathy is frequently associated with disorders in which there is higher than normal NO production. A high-capacity inducible NOS isoform is present in the myocardium of patients with idiopathic dilated cardiomyopathy and plasma nitrate was significantly increased in 39 patients with heart failure compared with 62 normal controls. Mean concentrations were 51 and 25 mol/L, but values overlapped considerably between the groups (298). Increases are also reported in chronic heart disease (299) and in infants with heart failure due to septal defects prior to cardiopulmonary bypass (300). In ischemic heart tissue, NO can be produced directly from nitrite and the significance of this pathway has not been evaluated (76). Urine and plasma nitrate measurements were unhelpful in determining the cause of low systemic vascular resistance syndrome after cardiopulmonary bypass (301) or of primary Raynauds phenomenon (302). After transesophageal variceal ligation in patients with portal hypertension, there was a prompt fall in serum nitrate (from 39 to 29 mol/L) associated with the changes in hemodynamics (303). However, there was no indication that serum nitrate would serve to predict a good long-term clinical outcome. The literature on nitrate and nitrite in preeclampsia is confusing. Mean serum nitrate concentrations were higher in 20 women with preeclampsia (47 mol/L) compared with 20 healthy pregnant (31 mol/L) and 12 nonpregnant (32 mol/L) controls. There was no dietary restriction and nitrate would be unhelpful in diagnosis because of extensive over204
Figure 5 Serum NOx concentration (means and SEM) for women with preeclampsia (PE), healthy normotensive pregnant (NTP) and nonpregnant (NP) women, and women with essential hypertension (EHT). Values represent means SEM and n the number of samples (* p 0.0001; p 0.005; ANOVA with Fisers tests). (Reproduced with permission from S. Karger AG, Basel from Nobunaga T, Tokugawa Y, Hashimoto K, et al. Plasma nitric oxide levels in pregnant patients with preeclampsia and essential hypertension. Gynecol Obstet Invest 1996; 41: 189 93 [305].)
lap between the groups. It was not clear whether the increases were due to increased production or decreased renal clearance (304) (Figure 4). Increases were found in pregnant women throughout pregnancy (mean NOx 30 mol/L), compared to nonpregnant controls and values were even higher (mean NOx 45 mol/L) in preeclampsia (305) (Figure 5). In this study, blood was taken after a 1215 h fast. Plasma NOx correlated positively with systolic blood pressure in the preeclamptic patients. Previous authors saw no change in NOx (not nitrite, as stated by the authors) in maternal serum at 3335 weeks gestation; at delivery, fetal side umbilical venous serum showed a slight increase over maternal (116). Also both nitrate and nitrite were lower in preeclampsia in the (non-fasting) group studied by Seligman et al. (115) and serum NOx (not nitrite) was inversely correlated with blood pressure in preeclampsia. Davidge et al. (306) found that urine NOx (not nitrite)/creatinine ratios were lower in 14 women with preeclampsia than in 20 normotensive pregnant women (0.37 vs. 0.69 mol NOx/mg creatinine), but mean plasma NOx was not significantly different (33 vs. 26 mol/L). Mean amniotic fluid nitrite decreases in late pregnancy at 37 41 weeks; exhaled NO is unchanged (307). Nitrate excretion and 15N arginine studies were used to study newborns with persistent pulmonary hypertension (308). The authors concluded that there was decreased arginine utilization during the acute vasoconstrictive stage of the disease, possibly leading to insufficient endogenous NO production in
this condition. Others found that urinary NOx concentrations by the Griess reaction were lower in newborns with persistent pulmonary hypertension than in controls (309). They also attributed this to reduced pulmonary NO production in these patients because of their lung disease. Values increased transiently after the initiation of extracorporeal membrane oxygenation (ECMO). This was believed to be due to enhanced lung production of NO with the improved tissue oxygenation caused by the ECMO. There was considerable overlap between controls and patients. In newborns receiving blood or indomethacin, NO metabolism (assessed by urine nitrite excretion) was affected by these treatments (310). ARGININE
SUPPLEMENTATION AND THE REGULATION OF
BLOOD PRESSURE AND BLOOD FLOW
Endothelial NO, synthesized from arginine, is an important second messenger for blood pressure control (53,311). Feeding arginine-deficient diets to rats after small-intestine resection causes hypertension (312). An infant with arginosuccinate lyase deficiency, who was unable to synthesize arginine, was hypertensive prior to arginine replacement (313). Arginine infusion induces hypotension and diuresis/natriuresis in man (314). The blood-pressurelowering effects of arginine infusion are short term in patients with essential hypertension, producing significant change on only the first of four infusion days (315). Both hypertension and angiotensin-converting enzyme therapy affect the renal response to L-arginine infusion (316). Arginine infusion in neonates with possible endothelial dysfunction and defective NO synthesis improved oxygenation (317). In short-term experiments, arginine infusion improved the circulation in affected ischemic limbs of patients with atherosclerosis (318). In dogs undergoing cardioplegic arrest and coronary artery ligation and release, arginine supplementation of the cardioplegia solution reduced postischemic injury (319). It inhibits platelet aggregation in healthy subjects (320). In partially nephrectomized rats, oral arginine gave some protection against renal failure (321). Its chronic use in drinking water has also been associated with attenuated cardiac hypertrophy in spontaneously hypertensive rats (322). In humans, oral L-arginine supplementation (0.1 0.2 g/kg) may increase NO excretion and plasma nitrate, without affecting blood pressure (323). Oral supplementation with lower doses may slightly increase insulin without effect on nitrite concentrations in plasma or nitrate excretion (324). In men with coronary artery disease, oral L-arginine, taken over a 3-day period, improved endothelium-dependent dilatation of the brachial artery and reduced monocyte/endothelial cell adhesion (325). The proposed beneficial effects of L-arginine may
Figure 6 Plasma NOx concentration (nitrite plus nitroso compounds, mol/L) for patients after liver transplant: (A) by clinical status, (B) by rejection grade on the day of biopsy confirmation. Bars show group means. (Reproduced with permission from Williams and Wilken from Devlin J, Palmer RMJ, Gonde CE, et al. Nitric oxide generation a predictive parameter of acute allograft rejection. Transplantation 1994; 58: 5925 [333].)
result in part from its ability to act as a scavenger of superoxides as well as a substrate for NO synthesis (326,327). If L-arginine therapy becomes established practice for specific indications, plasma or urine nitrate or NOx measurements along with exhaled NO may be useful in the assessment of the treatment regimes. However, there may be contraindications to arginine therapy. It enhances lipid peroxidation in poorly perfused rat kidney (328). In mouse malnutrition, supplementation with arginine alone may not be beneficial (329). Also some of the beneficial effects of the low protein diet in renal disease are believed to be a direct consequence of arginine restriction (330).
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NITRITE
AND NITRATE IN TRANSPLANTATION AND
REJECTION
NO is produced by various cells in the liver and may serve as a second messenger and as a defense against invading microorganisms, parasites and tumor cells (331). Exhaled NO was increased in a series of patients with hepatopulmonary syndrome and values returned to normal in one patient after transplantation (332). Plasma acid-labile NOx (nitrite and nitroso compounds, measured by chemiluminescence) was increased in liver transplant rejection in fifty consecutive patients. There was overlap in values between the groups, but the highest values were seen in Grade 2 and 3 rejection (333) (Figure 6). In this study, plasma nitrate did not correlate with rejection. Samples, with no reported anticoagulant, were separated within 20 min, to avoid the reported rapid conversion of nitrite to nitrate in whole blood (3). Others have criticized the use of plasma nitrite as a marker of NO production, because of its instability (334). Plasma nitrate was increased in patients with moderate to severe liver transplant rejection, but not in those with mild rejection. Mean values (mol/L) were 50 in the severe rejection group, compared with approximately 20 in groups with no or mild rejection at the time of liver biopsy. Values fell to normal after successful antirejection therapy with glucocorticoids (335). Mild increases in plasma nitrate were found in many patients in the postoperative period, perhaps linked to temporarily ineffective anti-rejection therapy (336). But rats show increased NO synthesis following partial hepatectomy (337), so the rise in nitrate following transplantation might be a nonspecific response to injury. In rats, heart transplant rejection was associated with an eight-fold increase in urine nitrate excretion, compared with controls. Unfortunately, rejection in transplanted animals that had been treated with dexamethasone and cyclosporine was much less dramatic, leading to only two- to three-fold increases (338). These increases were probably due to effects on the inducible NOS isoenzyme of the myocardium as well as increased macrophage NOS activity. Urine nitrate is increased in human heart transplant patients during rejection. In a thorough study of 86 patients, mean values (mol/mmol creatinine) were 100 in patients with no evidence of rejection and 128 in those showing rejection (339). The magnitude of these differences compared with intra- and interindividual differences was insufficient to make the test clinically useful for the diagnosis of rejection. However, Benvenuti et al. (340) found that serum NOx correlated with the severity of heart transplant rejection, as assessed by histological grade and a cutoff value of 20 mol/L could be used to help detect Grade 2 rejection. Serum NOx has been shown to increase in experimental small bowel rejection in the rat. Concentrations fell rapidly with the onset of anti-rejection therapy (341). In renal transplantation, urine nitrite
206
Figure 7 NOx concentrations (mol/L) in induced sputum in patients with asthma and normal controls. Bars represent mean values. (Reproduced with permission from Mosby, Inc. from Kanazawa H, Shoji S, Yamada M, et al. Increased levels of nitric oxide derivatives in induced sputum in patients with asthma. J Allergy Clin Immunol 1997; 99: 624 9 [347].)
dipstick methods may not have sufficient sensitivity to detect bacteriuria (342). NITRITE
AND NITRATE IN DISEASES OF THE BLOOD SYSTEM
Plasma NOx concentrations were increased in acute painful crises in sickle cell disease when compared with healthy control subjects (90). The reasons for this increase were not clear, but it is unlikely that routine NOx measurements will find a role in monitoring such patients because the increase was quite modest (mean NOx 50 vs. 30 mol/L) and sickle patients had elevated values when not in crisis; their mean NOx was 42 mol/L. Cell-free hemoglobin can remove NO rapidly (343) and by doing so, its presence may lead to abnormal thromboregulation as summarized by Marcus et al. (344). This may be relevant in the development and possible introduction of hemoglobin-based blood substitutes (343).
NITRITE
SMOKERS
AND NITRATE IN RESPIRATORY DISEASES AND IN
The bronchiolar lavage fluid mean NOx concentration was 20-fold increased in 20 lung cancer patients compared with 8 smoker controls, presumably due to cytokine activation (345). NOx in bronchio-alveolar lavage fluid was increased in 5 of 13 immunosuppressed children with pneumonia, compared with 31 controls. The mean value (approximately 21 mol/L) was about twice that of the controls; serum NOx was similar in the two groups (346). NOx by the Griess reaction is increased in induced sputum from patients with asthma (347). Mean concentrations (mol/L) were 1086 in 18 asthmatics and 577 in 10 controls. There was little overlap in values (Figure 7). However, exhaled NO (148,149,348,349) may give a more direct measurement of NO production in lung than its metabolites, nitrite or nitrate, and simple, sensitive NO analyzers are increasingly used in clinical medicine. The effects of smoking on NO metabolism are complex. Cigarette smoke is an excellent source of NO (up to 500 ppm), that can nitrate tyrosine (107). Its NO concentration varies widely, depending upon how the tobacco was grown and manufactured (350). Smoking impairs endothelium-dependent vessel relaxation (350), but other effects are somewhat unexpected. Smoking, particularly heavy smoking, is paradoxically associated with lower serum NOx (351). Moreover, exhaled NO increases after quitting smoking (352), perhaps implying better lung function. CSF
AND PLASMA NITRITE AND NITRATE IN NERVOUS
SYSTEM DISORDERS
In addition to acting as a neurotransmitter (353, 354), NO may cause damage to nerve cells, but its role in various diseases is not well understood (51, 62,63,355,356). Whether it causes benefit or harm may depend on the stage of the disease process (357). Male mice deficient in neuronal NOS exhibit bad behavior (358,359), but we know of no clinical studies where nitrite or nitrate have been measured in behavioral disorders. Much of the clinical neurology literature relating to changes in CSF and plasma nitrate and nitrite is conflicting. In two infants with Hemophilus influenzae meningitis, CSF nitrite concentration was increased. This was regarded as evidence for enhanced nitric oxide production in this condition (360). CSF nitrite was also increased in all six patients with bacterial meningitis and declined with successful therapy (361). In patients with recent stroke, arginine and nitrite were both increased in CSF and their concentrations correlated (362). The extent of possible overlap in values between affected patients and unaffected controls was not given, so it is difficult to assess whether CSF nitrite measurements could have a diagnostic role in this condition. Minimal changes in CSF nitrite and nitrate ocCLINICAL BIOCHEMISTRY, VOLUME 31, JUNE 1998
curred during the treatment of adult head injury patients with hypothermia, but values were slightly higher in non-survivors than in those who survived (363). CSF NOx was unchanged in Parkinsons disease (364) and in aseptic meningitis, multiple sclerosis and Guillain-Barre syndrome (365), or in Parkinsons disease, spinocerebellar ataxia and amyotrophic lateral sclerosis (366). It was unchanged in Huntingtons and Alzheimers disease, amyotrophic lateral sclerosis, and HIV infection, but values were significantly increased in a small group of patients with bacterial and viral meningitis (367). Others (224) described similar negative findings for CSF, but noted some increases in serum nitrite in generalized infections that may affect the brain, such as cytomegalovirus in AIDS. Lower than normal mean CSF nitrate was found in Alzheimers and Parkinsons diseases and in multiple system atrophy (368). But there were no changes in fasting plasma NOx (mean concentration 33 mmol/L) or CSF NOx (mean 5 mol/L) in the group of patients with Alzheimers studied by Navarro et al. (369) and CSF nitrite was increased in another Parkinsons disease group (370). Plasma nitrate was unchanged in Parkinsons disease according to another report (371). CSF nitrite and nitrate concentrations were statistically significantly higher in patients with lumbar spondylosis compared with those of controls, and the authors felt that NO may play a role in lumbar pain or nerve damage in sciatica and that CSF nitrite/nitrate may be used as a diagnostic parameter of spinal diseases (372). Unfortunately, individual values for the 18 affected patients and 18 controls with other CNS diseases are not shown, but there was significant overlap between the two groups with mean (SEM) values (mol/L) of 4.48 (0.34) and 3.48 (0.22), respectively. Serum NOx was increased in a group of demyelinating diseases including multiple sclerosis, inflammatory neurological diseases and AIDS patients studied by Giovannoni et al. (373). Mean NOx (mol/L) for the groups were 66, 56 and 58, compared with noninflammatory neurological disease, 41, and normal controls, 33. There was significant overlap in values between the groups. On the basis of higher CSF NOx seen in younger children (who were shorter in height and spinal length than older children), Surtees et al. (374) proposed that a rostrocaudal NOx gradient existed in CSF and that most CSF NOx originated from the brain. NITRITE
AND NITRATE MEASUREMENTS IN MISCELLANEOUS
CONDITIONS
Plasma nitrate concentrations were elevated in patients after burn injury. The highest values were in patients with 10 40% of the body involved (176). Minor burns are not associated with significantly increased plasma NOx; increased values were found only when there was therapeutic cerium nitrate contamination of the burn area, or generalized
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stress due to smoke inhalation injury (375). The nitrate concentration in human tear fluid (like that of the black vulture, Coragyps atratus) is lower than that of serum (181), but there are no reports of its use in the diagnosis of eye conditions (in either species); although the NO system is very important in many intraocular processes and in eye irritation (376). NO plays an important role in the initiation of apoptosis in various cell types, such as neuronal cells, pancreatic cells, chondrocytes and macrophages (64 67,377). NO interactions with the p53 tumor suppressor system are under intensive study and NO may actually support tumor growth (378). Plasma and urine NOx assays have not been used extensively to monitor apoptosis or tumor progression clinically, except where they are associated with inflammation. Plasma and CSF NOx were generally unhelpful in malaria (379), but higher plasma NOx was associated with deeper coma in cerebral malaria (380). NO plays an important role in intercellular communication in bone (381,382), but its metabolites have not been studied in bone and joint diseases, except in arthritis and the spondyloarthropathies (382). ENVIRONMENTAL
NITRITE AND NITRATE: POSSIBLE EFFECTS
ON THE INCIDENCE OF DIABETES AND OTHER DISEASES
There are tenuous connections between the NO system and several processes in diabetes (383). NO and cytokines are associated with islet cell death in diabetes (384 386) and high glucose concentrations induce NOS expression and superoxide anion in human aortic endothelial cell culture, implying a possible role for NO in the vascular complications of diabetes (387). NO mediates increased blood flow to pancreatic islets during hyperglycemia (388) and experimental hyperinsulinemia increases urinary NOx excretion (258). Type I diabetics have evidence of arterial endothelial dysfunction (389) and specific NOS inhibitors may influence urinary albumin loss and the formation of advanced glycation end products in the diabetic rat kidney (390). Alternative inhibitors may increase blood pressure and cause proteinuria in other rat models (391). There are early indications that tissue advanced glycation end products may be important modulators of NO-mediated responses (392). However, because of the wide variability of dietary nitrate intake (393), it is difficult to understand how disease incidence in childhood diabetes could be causally associated with higher nitrate concentrations in drinking water (394). The relative risk was 1.27. Others have found no associations between Type I diabetes and child or maternal nitrate intake from food and water, but they found a positive association with dietary nitrite (relative risk 2.3 for the fourth quartile of intake) (395). Drinking water (particularly well water) may become contaminated by nitrate from fertilizer run-off or from waste water contamination and this may
208
present an increasing problem (396). Associations with the concentration of nitrate in drinking water and disease incidence have also been described for bladder cancer (397), non-Hodgkins lymphoma (398,399), gastric and prostate cancer (400), spontaneous abortion in four women (401), chromatic/ chromosome breaks in children (402), and thyroid enlargement (403). In other studies, associations between environmental contamination and cancer incidence were deemed hypothetical and unproven (404). Bladder cancer incidence showed no association with drinking water nitrate, but it was linked to water chlorination (405). No association was found with brain tumors, but drinking water nitrate concentrations (16 mg/L) were not exceptionally high (406). However, pediatric brain tumor incidence appeared associated with maternal cured meat consumption assessed retrospectively (407). There was no association between nitrate intake (median 99 mg from foods and 4 mg from drinking water) and gastric cancer in a recent Netherlands study of over 120,000 men and women with ages 55 69 (408). In some areas where drinking water was seriously contaminated (up to mean nitrate 135 mg/L), leukocyte enzyme abnormalities were found and nitrosamines were detected in urine; but some water samples were mutagen-positive by the Ames test, so nitrates may not have been the only contaminants (409). In this study, salivary nitrite, salivary nitrate, and urine nitrate showed rough correlations with drinking water nitrate concentrations. If these associations with disease incidence are confirmed, it will be important to show what components in vegetarian diets protect against their high nitrate/nitrite content (6). Several have been suggested (407,410 413). Methemoglobin reductase is less well developed in infants and this may account for their well-recognized greater susceptibility to methemoglobinemia from drinking high concentrations of nitrate in drinking water or other environmental sources (414 417) or from therapeutic NO (418). Accidental substitution of nitrite for nitrate as a food preservative attests to its potential for toxicity (419). Conclusions Assays for nitrite and nitrate in plasma and urine, along with measurements of exhaled NO, have been used to study various aspects of NO metabolism. In most instances, because of its greater stability in vivo, nitrate is the more predominant ion. Occasionally, nitrite or labile NOx (nitrite and nitroso compounds) may have higher predictive value than nitrate. The involvement of NO in a wide range of biochemical and physiological functions tends to reduce the clinical utility of nitrite and nitrate measurements for individual disease conditions or pathological processes. Changes in metabolism that may involve constitutive NOS isozymes, or slowly developing, possibly chronic, conditions may not
register against the background noise of NO synthesis or nitrate intake. Variable intake of nitrite and nitrate from dietary sources, or less importantly, medications and NO intake from smoking and air pollution additionally confound interpretation, outside the experimentally-controlled environment. Plasma and urine nitrite and nitrate measurements may have a diagnostic or monitoring role for individual patients with conditions in which inducible NOS is massively up-regulated, such as infection, rejection, and inflammation. Acknowledgement
This work was supported by grants from The Physician Services Incorporated Foundation.
References
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Clinical Biochemistry, Vol. 31, No.

Nitrite and Nitrate Analyses: A Clinical Biochemistry Perspective

NITRITE AND NITRATE ANALYSES

NITRITE AND NITRATE ANALYSES

NITRITE AND NITRATE ANALYSES

NITRITE AND NITRATE ANALYSES

AND CARDIOVASCULAR DISEASE

NITRITE AND NITRATE ANALYSES

BLOOD PRESSURE AND BLOOD FLOW

AND NITRATE IN TRANSPLANTATION AND

NITRITE AND NITRATE ANALYSES

AND NITRATE IN RESPIRATORY DISEASES AND IN

ON THE INCIDENCE OF DIABETES AND OTHER DISEASES

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