Plasma nitrite and nitrate determinations are increasingly being used in clinical chemistry as markers for the activity of nitric oxide synthase and the production of nitric oxide radicals. However, a systematic evaluation of the determination of nitrite and nitrate in plasma has not been performed. In this study the recovery and stability of nitrite and nitrate in whole blood and in plasma, the relation between nitrite and nitrate concentrations in plasma, and possible sources of artifacts were investigated. The main conclusions are: (a) Recovery of nitrite and nitrate from plasma is near-quantitative (87%) and reproducible; (b) nitrite and nitrate are stable in (frozen) plasma for at least 1 year; (c) nitrite in whole blood is very rapidly (> 95% in 1 h) oxidized to nitrate, and therefore plasma nitrite determination alone is meaningless; (d) the ranges of nitrite and nitrate concentrations in plasma samples of 26 healthy persons are 1.3-13 mumol/L (mean 4.2 mumol/L) and 4.0-45.3 mumol/L (mean 19.7 mumol/L), respectively; (e) plasma nitrite and nitrate concentrations were not correlated (nitrite as % of total nitrite + nitrate varied from 3.9% to 88% in plasma samples); and (f) plasma samples should be deproteinized, and background controls for each sample should be included in the assay, to avoid measuring artifactually high nitrite and nitrate concentrations in plasma.

Nitrite and nitrate determinations in plasma: a critical evaluation.

CASE REPORTS Case 1 A 23-year-old woman presented with a 2-week history of bruising and fever. She was diagnosed as having acute myelogenous leukemia. Three days after beginning chemotherapy, she became disoriented and hypotensive. Her platelet count was 60×10 9 /L, and her white blood cell count was 1.0×10 9 /L, with an absolute neutrophil count of 0.48×10 9 /L. She was resuscitated with 3 L of saline and she was given dopamine at 5 μg·kg -1 ·min -1 and broad-spectrum antibiotics. Her chest radiograph revealed diffuse interstitial-alveolar infiltrates. She required mechanical ventilation for progressive hypoxemia. Pulmonary and radial arterial catheters were inserted and the following hemodynamic parameters were obtained: blood pressure, 90/35 mm Hg; mean arterial pressure (MAP), 53 mm Hg; heart rate, 124 beats per minute; cardiac index, 7.8 L·min -1 ·m -2 ; central venous pressure (CVP), 12 mm Hg; pulmonary artery pressure, 42/28 mm Hg; pulmonary capillary

Nitric oxide and septic shock.

We demonstrated that the pineal neurohormone melatonin exerts immunoregulatory effects via T-helper 2 (Th2) cell products. Th2 products may modulate the secretion and/or action of inflammatory cytokines, which play an important role in the development of septic shock associated with endotoxemia. Here we report that a single melatonin injection protects mice treated with a lethal dose of lipolysaccharide (LPS) especially when melatonin was injected 3 to 6 hr after LPS. This effect did not apparently involve Th cells or inhibition of inflammatory cytokines or macrophage nitric oxide (NO) generation. Nevertheless, plasma nitrate concentration, which reflects the rate of NO synthesis, showed a significant reduction at 18 and 24 hr after LPS administration. Melatonin is being studied in humans for cancer immunotherapy. The data presented here identify melatonin as potential therapy for septic shock.

Melatonin as a therapeutic agent in experimental endotoxic shock.

Excessive nitric oxide (NO) formation plays important roles in the pathogenesis of shock and multiple organ failure in sepsis and acute lung injury (ALI). Evidence from studies in large animal models of shock provide further insight into the role of NO and the varying nitric oxide synthase (NOS) isoforms. Nonselective NOS inhibition in sepsis models reversed sepsis-induced derangements in hemodynamic status, but was associated with side effects such as pulmonary vasoconstriction and decreases in global oxygen delivery. Results from studies on specific inhibition of inducible NOS (iNOS, NOS-2) and neuronal NOS (nNOS, NOS-1) in sepsis models remain inconclusive, but suggest that both isoenzymes are involved in the pathophysiological processes. While the long-term effects of NOS inhibition in models of burn and inhalation injury remain unknown, specific iNOS inhibition attenuated ALI without worsening injury-related pulmonary hypertension. Further investigation in large animal models is warranted to clarify the time course of increased expression and/or activity of different NOS isoenzymes and the effects of specific inhibition of the NOS isoforms at different time points.

Role of nitric oxide in shock: the large animal perspective.

1. In this investigation the NO production rate is quantified in the pig during normotensive endotoxin-induced shock with increased cardiac output and during subsequent treatment with the NO synthase inhibitor N omega-monomethy-L-arginine (L-NMMA). NO production rate was derived from the plasma isotope-enrichment of 15N-labelled nitrate (15NO3-). 2. Three groups of animals (control, n = 5; endotoxin, n = 6; endotoxin + L-NMMA, n = 6) were anaesthetized and instrumented for the measurement of systemic and pulmonary haemodynamics. Each animal received a primed-continuous infusion of stable, non-radioactively labelled Na15 NO3 (bolus 30 mg, infusion rate 2.1 mg h-1). Arterial blood samples were taken 5, 10, 15, 30, 60 and 90 min later and every 90 minutes until the end of the experiment. 3. Continuous i.v. infusion of endotoxin was incrementally adjusted until mean pulmonary artery pressure (PAP) reached 50 mmHg and subsequently titrated to keep mean PAP approximately 35 mmHg. Hydroxyethylstarch was administered as required to maintain mean arterial pressure (MAP) > 60 mmHg. Six hours after the start of the endotoxin continuous i.v. L-NMMA (1 mg kg-1 h-1) was administered to the endotoxin + L-NMMA group. Haemodynamic data were measured before as well as 9 h after the start of the endotoxin. 4. After conversion of NO3- to nitro-trimethoxybenzene and gas chromatography-mass spectrometry analysis the total NO3- pool, basal NO3- production rate and the increase per unit time in NO3- production rate were calculated from the time-course of the 15NO3- plasma isotope-enrichment. A two compartment model was assumed for the NO3- kinetics, one being an active pool in which newly generated NO3- appears and from which it is eliminated, the other being an inactive volume of distribution in which only passive exchange takes place with the active compartment. 5. Although MAP did not change during endotoxin infusion alone, cardiac output (CO) increased by 42 +/- 40% (P < 0.05 versus baseline) by the end of the experiment due to a significant (P < 0.05 versus baseline) fall in systemic vascular resistance (SVR) to 65 +/- 25% of the baseline value. L-NMMA given with endotoxin did not change MAP, and both CO and SVR were maintained close to the pre-shock levels. 6. Baseline plasma NO3- concentrations were 43 +/- 13 and 40 +/- 10 mumol l-1 in the control and endotoxin animals, respectively, and did not differ at the end of the experiment (39 +/- 8 and 44 +/- 15 mumol l-1, respectively). The mean NO3- pool and basal NO3- production rate were 1155 +/- 294 mumol and 140 +/- 32 mumol h-1, respectively, without any intergroup difference. Endotoxin significantly increased NO3- production rate (23 +/- 10 mumol h-2, P < 0.05 versus control (6 +/- 7 mumol h-2) and endotoxin + L-NMMA groups). L-NMMA given with endotoxin (-1 +/- 2 mumol h-2, P < 0.05 versus control and endotoxin groups) had no effect. 7. Analysis of the time course of the 15NO3- plasma isotope enrichment during primed-continuous infusion of Na15NO3 allowed us to quantify the endotoxin-induced increase in NO3- production rate independently of total NO3- plasma concentrations. Low-dose L-NMMA blunted the increase in NO3- production rate while maintaining basal NO3- formation.

In vivo quantification of endotoxin-induced nitric oxide production in pigs from Na15NO3-infusion

Nitric oxide (NO), an endothelium-derived relaxing factor (EDRF), is released by different types of cells under the influence of endotoxin and various cytokines: a causative role of endothelium-derived NO in the endotoxin-induced hypotension has thus been suggested. To test the hypothesis that NO may be involved in the acute hypotension following endotoxin challenge, we administered a competitive inhibitor of NO synthase, L-N-monomethylarginine (L-NMMA) to anesthetized dogs in the presence and absence of endotoxin. Dogs were randomly allocated to three groups. Group 1 (n = 3) was given Escherichia coli endotoxin (3 mg/kg, i.v.), group 2 (n = 3) was given L-NMMA (5 mg/kg, i.v. bolus) 15 min after endotoxin and group 3 (n = 3) was given L-NMMA only. One additional dog was given L-arginine (100 mg/kg, i.v. bolus) after L-NMMA and endotoxin to reverse the inhibition of NO synthase. In each animal, saline was infused intravenously throughout the experiment to restore and maintain pulmonary artery occluded pressure at baseline level. After L-NMMA, the increases in mean arterial pressure were similar in group 2 (from 55 +/- 18 to 75 +/- 15 mm Hg, p < 0.01) and in group 3 (from 107 +/- 27 to 128 +/- 24 mm Hg, p < 0.01). Systemic vascular resistance increased from 2,994 +/- 72 to 3,658 +/- 673 dyn.s.cm-5 (p < 0.01) in group 3. Group 1 had lower plasma lactate levels than group 2 (3.5 +/- 2.3 +/- vs. 2.0 +/- 1.6 mEq/l, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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Is endotoxin-induced hypotension related to nitric oxide formation?

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Is endotoxin-induced hypotension related to nitric oxide formation?