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PubMed1997

Nasal nitric oxide is increased in patients with asthma and allergic rhinitis and may be modulated by nasal glucocorticoids.

Nitric oxide (NO) is produced in large amounts in the noses of normal individuals. We have measured NO by chemiluminescence in the noses and exhaled air of subjects with symptomatic allergic rhinitis, some of whom had concomitant asthma, during the pollen season and compared this with values measured in normal subjects and in patients treated with nasal and/or inhaled glucocorticoids. We found that nasal levels of NO were significantly (p < 0.001) elevated in patients with untreated rhinitis (1527 +/- 87 ppb, n = 12) compared with normal individuals (996 +/- 39 ppb, n = 46) or subjects treated with nasal steroids (681 +/- 34 ppb, n = 10), whereas exhaled NO in patients with untreated rhinitis was similar to that in normal subjects (10 +/- 2 ppb vs 7 +/- 0.6 ppb, respectively). In five subjects who were nasally challenged with allergen, there was a significant decrease in nasal NO 1 hour after challenge, and this was significantly correlated with increased rhinitis symptoms. In patients with rhinitis and concomitant asthma, nasal NO was also significantly elevated (1441 +/- 76 ppb, n = 16) but not when they were treated with nasal or inhaled steroids; whereas exhaled NO was elevated in untreated patients and in patients treated with nasal, but not inhaled, steroids. Our data suggest that the increase in exhaled NO in patients with allergic rhinitis is likely to be due to increased local production, caused by long-term exposure to allergen, which is suppressed by locally administered steroids. Measurement of nasal NO may be useful to study the inflammatory response in rhinitis and its response to antiinflammatory treatments.

Administration, Inhalation↗
PubMed2000

Relationship between hepatic mitochondrial functions in vivo and in vitro in rats with carbon tetrachloride-induced liver cirrhosis.

BACKGROUND/AIMS: The metabolic capacity of liver mitochondria is impaired in rats with carbon tetrachloride (CCl4)-induced cirrhosis. These studies were performed to find out whether benzoate and/or palmitate are suitable substrates for assessing hepatic mitochondrial function in vivo. METHODS: In vivo metabolism of benzoate and 1-14C-palmitate was assessed by monitoring urinary excretion of hippurate and exhalation of 14CO2, respectively, in cirrhotic and control rats (n=8 for each group). Isolation of liver mitochondria, and in vitro benzoate and palmitate metabolism were performed by methods published previously. The hepatic content of mitochondria was assessed by stereological analysis of the volume of hepatocytes and by biochemical determination, using the activity of citrate synthase. RESULTS: Renal excretion of hippurate following i.p. administration of benzoate was reduced in cirrhotic rats (64+/-15 vs. 85+/-14% of administered dose over 24 h), and showed a linear correlation with hippurate formation by isolated mitochondria. The activities of benzoyl-CoA synthase and benzoyl-CoA:glycine N-acyltransferase were reduced by approximately 60%, and the coenzyme A content by 50% in hepatic mitochondria from cirrhotic rats, explaining impaired hippurate formation. Peak exhalation of 14CO2 after i.p. administration of 1-14C-palmitate was reduced by 44% and the area under the 14CO2 exhalation-time curve by 34% in cirrhotic rats. Peak 14CO2 exhalation revealed a linear correlation with oxidative metabolism of palmitoylcarnitine in isolated mitochondria. Both in vivo benzoate and palmitate metabolism showed a linear correlation with the volume fraction of hepatocytes. The mitochondrial protein content was reduced in cirrhotic rats per g liver and per liver but equal to control rats per volume of hepatocytes. CONCLUSIONS: In vivo metabolism of both palmitate and benzoate reflects hepatic mitochondrial function in rats with CCl4-induced cirrhosis. Hepatic mitochondrial function is impaired in rats with CCl4-induced cirrhosis due to both reduced mitochondrial volume per liver and impaired metabolism of the remaining mitochondria. In contrast to rats with secondary biliary cirrhosis, rats with CCl4-induced cirrhosis showed no hepatic mitochondrial proliferation to counteract reduced mitochondrial function.

Animals↗
PubMed1996

Uncertainties in CT-based radiation therapy treatment planning associated with patient breathing.

PURPOSE: To evaluate uncertainties associated with treatment-planning computed tomography (CT) data obtained with the patient breathing freely. METHODS AND MATERIALS: Patients with thoracic or abdominal tumors underwent a standard treatment-planning CT study while breathing quietly and freely, followed by CT scans while holding their breath at normal inhalation and normal exhalation. Identical treatment plans on all three CT data sets for each patient pointed out differences in: (a) radiation path lengths; (b) positions of the organs; (c) physical volumes of the lung, liver, and kidneys; (d) the interpretation of plan evaluation tools such as dose-volume histograms and normal tissue complication probability (NTCP) models; and (e) how well the planning CT data set represented the average of the inhalation and exhalation studies. RESULTS: Inhalation and exhalation data differ in terms of radiation path length (nearly one quarter of the cases had path-length differences > 1 cm), although the free breathing and average path lengths do not exhibit large differences (0-9 mm). Liver and kidney movements averaged 2 cm, whereas differences between the free breathing and average positions averaged 0.6 cm. The physical volume of the liver between the free breathing and static studies varied by as much as 12%. The NTCP calculations on exhale and inhale studies varied from 3 to 43% for doses that resulted in a 15% NTCP on the free-breathing studies. CONCLUSION: Free-breathing CT studies may improperly estimate the position and volume of critical structures, and thus may mislead evaluation of plans based on such volume dependent criteria such as dose-volume histograms and NTCP calculations.

Abdominal Neoplasms↗
PubMed2002

Toluene metabolites as biological indicators of exposure.

The measurement of exhaled and excreted xenobiotics and their metabolites can provide accurate, non-invasive, and time-flexible measurements of internal dose. We analyzed rates of exhaled (2)H(8)-toluene and excreted urinary metabolites from 33 exposures of men to 50 ppm of (2)H(8)-toluene for 2 h at rest. The total dose was distributed as follows: exhaled (2)H(8)-toluene, 13 +/- 6.2%; (2)H(5)-hippuric acid, 75 +/- 6.4%; (2)H(7)-o-cresol, 0.31 +/- 0.22%; (2)H(7)-m-cresol, 0.53 +/- 0.44%; and (2)H(7)-p-cresol, 11 +/- 3.8%. Interindividual variability was assessed using the coefficients of variation for peak exhalation or excretion rates, and fractions of dose excreted: (2)H(8)-toluene, c.v.=60, 47%; (2)H(5)-hippuric acid, 29, 8.6%; (2)H(7)-o-cresol, 80, 73%; (2)H(7)-m-cresol, 37, 83%; and (2)H(7)-p-cresol, 38, 34%. Excretion rates of the cresols were stable over the first 5 h post-exposure, and o-cresol was determined to be the best urinary indicator of exposure, given the lower background levels of this isomer. The hippuric acid/cresol rate ratios for the first 5 h post-exposure could be described by single exponential terms, and thus provided a means for estimating time since exposure for any finite toluene duration/exposure combination.

Adult↗
PubMed2000

Pulmonary blood flow alters nitric oxide production in patients undergoing device closure of atrial septal defects.

OBJECTIVE: To determine the effect of pulmonary blood flow (Qp) on nitric oxide (NO) production in patients with increased Qp due to an atrial septal defect (ASD). BACKGROUND: Alterations in pulmonary vascular NO production have been implicated in the development of pulmonary hypertension secondary to increased Qp. In vitro, acute changes in flow or shear stress alter NO production. However, the effect of Qp on lung NO production in vivo is unclear. METHODS: Nineteen patients (2.4-61 years of age, median 17) with secundum ASD undergoing device closure were studied. Before, and 30 min after ASD closure, exhaled NO and plasma nitrate concentration were measured by chemiluminescence (NOA 280, Sievers, Boulder, Colorado). RESULTS: Before ASD closure, all patients had increased Qp (Qp: systemic blood flow [Qs] of 2.0 +/- 0.7) and normal mean pulmonary arterial pressure (13.4 +/- 3.1 mm Hg). Atrial septal defect device closure decreased Qp from 6.0 +/- 2.5 to 3.6 +/- 1.3 L/min/m2 (p < 0.05). Mean pulmonary arterial pressure was unchanged. Associated with the decrease in Qp, both exhaled NO (-22.1%, p < 0.05) and plasma nitrate concentrations (-17.9%, p < 0.05) decreased. CONCLUSIONS: These data represent the first demonstration that acute changes in Qp alter pulmonary NO production in vivo in humans. Exhaled NO determinations may provide a noninvasive assessment of pulmonary vascular NO production in patients with congenital heart disease. Potential correlations between exhaled NO, pulmonary vascular reactivity and pulmonary hypertension warrant further study.

Adolescent↗
PubMed2002

Retronasal transport of aroma compounds.

A comparison was made between the amounts of volatiles in the headspace above a solution and the breath volatile content (exhaled from the nose or mouth) after consumption of the same solution. The amounts of volatiles in the breath were lower than those in the headspace, with breath exhaled via the mouth containing, on average, 8-fold more volatiles than breath exhaled via the nose. Dilution of the sample by saliva in-mouth did not appear to be a major factor affecting volatile delivery. Instead, the rate of in vivo equilibration (mass transfer) appeared to be the most significant factor, principally affecting volatile delivery from the solution to the gas phase. Thereafter, gas-phase dilution of the volatile as it passed through the upper airway resulted in a further decrease in volatile concentration. The final factor affecting the volatile concentration exhaled from the nose was absorption of volatiles to the nasal epithelia, which was greatest for those compounds with the lowest air/water partition coefficients.

Acetone↗
PubMed2005

Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo.

1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates

Acid-Base Equilibrium↗
PubMed2002

Increased nitric oxide elimination from the airways after smoking cessation.

Smokers have been found to have low exhaled nitric oxide (NO) levels. The aim of the present study was to investigate where in the respiratory system the decrease in NO occurs, and whether this decrease was affected by smoking cessation. Measurements of exhaled NO were carried out in smokers (n=20) and non-smoking control subjects (n=30). In nine of the smokers, exhaled NO was analysed 1, 2 and 4 weeks after smoking cessation. The level of exhaled NO at a flow rate of 0.1 litre/s was significantly lower in smokers (4+/-2 p.p.b.) than in non-smokers (7+/-5 p.p.b.; P=0.007). A calculation of the contributions from different areas of the lung showed that the NO flux from the airways was significantly lower (14+/-10 compared with 36+/-26 nl/min; P=0.0001) and the alveolar fraction was significantly higher (2.1+/-0.8 compared with 1.5+/-0.9 p.p.b.; P=0.006) in smokers than in non-smokers. Nine smoking subjects refrained from smoking for 4 weeks, and this resulted in increased NO flux from the airways of 28+/-17 nl/min, which was no longer significantly different from controls. In conclusion, endogenous production of NO in the airways is decreased in smokers, but can be restored to normal values by 4 weeks after cessation of smoking. Smokers have an increased alveolar fraction of NO, and this might be a diagnostic sign of lung damage. Thus NO monitoring can be used to indicate improvements when a smoker decides to stop smoking.

Adult↗
PubMed1997

Lung distension and carbon dioxide affect pulmonary nitric oxide formation in the anaesthetized rabbit.

Positive end-exspiratory pressure (PEEP) and nitric oxide (NO) can influence lung VA/Q-matching and pulmonary vascular resistance, and application of PEEP can increase exhaled NO in animals. To obtain a better understanding of these mechanisms, we examined how different types of ventilation or changes in CO2 affect the formation of endogenous NO. Exhaled NO in pentobarbital-anaesthetized rabbits was monitored by chemiluminescence. The animals were enclosed in a chamber and subjected to various modes of positive as well as negative pressure ventilation which was adjusted to induce similar changes in functional residual capacity (FRC) with maintained ventilatory rate and tidal volume. In addition, stepwise increase in FiCO2 (1.0-10%) was studied. Negative extrathoracic end-exspiratory pressure during negative extrathoracic pressure ventilation produced an increase in NO production similar to that of positive end-exspiratory pressure during positive pressure ventilation, the increase consisting of an initial peak followed by a plateau. The faster the FRC was increased, the higher was the initial peak in NO. The greater the increase in FRC, the higher was the plateau NO concentration. Increased FiCO2 caused a dose-dependent reduction in exhaled NO. The observations of lung distension effects on exhaled NO suggest the possibility of stretch receptors or -receptive mechanisms coupled to NO formation within the lung. In addition, NO formation in the lung is influenced by CO2 in a reciprocal fashion.

Anesthesia↗
PubMed2004

[Non-invasive methods for monitoring airway inflammation: a comparison of expenditures, gain and clinical value].

Among the noninvasive procedures for the assessment of airway inflammation, the analysis of spontaneous sputum is currently the only method, the expenses of which are covered by health insurance in Germany. It can easily be used for semiquantitive cytological analyses by practising pneumologists. Recent data also indicate the usefulness of sputum induction, particularly in asthma diagnosis and therapy control, and demonstrate its capability of reducing total costs per patient. In contrast to sputum analysis, the measurement of exhaled nitric oxide (NO) yields a read-out without time delay. NO as associated with eosinophils also seems suitable for monitoring airway inflammation. The number of studies regarding NO, both its pathophysiological role and clinical use, is far greater than that regarding any other marker of exhaled air. Measurements are easy and fast, but the costs of analysers are still prohibitive in clinical practice. The analysis of other compounds of exhaled air, particularly those of exhaled breath condensate (EBC), offers fascinating perspectives, owing to the scope of markers that might be measured, and could enable the assessment of multivariate profiles that are useful for diagnosis and therapy control. Currently, however, the method still faces methodological questions, and data indicating its usefulness and cost-efficiency in clinical practice are scarce. Compared to NO, the expenses per measurement in clinical use are mainly due to the costs per marker detection after sampling, as well as storage and transport of samples. The on-site analysis of pH in the EBC could be a first step to circumvent this obstacle.

Airway Obstruction↗
PubMed2000

Endogenous nitric oxide in allergic airway disease.

There has been intense research into the role nitric oxide (NO) plays in physiologic and pathologic mechanisms. The presence of NO in exhaled breath and the high concentrations in nasal airways stimulated many studies examining exhaled and nasal NO as potential markers of airway inflammation, enabling repeated monitoring of airway inflammation not possible with invasive tests (eg, bronchoscopy). In airway inflammation, NO is not merely a marker but may have anti-inflammatory and proinflammatory effects. Nasal NO measurement may be used in the noninvasive diagnosis and monitoring of nasal disease. This review was compiled by speakers who gave presentations on NO at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in 1999 on exhaled and nasal NO, in vitro studies of NO, the chemistry of airway NO formation, and standardized measurement of exhaled mediators.

Asthma↗
PubMed2000

Determination of biokinetic interactions in chemical mixtures using real-time breath analysis and physiologically based pharmacokinetic modeling.

Regulatory agencies are challenged to conduct risk assessments on chemical mixtures without full information on toxicological interactions that may occur at real-world, low-dose exposure levels. The present study was undertaken to investigate the pharmacokinetic impact of low-dose coexposures to toluene and trichloroethylene in vivo in male F344 rats using a real-time breath analysis system coupled with physiologically based pharmacokinetic (PBPK) modeling. Rats were exposed to compounds alone or as a binary mixture, at low (5 to 25 mg/kg) or high (240 to 800 mg/kg) dose levels. Exhaled breath from the exposed animals was monitored for the parent compounds and a PBPK model was used to analyze the data. At low doses, exhaled breath kinetics from the binary mixture exposure compared with those obtained during single exposures, thus indicating that no metabolic interaction occurred with these low doses. In contract, at higher doses the binary PBPK model simulating independent metabolism was found to underpredict the exhaled breath concentration, suggesting an inhibition of metabolism. Therefore the binary mixture PBPK model was used to compare the measured exhaled breath levels from high- and low-dose exposures with the predicted levels under various metabolic interaction simulations (competitive, noncompetitive, or uncompetitive inhibition). Of these simulations, the optimized competitive metabolic interaction description yielded a Ki value closest to the Km of the inhibitor solvent, indicating that competitive inhibition is the most plausible type of metabolic interaction between these two solvents.

Anesthetics, Inhalation↗
PubMed2002

Evaluation of the dermal absorption of aqueous toluene in F344 rats using real-time breath analysis and physiologically based pharmacokinetic modeling.

Toluene is a ubiquitous chemical that is commonly used for its solvent properties in industry and manufacturing, and is a component of many paint products. Because of its widespread use, there is potential for both occupational and nonoccupational dermal exposure to toluene. To understand the significance of these exposures, the dermal bioavailability of toluene was assessed in F344 male rats using a combination of real-time exhaled breath analysis and physiologically based pharmacokinetic (PBPK) modeling. Animals were exposed to toluene at 0.5 or 0.2 mg/ml aqueous concentration (0.05% or 0.02%) using a 2.5-cm-diameter occluded glass patch system attached to a clipper-shaved area on the back of the rat. Immediately following exposure, individual animals were placed in a glass off-gassing chamber and exhaled breath was monitored as chamber concentration in real time using an ion-trap mass spectrometer (MS/MS). The real-time exhaled breath profile clearly demonstrated the rapid absorption of toluene, with peak chamber concentrations observed within 1 h from the start of exposure. The PBPK model describing the exposure and off-gassing chamber was used to estimate a dermal permeability coefficient (K(p)) to describe each set of exhaled breath data. Regardless of exposure level, a single K(p) value of 0.074 +/- 0.005 cm/h provided a good fit to all data sets. These rat studies using aqueous toluene will form the basis for comparing the dermal bioavailability of toluene in various paint products and may ultimately aid in understanding human health risk under a variety of exposure scenarios.

Algorithms↗
PubMed2005

Peripheral inflammation in patients with asthmatic symptoms but normal lung function.

Some patients with asthmatic symptoms and eosinophilic airway inflammation have normal lung function and thus do not meet the current diagnostic criteria of asthma. Exhaled nitric oxide (NO) measurement at multiple exhalation flow rates can be used to assess alveolar and bronchial NO output and inflammation. We tested whether alveolar or bronchial NO output is increased in subjects having asthmatic symptoms but normal lung function. Exhaled NO concentration was measured at three exhalation flow rates (100, 175, and 370 mL/s) to assess alveolar NO concentration and bronchial NO flux in 23 patients with asthmatic symptoms but normal lung function ("asthmatic symptoms group"), 40 patients with asthma, and 40 healthy control subjects. The asthmatic symptoms group had increased bronchial NO flux (1.7 +/- 0.3 nL/s, p = 0.016) and alveolar NO concentration (1.8 +/- 0.2 parts per billion (ppb), p = 0.010) compared with healthy controls (0.7 +/- 0.1 nL/s and 1.0 +/- 0.1 ppb, respectively). Patients with asthma had even higher bronchial NO flux (2.5 +/- 0.3 nL/s, p = 0.024) but normal alveolar NO concentration (1.1 +/- 0.2 ppb, p = 0.664). In asthmatic symptoms group, alveolar NO concentration correlated positively with blood eosinophil count and negatively with small airway function (FEF50% and FEF75%). In conclusion, patients with asthmatic symptoms but normal lung function have increased alveolar NO concentration and mildly elevated bronchial NO flux suggesting a more peripheral inflammation than in patients with asthma.

Adult↗
PubMed2003

A real-time method to evaluate the nasal deposition and clearance of acetone in the human volunteer.

Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled [(13)C]acetone at approximately 1 ppm concentration for 30 min under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhale mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 s. A second ion-trap mass spectrometer simultaneously sampled from the volunteer's exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the [(13)C]acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart-rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in [(13)C]acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analyses of [(13)C]acetone concentrations indicate that between 40 and 75% of the compound is absorbed upon inhalation and nearly all of that absorbed is released back into the breath stream during exhalation.

Acetone↗
PubMed2003

Evaluation of the dermal bioavailability of aqueous xylene in F344 rats and human volunteers.

Xylene is a clear, colorless liquid used as a solvent in the printing, rubber, and leather industries and is commonly found in paint thinners, paints, varnishes, and adhesives. Although humans are most likely to be exposed to xylene via inhalation, xylene is also found in well and surface water. Therefore, an assessment of the dermal contribution to total xylene uptake is useful for understanding human exposures. To evaluate the significance of these exposures, the dermal absorption of o-xylene was assessed in F344 male rats and human volunteers using a combination of real-time exhaled breath analysis and physiologically based pharmacokinetic (PBPK) modeling. Animals were exposed to o-xylene dermally. Immediately following the initiation of exposure, individual animals were placed in a glass off-gassing chamber and exhaled breath was monitored. Human volunteers participating in the study placed both legs into a stainless steel hydrotherapy tub containing an initial concentration of approximately 500 microg/L o-xylene. Exhaled breath was continually analyzed from each volunteer before, during, and after exposure to track absorption and subsequent elimination of the compound in real time. In both animal and human studies, a PBPK model was used to estimate the dermal permeability coefficient (K(p)) to describe each set of exhaled breath data. Rat skin was found to be approximately 12 times more permeable to aqueous o-xylene than human skin. The estimated human and rat aqueous o-xylene K(p) values were 0.005 +/- 0.001 cm/h and 0.058 +/- 0.009 cm/h, respectively.

Absorption↗
PubMed1987

Metabolism and distribution of [14C]glucose in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Male Sprague-Dawley rats were given a single, usually lethal, dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 125 micrograms/kg ip in corn oil), or vehicle alone. Twenty-four hours after ip administration of TCDD the animals received an ip injection of 14C-labeled glucose, and the time course and amount of exhalation of 14CO2 were monitored for 8 h continuously and once daily for 20 min for the subsequent 5 d. TCDD treatment reduced the amount of 14CO2 exhaled within 8 h after the injection of [14C]glucose by 33%, as compared to pair-fed controls. Blood levels of radioactivity were affected by TCDD accordingly. No particular organ appeared to act as a sink for the radioactivity not exhaled during these 8 h by the treated animals. TCDD (125 micrograms/kg) induced significant changes in the disposition of radioactivity in heart and brown adipose tissue between 25 and 125 min after the iv injection of [14C]glucose. The areas under the curve of [14C]glucose-derived radioactivity were the same after either iv or ip injection in the blood of TCDD-treated rats, allowing a direct comparison of experiments with iv or ip injection of [14C]glucose. The half-lives of radioactivity in the exhaled air and in feces of treated animals were greatly elevated during the 5 d following administration of [14C]glucose. These results indicate that TCDD induces in rats, within 24 h after dosing, alterations in the metabolism of glucose that preceded changes in insulin homeostasis, because hypoglycemia and hypoinsulinemia in rats do not occur until about a week after TCDD treatment. Since overt signs of acute toxicity (reduced feed intake and body weight loss) are also not noticeable until several days after a lethal dose of TCDD, it is probable that this earlier disturbance of glucose metabolism is part of the biological changes that result in wasting away and eventually in death.

Animals↗
PubMed2000

Impairment of airway mucociliary transport in patients with sinobronchial syndrome: role of nitric oxide.

Nitric oxide (NO) produced within the respiratory tract can stimulate ciliary motility of airway epithelial cells and hence mucociliary transport. In this study, to determine the role of NO in mucociliary dysfunction in sinobronchial syndrome (SBS), we measured NO concentrations in the exhaled air by chemiluminescence analyzer and nasal clearance time (NCT) by saccharin test. Exhaled NO concentrations in patients with SBS were 39% of those in healthy nonsmokers and 55% of those in healthy smokers. The patients also showed prolonged NCT compared with healthy subjects, and there was a significant negative correlation between exhaled NO concentrations and NCT. Furthermore, concentrations of chloride (Cl) in the sputum supernatant were higher in SBS patients than in healthy subjects, and there was a significant negative correlation between sputum Cl concentrations and exhaled NO concentrations. These results suggest that airway mucociliary clearance is impaired in patients with SBS and that this impairment might result from the reduced production of NO and the impaired availability of the molecule in the mucociliary apparatus.

Adult↗