Pulmonary Metabolism Research Articles

Pulmonary surfactant metabolism in infants lacking surfactant protein B.

Infants with inherited deficiency of pulmonary surfactant protein (SP) B develop respiratory failure at birth and die without lung transplantation. We examined aspects of surfactant metabolism in lung tissue and lavage fluid acquired at transplantation or postmortem from ten infants born at term with inherited deficiency of SP-B; comparison groups were infants with other forms of chronic lung disease (CLD) and normal infants. In pulse/chase labeling studies with cultured deficient tissue, no immunoprecipitable SP-B was observed and an approximately 6-kD form of SP-C accumulated that was only transiently present in CLD tissue. SP-B messenger RNA (mRNA) was approximately 8% of normal in deficient specimens, and some intact message was observed after, but not before, explant culture. Transcription rates for SP-B, assessed by nuclear run-on assay using probes for sequences both 5' and 3' of the common nonsense mutation (121ins2), were comparable in all lungs examined. The minimal surface tension achieved with lavage surfactant was similarly elevated in both deficient and CLD infants (26-31 mN/m) compared with normal infants (6 mN/m). Both SP-B-deficient and CLD infants had markedly decreased phosphatidylglycerol content of lavage and tissue compared with normal lung, whereas synthetic rates for phospholipids, including phosphatidylglycerol, were normal. We conclude that the mutated SP-B gene is transcribed normally but produces an unstable mRNA and that absence of SP-B protein blocks processing of SP-C. Chronic infant lung disease, of various etiologies, reduces surfactant function and apparently alters phosphatidylglycerol degradation.

Hepatic and pulmonary enzyme activities in horses.

To determine hepatic and pulmonary phase-I and phase-II enzyme activities in horses. Pulmonary and hepatic tissues from 22 horses that were 4 months to 32 years old. Pulmonary and hepatic tissues from horses were used to prepare cytosolic (glutathione S-transferase and soluble epoxide hydrolase) and microsomal (cytochrome P450 monooxygenases) enzymes. Rates of microsomal metabolism of ethoxyresorufin, pentoxyresorufin, and naphthalene were determined by high-performance liquid chromatography. Activities of glutathione S-transferase and soluble epoxide hydrolase were determined spectrophotometrically. Cytochrome P450 content was determined by carbon monoxide bound-difference spectrum of dithionite-reduced microsomes. Activity was expressed relative to total protein concentration. Microsomal protein and cytochromeP450 contents were detectable in all horses and did not vary with age. Hepatic ethoxyresorufin metabolism was detected in all horses; by comparison, pulmonary metabolism of ethoxyresorufin and hepatic and pulmonary metabolism of pentoxyresorufin were detected at lower rates. Rate of hepatic naphthalene metabolism remained constant with increasing age, whereas rate of pulmonary naphthalene metabolism was significantly lower in weanlings (ie, horses 4 to 6 months old), compared with adult horses. Hepatic glutathione S-transferase activity (cytosol) increased with age; however, these changes were not significant. Pulmonary glutathione S-transferase activity (cytosol) was significantly lower in weanlings than adult horses. Hepatic and pulmonary soluble epoxide hydrolase did not vary with age of horses. Activity of cytochrome P450 isoforms that metabolize naphthalene and glutathione S-transferases in lungs are significantly lower in weanlings than adult horses, which suggests reduced ability of young horses to metabolize xenobiotics by this organ.

Pulmonary Nitric Oxide Metabolism Following Infrarenal AorticCross-clamp-induced Ischaemia–Reperfusion Injury

Objectives to investigate endogenous pulmonary nitric oxide metabolism following infrarenal aortic cross-clamp-induced ischaemia–reperfusion injury. Methods groups of male Wistar rats (n=6) were subjected to 60 minutes of infrarenal aortic cross-clamping under general anaesthesia. Rats were culled after 0, 60 and 120 minutes» reperfusion, following release of the aortic clamp. A sham-operated control group was also studied. Acute lung injury (ALI) was quantified by measuring the protein concentration in lung bronchoalveolar lavage (BAL) fluid. Pulmonary myeloperoxidase activity (MPO) was measured as an index of neutrophil infiltration and degranulation in the lung. Plasma tumour-necrosis factor-alpha (TNF-α) was measured as an index of the pro-inflammatory cytokine response and pulmonary nitric oxide synthase (NOS) activity was determined by measuring conversion of3H L-arginine to3H L-citrulline in tissue homogenates. Results these data show significant ALI with increased pulmonary microvascular permeability and MPO activity in animals subject to 60 minutes» ischaemia and 60 minutes or 120 minutes of reperfusion compared to control animals (p<0.01). Plasma TNF-α levels were significantly increased following 60 minutes of ischaemia compared to controls (p<0.01) and remained significantly increased in animals subject to reperfusion (p<0.01). Pulmonary NOS activity was significantly increased in animals subject to reperfusion (p<0.01). Conclusions the reperfusion phase of infrarenal aortic cross-clamping provokes a significant increase in pulmonary NOS metabolism. The increase in plasma TNF-α and MPO activity suggests that this response may be secondary to inducible NOS expression. Manipulation of this response may benefit patients at risk of acute injury following infrarenal aortic reconstruction.

Use of stable isotope labeling technique and mass isotopomer distribution analysis of [(13)C]palmitate isolated from surfactant disaturated phospholipids to study surfactant in vivo kinetics in a premature infant.

Pulmonary surfactant is a complex mixture of phospholipids and proteins which lowers surface tension and maintains alveolar expansion at end expiration. Developmental and genetic disruption of pulmonary surfactant metabolism leads to respiratory distress in newborns. Stable isotope labeling of metabolic precursors of disaturated phospholipids, the most abundant and specific component of pulmonary surfactant, permits the measurement of the kinetics of surfactant metabolism in vivo. We measured [U-(13)C(6)]glucose incorporation into palmitic acid derived from disaturated surfactant phospholipids. A 24 h infusion of [U-(13)C(6)]glucose (140 mg kg(-1)) was administered to a premature infant who required mechanical ventilation for respiratory distress syndrome; tracheal aspirate samples were obtained at the start of the infusion and at regular intervals for the next 70 h. Each tracheal aspirate sample was incubated with osmium tetroxide to isolate disaturated surfactant phospholipids. Methyl esters of the fatty acids in the disaturated phospholipids were prepared and the enrichment of [(13)C]methyl palmitate was measured by gas chromatography/mass spectrometry (GC/MS) and gas chromatography/combination/isotope ratio mass spectrometry (GC/C/IRMS). Mass isotopomer distribution analysis (MIDA) was used to calculate the fractional synthetic rate (FSR) of palmitate synthesized from acetate. With both GC/MS and GC/C/IRMS, palmitate (13)C enrichment was first detected 12.3 h after the start of the tracer infusion. The enrichment increased in a linear fashion, reached a peak at 47 h and remained constant in the remainder of the samples. The FSR of palmitate from acetate was 5.2% per day. Stable isotope techniques and MIDA will provide insights into the kinetics of surfactant metabolism in newborns with respiratory dysfunction.

Species comparison of hepatic and pulmonary metabolism of benzene

Benzene is an occupational hazard and environmental toxicant found in cigarette smoke, gasoline, and the chemical industry. The major health concern associated with benzene exposure is leukemia. Studies using microsomal preparations from human, mouse, rabbit, and rat to determine species differences in the metabolism of benzene to phenol, hydroquinone and catechol, indicate that the rat is most similar, both quantitatively and qualitatively, to the human in pulmonary microsomal metabolism of benzene. With hepatic microsomes, rat is most similar to human in metabolite formation at the two lower concentrations examined (24 and 200 μM), while at the two higher concentrations (700 and 1000 μM) mouse is most similar in phenol formation. In all species, the enzyme system responsible for benzene metabolism approached saturation in hepatic microsomes but not in pulmonary microsomes. In pulmonary microsomes from mouse, rat, and human, phenol appeared to competitively inhibit benzene metabolism resulting in a greater proportion of phenol being converted to hydroquinone when the benzene concentration increased. The opposite effect was seen in hepatic microsomes. These findings support the hypothesis that the lung plays an important role in benzene metabolism, and therefore, toxicity.

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

The profile of urinary metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats is determined by its pulmonary metabolism

Metabolism of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats was compared to metabolism in primary lung and liver cells. Untreated rats and rats pretreated with phenobarbital, acetone or phenethyl isothiocyanate (PEITC) were used for all experiments. Also the influence of [-]-1-methyl-2-[3-pyridyl]-pyrrolidine (nicotine) administered concomitantly with NNK, or incubated with isolated cells, upon NNK metabolism was investigated and found to be only marginal upon α-hydroxylation and pyridine N-oxidation in vivo. In hepatocytes nicotine inhibited NNK pyridine N-oxidation, α-hydroxylation and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), whereas in lung cells the influence of nicotine was not as pronounced. In vivo phenobarbital induced α-hydroxylation and pyridine N-oxidation. In vitro the effects of the modulators were most pronounced upon hepatocytes, where phenobarbital greatly induced pyridine N-oxidation and PEITC inhibited α-hydroxylation. NNAL was conjugated to its β-glucuronide in lung cells at four times higher rates than in hepatocytes. The ratios of the sum of N-oxides to the sum of α-hydroxylation products in vivo were similar to those in lung cells, especially at low NNK concentrations (1 μM), while in hepatocytes α-hydroxylation was more pronounced. The same correlation of metabolism in isolated lung cells with whole rats was observed if oxidative NNAL metabolism was related to oxidative NNK metabolism. Here hepatocytes showed a much higher formation of NNAL oxidation products than either lung cells formed, or rats excreted in urine. This was true despite a lower rate of metabolism in the lung than in liver if based on cell number, the rate based on mg protein was four times higher in lung than liver. Only after phenobarbital treatment was the contribution of hepatic metabolism to excreted metabolites important. In conclusion the lung which is also the target of NNK carcinogenesis, and not the liver, is the organ with the most important contribution to NNK and NNAL metabolism at concentrations relevant to human exposure.

Establishment and validation of an isolated rat lung model for pulmonary metabolism studies

Establishment and validation of an isolated rat lung model for pulmonary metabolism studies

Establishment and validation of an isolated rat lung model for pulmonary metabolism studies.

An isolated rat lung model was established and validated for use in pulmonary metabolism studies. During the establishment phase of the study, several problems were encountered and overcome in order to maintain the lungs in physiological condition. In the validation phase of the study, the lungs were removed, ventilated and perfused from 34 male Fischer 344 rats. After an equilibration period, lungs were ventilated and perfused for up to 4 h. Morphological, biochemical and functional parameters were evaluated to validate the physiological condition of the lungs. Morphological parameters included wet/dry lung weight ratios and gross and histological scoring for edema. Biochemical parameters included assays for tissue ATP and reduced glutathione content, glutathione reductase activity and glucose utilization. Functional parameters included changes in lung tidal volume, dynamic compliance and airway resistance. Results indicated that edema formation was only detected histologically, that lungs remained nearly biochemically normal for 210 min and that pulmonary function declined to about 80-90% of normal. Overall, these findings indicated that the isolated, perfused rat lung remained in acceptable physiological condition for ca. 210 min. This period of time should be adequate for conducting pulmonary metabolism studies with a variety of exogenous compounds.

Health effects of sulfur-related environmental air pollution: the pulmonary surfactant system is not disturbed by exposure to acidic sulfate and neutral sulfite aerosols.

The goal of this study was to assess the impact of long-term exposure to environmental sulfur-related aerosols on the biochemical and biophysical properties of lung surfactant. Eight Beagle dogs were housed under clean air conditions for 450 days, followed by an exposure period of 400 days to 0.36 mg/m3 of sulfite (16.5 h/d) and to 5.66 mg/m3 of sulfate (6 h/d) equivalent to a pulmonary hydrogen burden of 15 mumol/m3. Other dogs kept in clean air for the whole study period were additional controls. Serial bronchoalveolar lavages (BALs) were analyzed for total phospholipid concentration, content and ratio of a surfactant-rich large aggregate (LA) fraction and a small aggregate (SA) fraction, in vitro surface area cycling of LAs into SAs as a measure of alveolar extracellular pulmonary surfactant aggregate metabolism, and surface activity of native and lipid-extracted LA. No significant changes over time and no differences between the clean air period and the exposure period were observed. Thus, long-term environmental exposure of dogs to the sulfur-related air pollution tested does not lead to alterations in the amount, extracellular metabolism, or surface-active properties of pulmonary surfactant.

Metabolism of remifentanil during liver transplantation

We have investigated the pharmacokinetics of remifentanil and its less potent metabolite, GR90291, in six adult patients undergoing orthotopic liver transplantation (OLT). A single bolus infusion of remifentanil 10 micrograms kg-1 min-1 was given at the beginning of the dissection and anhepatic phases of OLT. Remifentanil and GR90291 concentrations were measured in subsequent serial arterial and mixed venous blood samples. Mean arterial clearance of remifentanil was significantly greater (P = 0.02) in the dissection phase (79.54 ml min-1 kg-1) than in the anhepatic phase (39.57 ml min-1 kg-1). Steady state volumes of distribution were not significantly different. Clearance of remifentanil during the anhepatic phase was similar to that of healthy adult patients. Mean maximum concentration (Cpmax) of GR90291 was lower in the dissection phase than in the anhepatic phase (P = 0.026). There was no significant pulmonary metabolism of remifentanil.

Neutral endopeptidase 3.4.24.11 inhibition potentiates the inhibitory effects of type-C natriuretic peptide on leukotriene D4-induced airway changes.

1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type-C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4-induced airway microvascular leakage and bronchoconstriction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor. 2. Anaesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 micrograms/kg LTD4 and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage. 3. Intravenous administration of CNP (100, 300 and 1000 micrograms/kg) significantly inhibited the LTD4-induced microvascular leakage and bronchoconstriction in a dose-dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP. 4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.

Biodistribution of, antimutagenic efficacies in Salmonella typhimurium of, and inhibition of P450 activities by ellagic acid and one analogue.

Ellagic acid (EA) is generated by hydrolysis of ellagitannins present in fruit berries and edible nuts and grapes. Large doses of EA prevent lung tumorigenesis induced by the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. In this study, we document the efficacies of the EA structural analogue (3,4,7,8-tetrahydroxy-6H-benzo[b,d]pyran-6-one) (analogue 1) to inhibit specific P450 activities, pulmonary metabolism of NNK in A/J mice, and NNK-induced mutations in Salmonella typhimurium. Mouse lung microsomes metabolized benzyloxyresorufin, a marker of cytochrome P450 2B1 activity, more extensively than methoxyresorufin or ethoxyresorufin. The EA analogue was more effective than EA in inhibiting dealkylation of the three alkoxyresorufins, suggesting that it is a nonspecific inhibitor of P450s. Mouse lung microsomes hydroxylate testosterone in the 7alpha and 6beta positions, suggesting contributions of P450 2A1 and P450 3A2 isozymes, respectively. Inhibition of both pathways was more effective with the EA analogue than with EA. Mouse lung explants metabolized NNK by alpha-carbon hydroxylation (activation) and pyridine N-oxidation (deactivation). Both pathways were inhibited when 100 microM EA was added to the culture medium. The EA analogue was a better inhibitor of the activation of NNK to electrophilic species than EA. Mouse lung microsomes activate NNK to intermediates mutagenic to S. typhimurium. Inhibition of NNK mutagenicity by EA or the EA analogue was 20 or 65%, respectively. The distribution of the EA analogue in lung and liver was determined following gavage with 1.7 mmol of the EA analogue. In the lung, a maximal level of EA analogue corresponding to 105 nmol was observed 30 min after administration of the analogue. The level in liver tissues was 4-fold lower than in the lung. Results of this study demonstrate that the EA analogue is more effective than EA in inhibiting the pulmonary activation of NNK and suggest that the EA analogue could be effective in preventing lung tumorigenesis.

Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure.

Plasma endothelin-1 (ET-1) increases in congestive heart failure (CHF). The pulmonary vascular bed could contribute to this increase through a reduced clearance. We evaluated the effect of tachycardia-induced CHF on pulmonary ET-1 kinetics. To discern between changes due to variations in pulmonary hemodynamics from true alterations of endothelial cell functions, we quantified ET-1 kinetics in isolated rat lungs under variable pressure and flow-rate conditions. Indicator-dilution studies were performed in anesthetized dogs (n = 14) before and 3 weeks after rapid ventricular pacing and in isolated lungs from healthy rats (n = 4). In isolated lungs, graded increases in perfusion rate from 5-25 ml/min caused gradual reductions in ET-1 extraction from 60 +/- 1.5% to 17 +/- 4.9% (mean +/- S.D.). The capacity to clear ET-1 from the circulation, as computed from the permeability-surface area product (PS), however did not vary over this range of flows. CHF increased plasma ET-1 (11.2 +/- 11.4 vs. 5.2 +/- 1.6 fmol/ml, p < 0.01), did not affect pulmonary ET-1 extraction (29.4 +/- 12.5% vs. 29.9 +/- 12.9%), but decreased the PS (8.3 +/- 5.4 cm3/s vs. 14.4 +/- 9.9 cm3/s, p = 0.038). Contrary to the invariability of the PS in normal isolated rat lungs, CHF was associated with a positive relationship between the PS and pulmonary plasma flow (r = 0.65, p < 0.01). ET-1 binding studies in lung tissues showed no significant variations in ETA and ETB receptors densities but revealed a threefold decrease in binding affinity (p < 0.01) that may explain the reduced clearance. CHF causes a reduction of pulmonary ET-1 clearance that likely contributes to the increased circulating ET-1 levels and reflects pulmonary metabolic dysfunction associated with this condition.

Influence of age and gender on iodine-123 MIBG kinetics in normal lung.

Iodine-123 MIBG is a biochemical marker that can be used to monitor pulmonary norepinephrine (NE) metabolism. The purpose of this study was to characterize pulmonary I-123 MIBG kinetics in relation to age and gender. Seventeen healthy volunteers and 14 patients with no cardiac or pulmonary disorders were included in this study (age range: 24 to 88 years, mean age 50.2 +/- 17.6 years; 16 males, 15 females). Planar images were obtained 15 min (early) and 3 h (delayed) after injection of I-123 MIBG (111 MBq). Pulmonary uptake of I-123 MIBG was quantified based on the lung-to-mediastinum ratio (LMR) on early and delayed images. The lung clearance rate (LCR) was calculated form both the early and delayed images. Both early and delayed LMR values increased slightly, although they showed no significant correlations with age. There was a significant inverse correlation between LCR and age (r = -0.57, p < 0.001). Neither LCR nor LMR differed significantly between male and female patients, but the mean age of the men was lower than that of the women. Pulmonary I-123 MIBG kinetics may reflect age-dependent changes in NE metabolism. The effects of age should be taken into account when assessing pulmonary NE metabolism with I-123 MIBG.

LOW-SODIUM DIET IMPROVES EXERCISE PULMONARY FUNCTION IN EXERCISE-INDUCED ASTHMA

1069 Subjects with exercise-induced asthma (EIA) typically demonstrate marked reductions in pulmonary function post-exercise. Little data is available regarding pulmonary function during exercise in EIA. Additionally, there are no data regarding the potential role of dietary sodium on the severity of EIA. This study investigated the role of low- (LSD) and high-sodium (HSD) diets on pulmonary function and metabolism during exercise. Fifteen, clinically-diagnosed EIA subjects participated in a randomized, double-blind, crossover study. Subjects were studied on their normal sodium diet (NSD) and then randomized to LSD (≈1500 mg/d) or HSD(≈4000 mg/d) for 2 wks, followed by a 1-wk washout on NSD, then crossed over to the opposite diet for 2 wks. 24-hr urine collections documented sodium intake. EIA medication was withheld prior to the exercise test. Subjects performed a treadmill test to 90% of age-predicted heart rate, which was held for 5 min. Oxygen saturation (SaO2) was measured by ear oximetry; VO2 and VCO2 were measured by analysis of breath-by-breath expired gases. LSD improved (93%sat) and HSD worsened (78%sat) SaO2 during exercise. Tidal volume/frequency selection during LSD vs. HSD implied reduced airway resistance. In each case, the values on NSD were intermediate to those on LSD and HSD. All measured variables indicated that pulmonary gas exchange improved on LSD and worsened on HSD, and that airway resistance may have been less during LSD. Dietary sodium restriction improved pulmonary function while usual and elevated sodium intakes demonstrated progressive decrements in pulmonary function during exercise in subjects with EIA.

Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension

Objective Pulmonary hypertension (PHT) is associated with increased endothelin-1 (ET-1) levels that correlate with the severity of the disease. The pulmonary circulation is an important site for ET-1 metabolism and may modulate plasma ET-1 through an increase in production, a reduction in removal, or a combination of both. We measured and compared pulmonary metabolism of circulating ET-1 in controls and in patients with PHT. Methods and Results The indicator-dilution technique was combined with measurements of ET-1 levels to quantify pulmonary metabolism of ET-1 in controls ( n = 13) and in patients with PHT ( n=17). ET-1 levels doubled in PHT ( p < 0.05) and, although there was no difference between aortic and pulmonary artery levels in controls (0.68 ± 0.09 and 0.61 ± 0.08 pg/ml, respectively, p=0.22), they tended to be higher in PHT (1.23 ± 0.26 vs 1.07 ± 0.19 pg/ml, p=0.08). Pulmonary extraction of tracer iodine-125–ET-1 was reduced from 47% ± 2.0% in the controls to 34% ±3.6% in PHT ( p = 0.005) and inversely correlated with the severity of pulmonary hypertension ( r = –0.524, p = 0.03). Consequently, circulating ET-1 clearance was reduced by PHT from 1424± 77 ml/min to 892 ± 119 ml/min ( p < 0.001). Pulmonary production of circulating ET-1 (in picograms per minute) was not different but the quantity of ET-1 that survives passage through the lungs was increased by PHT (1860 ± 359 pg/min vs 992±152pg/min, p = 0.037). Conclusion PHT is associated with a reduced pulmonary clearance of ET-1 that contributes to the increase in circulating levels. (Am Heart J 1998;135:614-20.)

Effects of inhaled nitric oxide on platelet-activating factor-induced pulmonary hypertension in dogs.

Platelet-activating factor (PAF), a lipid mediator released during endotoxin shock, induces pulmonary hypertension, systemic hypotension and cardiac dysfunction. In this study, we compared the effect of inhaled nitric oxide (NO) on PAF-induced pulmonary hypertension and NO metabolism with that on pulmonary hypertension induced by a stable thromboxane A2 mimetic, U46619. Since PAF-induced hypotension might be mediated by NO, the effect of inhaled NO combined with an intravenously administered NO synthase inhibitor, NG-nitro-L-arginine (L-NNA), on PAF-induced hemodynamic change was also investigated. In a total of 28 beagles anesthetized with pentobarbital the following substances were intravenously administered: PAF 0.56 +/- 0.30 microgram.kg-1.min-1 (group PAF), L-NNA 10 mg.kg-1 + PAF 0.04 +/- 0.03 microgram.kg-1.min-1 (group L-NNA + PAF), U46619 0.60 +/- 0.11 microgram.kg-1.min-1 (group U46619) or L-NNA 10 mg.kg-1 + U46619 0.61 +/- 0.23 microgram.kg-1.min-1 (group L-NNA + U46619) to obtain a mean pulmonary arterial pressure (MPAP) of 25 mmHg. Nitric oxide was then inhaled at 5, 10, 20 and 40 ppm for 15 min at 15-min intervals in the order of increasing concentration. An additional 7 dogs (control group) inhaled NO at normal MPAP (17 mmHg). Hemodynamic and respiratory parameters, NOHb, NO2- + NO3-, and MetHb levels in blood were measured before and during NO administration. In the control group, hemodynamic and respiratory values did not change significantly during NO administration. In group PAF, NO significantly reversed the PAF-induced pulmonary hypertension. PAF induced a marked systemic hypotension and cardiac output reduction, but these changes were not affected by inhalation of NO. L-NNA pretreatment markedly decreased the dose of PAF required to maintain a MPAP of 25 mmHg, and abolished the PAF-induced hypotension. In group L-NNA + PAF, the diminishing effect of inhaled NO on pulmonary vascular resistance (PVR) was significantly greater than that in group PAF. U46619 induced pulmonary hypertension and increases in blood pressure, intrapulmonary shunt and peak airway pressure. L-NNA pretreatment did not change the dose of U46619 required to maintain a MPAP of 25 mmHg. The effects of inhaled NO on PVR decrease were similar in groups U46619 and L-NNA + U46619. No NOHb was detected in any group. NO2- + NO3- concentration increased during NO administrations. There were no significant differences in NO2- + NO3- concentration among groups. Inhaled NO at the dose of 5-40 ppm effectively reversed PAF-induced pulmonary hypertension, especially following pretreatment with L-NNA. Inhaled NO did not affect PAF-induced hypotension or cardiac dysfunction. These findings indicate that low concentrations of inhaled NO may be useful in reversing pulmonary hypertension in the endotoxemia where PAF may be one mediator.

Route dependent pulmonary first-pass metabolism of a series of biphenylacetic acid esters in rats

The influence of route of administration of a series of biphenylacetic acid aliphatic esters on their pulmonary first-pass metabolism in rats was investigated. The results were compared with in vitro data and with the physicochemical properties of the esters. Pre- and post-absorptive first-pass metabolism was assessed by comparing area under blood concentration-time curves after intra-arterial administration of the esters with those seen after intravenous (to assess post-absorptive) and intratracheal (to assess pre-absorptive) administration. The extent of pulmonary metabolism was dependent on the route of administration. For all the esters studied there was insignificant post-absorptive first-pass extraction, however there was a large pre-absorptive first-pass extraction (greater than 80%). Enzyme kinetics derived in vitro using the ‘well-stirred’ model (Dickinson and Taylor, 1995. Int. J. Pharm. 116, 231–236) predicted the extent of post-absorptive but not the pre-absorptive, first-pass metabolism.

METABOLISM OF STYRENE OXIDE TO STYRENE GLYCOL BY MOUSE LIVER AND LUNG

Styrene is a widely used chemical that causes both liver and lung damage in mice. Strain and sex differences in susceptibility to styrene-induced toxicity have been reported. Understanding the relationship of the metabolism of styrene to its toxicity depends upon knowing the balance between the bioactivation of styrene to the epoxide by cytochromes P-450 and the detoxication of the oxide to the glycol by microsomal epoxide hydrolase. When hepatic and pulmonary microsomal preparations from non-Swiss albino (NSA) and Swiss (CD-1) mice were compared for their abilities to metabolize racemic, S - and R -styrene oxide to styrene glycol, enzymic activities were higher in liver than in lung. R -Styrene glycol formation was favored with racemic styrene oxide as the substrate. Only minor strain differences were found that could not account for the differences in reported susceptibility to styrene-induced toxicity. While the oxidation of styrene to styrene oxide was similar in male and female NSA mice, male hepatic microsomes were more active in the metabolism of the oxide to the glycol. Hepatic metabolism of styrene oxide to styrene glycol was inducible by butylated hydroxyanisole, whereas pulmonary metabolism was not. The data indicate that strain differences in susceptibility cannot be accounted for by this detoxication step, and there are sex differences in this reaction.