Pulmonary Metabolism Research Articles

Absence of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by flavin-containing monooxygenase (FMO).

The N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in tobacco and tobacco smoke. Carbonyl reduction, alpha-carbon hydroxylation (activation) and N-oxidation of the pyridyl ring (detoxification) are the three main pathways of metabolism of NNK. In this study, metabolism of NNK was studied with lung and liver microsomes from F344 rats, Syrian golden hamsters and pigs and cloned flavin-containing monooxygenases (FMOs) from human and rabbit liver. Thermal inactivation at 45 degrees C for 2 min reduced FMO S-oxygenating activity but did not affect N-oxidation of NNK, leading to the conclusion that FMOs are not implicated in the detoxification of NNK. Detoxification of NNK was not increased by n-octylamine or by incubation at pH 8.4, supporting the conclusion that FMOs are not involved in the metabolism of NNK. SKF-525A (1 mM) significantly reduced N-oxidation and alpha-carbon hydroxylation, suggesting that these two pathways were catalyzed by cytochromes P450. Metabolism of NNK was lower with lung microsomes than with liver microsomes. Inhibition of metabolism of NNK by SKF-525A was also observed with rat lung microsomes, leading to the conclusion that cytochromes P450 are involved in pulmonary metabolism of NNK. Cloned FMOs did not metabolize NNK. In conclusion, cytochromes P450 rather than FMOs are involved in N-oxidation of NNK. The high capacity of hamster liver microsomes to activate NNK does not correlate with the resistance of this tissue to NNK-induced hepatocarcinogenesis.

The use of precision-cut rat lung slices for studying PGF 2 α metabolism

The suitability of a dynamic lung slice culture system as an in vitro model for studying pulmonary metabolism of PGF 2 α was assessed. [ 3H]Prostaglandin F 2 α ([ 3H]PGF 2 α ), a twenty carbon fatty acid that contains a five-carbon ring and is known to be metabolized by lung in vivo, was incubated with precision-cut rat lung slices in 1.7 ml of Waymouth's buffer fortified with 10% fetal calf serum. At 0, 2, 4 and 8 h after addition of [ 3H]PGF 2 α (1.82 ng/μCi), incubation was stopped and the contents of each vial were analyzed for [ 3H]PGF 2 α and its metabolites using reversed-phase HPLC with radiochemical detection. PGF 2 α was metabolized to 15-keto PGF 2 α , 13,14-dihydro-15-keto PGF 2 α , and two unknown minor polar metabolites. These results indicate that PGF 2 α was metabolized in lung slices pathways similar to those seen in vivo. Slice viability was assessed by protein synthesis and light microscopic examination of lung slices through 24 h of incubation. Protein synthesis was maintained and no tissue necrosis was observed over the entire 24 h incubation, indicating that the lung slices were viable for at least 24 h. These results indicate that the dynamic lung slice culture system is an appropriate in vitro model for studying the pulmonary metabolism of PGF 2 α .

Ontogeny of gamma-glutamyltransferase in the rat lung.

gamma-Glutamyltransferase (gamma-GT) is a key enzyme in the metabolism of glutathione and glutathione-substituted molecules. The gamma-GT gene is expressed in two epithelial cells of the adult lung, the bronchiolar Clara cell and the alveolar type II cell. Because pulmonary glutathione metabolism may be important in the perinatal period, we studied gamma-GT ontogeny in the developing rat lung. In the late fetal and early postnatal lung, gamma-GT mRNA was below detectable limits on Northern blots. Pulmonary gamma-GT protein and enzyme activity were present at low levels after fetal day 18. gamma-GT protein appeared as a high-molecular-mass band (>95 kDa), with small amounts of enzymatically active gamma-GT heterodimer. Between the 2nd and 3rd postnatal wk, pulmonary gamma-GT mRNA expression increased in association with an increase in gamma-GT protein and enzyme activity that reached adult lung levels. At this time, gamma-GT protein appeared predominantly in the heterodimeric form with small amounts of the >95-kDa protein. Immunocytochemistry revealed that, in the fetal and early postnatal lung, gamma-GT was expressed only in the alveolar type II cell, whereas the Clara cell became the major site of gamma-GT mRNA and protein expression by 2-3 wk and in the adult. Type II cells isolated from the fetal lung express gamma-GT mRNA and synthesize the >95-kDa form of gamma-GT in excess of the heterodimer. These studies demonstrate that the alveolar type II cell is the only cell producing gamma-GT in the newborn lung and that it synthesizes a form of gamma-GT that appears to differ from that produced at a later time point by the Clara cell.

1,3-Butadiene metabolism by lung airways isolated from mice and rats

1,3-Butadiene (BD) is oxidized by cytochrome P450 to reactive metabolites, including 1,2-epoxy-3-butene (BMO) and 1,2:3,4-diepoxybutane (BDE), which are thought to be responsible for BD genotoxicity and carcinogenicity. Alveolar-bronchiolar neoplasms were observed in mice but not rats following chronic exposure to BD. The site-specific carcinogenicity of BD in mice may result from metabolic activation in pulmonary tissue. We have incubated bronchioles isolated from both male B6C3F 1 mice and male Sprague-Dawley rats with 34 μM BD (final concentration in the aqueous reaction medium) to assess species differences in pulmonary metabolism of BD and to enhance our understanding of species- and site-dependent BD carcinogenicity. Bronchioles from both mice and rats formed BMO, although mouse tissue produced 2-fold more than rat tissue. These preliminary results suggest that pulmonary activation of BD may play a role in the carcinogenicity of BD following inhalation exposure; however, other factors in addition to metabolic differences, probably contribute to the observed differences in susceptibility to BD toxicity.

A.283 Pulmonary metabolism of propofol in pigs during anhepatic phase of orthotopic liver transplantation

A.283 Pulmonary metabolism of propofol in pigs during anhepatic phase of orthotopic liver transplantation

Pulmonary Activation and Toxicity of Cyclopentadienyl Manganese Tricarbonyl

Cyclopentadienyl manganese tricarbonyl (CMT) produces acute pulmonary injury following cytochrome P450 mixed-function oxidase (CYP450) activation. The current studies were designed to characterize the role of hepatic and/or pulmonary CMT activation and the subsequent pneumotoxicity of this compound following subcutaneous injection in the male Sprague–Dawley rat. Both pulmonary and hepatic tissues were capable of CYP450-dependent CMT metabolismin vitro.Phenobarbital pretreatment, which induced hepatic but not pulmonary CMT metabolism, protected against CMT-depended pneumotoxicity suggesting escape of an active CMT metabolite from the liver is not responsible for the pneumotoxic response. Animals were also pretreated with eitherm-xylene or 3-methylindole, each of which reduce CMT metabolism in the lung but not in the liver. These pretreatments also reduced CMT-dependent pulmonary damage. Protection against toxicity by two compounds that inhibit pulmonary but not hepatic CMT metabolism provides strong evidence that CMT-induced pneumotoxicity is due to the activation of CMT within the lungs. Histopathological studies revealed that CMT induced an alveolar injury without apparent damage to the bronchiolar airways. Based on this pattern of injury, studies were performed with freshly isolated alveolar type II (ATII) cells as these cells are thought to contain significant CYP450 activity. However, CMT metabolism was not detectable in ATII cellsin vitro.Although CMT was cytotoxic to ATII cellsin vitro,this response was not inhibited by metyrapone indicating CYP450 activation was not involved in thein vitrophenomenon. Together these data suggestin situactivation of CMT is necessary for the alveolar toxicity of this compound; however, activation does not occur in ATII cells.

Pulmonary first-pass and steady-state metabolism of phenols.

To study (A) the effect of the administration route (i.v. and i.t.) on pre- and post-absorptive metabolism of phenol and 1-naphthol by the lung and (B) pulmonary extraction of phenol at steady-state. Phenols were administered intra-arterially, intravenously and intratracheally and the pre- and post-absorptive metabolism assessed by comparing the AUCs in arterial blood. Phenol was infused to steady-state and the pulmonary extraction assessed by measuring jugular vein and carotid artery blood concentrations. In contrast to previously published data (e.g., Mistry and Houston, Drug Metab.Dispos.l3:740-745 (1985)) we could not detect pulmonary first-pass metabolism of the phenols; reasons for this disparity are discussed. An apparent negative pulmonary extraction of phenol at steady-state was observed, probably as a consequence of extraction by organs which are in series, and not parallel, with the lungs (e.g. liver, kidneys and GIT). (A) Phenol and 1-naphthol do not undergo pulmonary first-pass metabolism. (B) Traditional methods of assessing organ extraction and clearance at steady-state cannot be utilised when metabolising organs are in series.

Textbook of Critical Care

Resuscitation Cell Injury and Cell Death Monitoring Imaging Pulmonary Abdominal Organ Dysfunction Metabolism and Pharmacology Infectious Diseases Hematology/Oncology Trauma Central Nervous System Transplantation Issues in Patient Care Organization and Management of Critical Care Ethical Decision Making in Critically Ill Patients.

Surfactant subfractions during nosocomial infection in ventilated preterm human neonates.

Long after resolution of the neonatal respiratory distress syndrome, deterioration of respiratory function in ventilated premature infants during severe nosocomial infections is commonly observed. Based on an increased oxygen demand and ventilatory support, impairment of the pulmonary surfactant system was hypothesized to occur. The clinical course of 10 premature neonates (764 +/- 57 g, 26.6 +/- 0.4 wk) with nosocomial infection mainly due to Staphylococcus epidermidis was divided into four periods in each individual patient: "before deterioration" (average 8 to 11 d of life), "deterioration" (11 to 17 d), "peak" (17 to 22 d), and "recovery" (22 to 24 d). A total of 810 airway specimens were obtained by small volume lavage (1 ml/kg bw), pooled to yield appropriate amounts for differential centrifugation into two distinct subfractions known as large surfactant aggregates (LA) and small surfactant aggregates (SA). "Before deterioration" the amount of phospholipids recovered was constant, and the two fractions were characterized by electron microscopic morphology and biochemical analysis. In the LA fraction lamellar body-like lipid structures were demonstrated, and the phospholipid composition was typical of pulmonary surfactant in premature neonates with a high content of phosphatidylcholine and phosphatidylinositol. With "deterioration" and "peak" the masses of total phospholipids and of phosphatidylcholine recovered were reduced (p < 0.05). At the same time the mass ratio of SA/LA for phosphatidylcholine decreased from 0.32 +/- 0.10 to 0.18 +/- 0.03, indicating a more pronounced decrease of the SA fraction (p < 0.05). The phospholipid composition in the LA fraction did not change during the course of nosocomial infection. In the SA fraction a decrease of phosphatidylcholine and a concomitant increase in lysophosphatidylcholine were observed at the "peak" of the infection. We concluded that, in ventilated premature neonates during nosocomial infection and respiratory deterioration, changes in phospholipid subfractions occur, possibly indicating impairment of pulmonary surfactant metabolism. These findings may be important when considering treatment of acute lung injury with nebulized exogenous surfactant.

In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism of propofol in the rat.

The relative contribution of the intestinal mucosa, liver and lung to the in vivo disposition of propofol in the rat was investigated. Propofol (4.9-5.1 mg.kg-1) was administered to groups of rats (n = 4) via the intra-arterial, intravenous, hepatic portal venous and oral routes. The AUC's of propofol were estimated and the fractions of the administered dose escaping first pass metabolism by the gut wall (fG), liver (fH) and lung (fL) were calculated. In addition, transport experiments were carried out using Caco-2 cell monolayers to rule out the possibility that intestinal permeability is limiting the oral absorption of propofol. Values for fG, fH and fL were the following: 0.21 +/- 0.07, 0.61 +/- 0.13, and 0.82 +/- 0.09, respectively. The apparent permeability coefficient of propofol across Caco-2 cell monolayers was 24.2 +/- 0.3 x 10(-6) cm.sec-1, which is similar to the apparent permeability coefficient obtained for propranolol (30.7 +/- 1.7 x 10(-6) cm.sec-1), a compound known to easily cross the intestinal epithelial membranes. The formation of propofol glucuronide, a major metabolite of propofol, could not be demonstrated during the flux experiments across the Caco-2 cell monolayers. The intestinal mucosa is the main site of first pass metabolism following oral administration of propofol in the rat. Intestinal metabolism could therefore also contribute to the systemic clearance of propofol.

Comparison of rat hepatic and pulmonary microsomal metabolism of benzene and the lack of benzene-induced pneumotoxicity and hepatotoxicity

Since little is known about the toxicity of benzene in the lung or if the lung is capable of metabolizing benzene, the ability of the lung to bioactivate or detoxify benzene and the pneumotoxicity of benzene were determined. While overall metabolism was lower, pulmonary microsomes converted benzene (17.5 μM) to hydroquinone, considered to be a marker for benzene toxicity, in proportionately greater amounts than did hepatic microsomes. Treatment of rats with pyridine, an inducer of CYP2E1, enhanced hepatic microsomal metabolism of benzene, although benzene, which is also considered to be an inducer of CYP2E1, did not. Neither pyridine nor benzene treatment induced the pulmonary microsomal metabolism of benzene. When hepatic and pulmonary microsomes from control and pyridine-treated rats were incubated with benzene (17.5 μM) and the CYP2E1 inhibitor, diethyldithiocarbamate, benzene metabolism was significantly inhibited, indicating that CYP2E1 is the predominant cytochrome P-450 isozyme involved in hepatic and pulmonary metabolism in microsomes from control and pyridine-treated rats. Benzene (600 mg/kg body weight i.p.) did not cause significant lung cell damage as determined by measurement of γ-glutamyltransferase and lactate dehydrogenase in bronchoalveolar lavage fluid. Induction of CYP2E1 and CYP2B1/2 with pyridine and phenobarbital, respectively, did not alter this lack of effect. Thus, the primary concern about benzene and the lung should focus on benzene metabolism as opposed to acute toxicity.

Psychology of dance

Part 1 Anatomical and physiological considerations - effects of aging and cardiovascular disease: structural changes in the heart systolic and diastolic function peripheral vasculature conduction system and electrocardiogram maximal oxygen uptake heart rate and blood pressure pulmonary system nervous system metabolism muscle and bone. Part 2 Exercise testing: methodology interpretation of results radionuclide evaluations. Part 3 Exercise prescription: entering the program determining the exercise prescriptions additional considerations for the exercise prescription the impact of medication resistance training home exercise. Part 4 Training adaptations: responses to training in the healthy elderly responses to training in the elderly cardiac patient. Part 5 Characteristics of participants in outpatient exercise training: risk factors descriptive characteristics and risk factors in elderly cardiac rehabilitation outpatients special populations within the elderly. Part 6 Program design considerations: risk stratification safety, attendance and compliance economic considerations exercise programming quality of life. Appendices: warm-up, stretching and flexibility exercises home exercises program log book.

METHODOLOGY FOR THE ASSESSMENT OF LUNG PROTECTION

This investigation was designed to show an original methodology for the assessment of lung preservation and to analyze the efficacy of a low potassium polygelin solution (haemaccel [HM]) on isolated human pulmonary artery endothelial cells. The effects of HM were compared with those of low potassium dextran (LPD), Belzer (University of Wisconsin [UWS]), and Euro-Collins solutions. The viability of the endothelial cultures was assessed by means of both total protein content and recovery of metabolic cellular function expressed as the protein synthesis rate after 6 hr and 16 hr of incubation at 10 degrees C. Our results failed to show any significant difference in the total protein content for HM, LPD, and UWS, both after 6 and 16 hr of incubation; however, the Euro-Collins-preserved sample revealed a significant drop in this parameter as early as 6 hr after the start. This finding was regarded as a clear indication of cellular cytotoxicity. In contrast, the metabolism recovery capacity of the cells varied significantly between HM and UWS at 6 hr and among HM, LPD, and UWS at 16 hr; at 6 hr, however, no significant difference was observed between HM and LPD. In conclusion, HM appears to exert a more significant effect on human pulmonary artery endothelial cell metabolism recovery than do the other fluids, thus suggesting its suitability as a long-term pulmonary perfusate.

Pulmonary Surfactant Subtype Metabolism Is Altered after Short-Term Ozone Exposure

Rats were exposed to 0.8 ppm ozone for 2 or 12 hr. The latter condition resulted in lung damage and inflammation while the former did not. Directly after exposure surfactant was isolated and two morphologically and functionally different surfactant subtypes were obtained by differential centrifugation. Surfactant subtypes isolated from rats exposed to 0.8 ppm ozone for 2 and 12 hr showed an increase in the amount of heavy subtype and a decrease in light subtype. These results suggest that acute ozone exposure of rats can alter surfactant subtype composition. The conversion in vitro of heavy to light subtype was increased in ozone-exposed rats. Degradation of surfactant protein A (SP-A) was observed during in vitro conversion of heavy subtype isolated from ozone-exposed rats. This suggests that oxidation of SP-A may lead to enhanced susceptibility for degradation. The observed effects were more pronounced in rats exposed for 12 hr than those exposed for 2 hr, indicating that proteolytic enzymes from inflammatory cells may aggravate the observed effects. We conclude that extracellular surfactant metabolism is altered by short-term exposures to ozone and that oxidation of SP-A may contribute to the observed alterations.

Metabolic activation and toxicity of some chemical agents to lung tissue and cells

Selected topics: Pulmonary bronchiolar epithelial cytotoxicity: microanatomical considerations, C. G. Plopper. Xenobiotic metabolism by isolated pulmonary bronchiolar and alveolar cells, T. R. Devereux et al . Localization, distribution, and induction of xenobiotic-metabolizing enzymes and aryl hydrocarbon hydroxylase activity within lung, J. Baron & J. M. Voi t. Purification and characterization of lung enzymes involved in xenobiotic metabolism, F. P. Guengerich. Action by the lungs on circulating xenobiotic agents, with a case study of physiologically based pharmacokinetic modeling of benzo(a)pyrene disposition, R. A. Roth & A. Vinega . Metabolism of endogenous and xenobiotic substances by pulmonary vascular endothelial cells, U. S. Ryan & A. P. Li. Naphthalene and 2-methylnaphthalene-induced pulmonary bronchiolar epithelial cell necrosis: metabolism and relationship to toxicity, R. B. Franklin et al . Pulmonary toxicity of 4-ipomeanol, T. E. Gram. Pulmonary toxicity induced by phosphorothioate impurities present in organophosphate insecticides, J. Gandy et al . The metabolic basis of 3-methylindole-induced pneumotoxicity, T. M. Bray & J. B. Kir land. Metabolism and pulmonary toxicity of butylated hydroxytoluene, H. Witschi et al . Hepatic nonaltruism and pulmonary toxicity of pyrrolizidine alkaloids, R. J. Huxtable. Cyclophosphamide: pulmonary metabolism, toxicity and protective effect of vitamin E, J. M. Patel. Metabolic activation and biological effects of nitrosamines in the mammalian lung, H. M. Schuller et al . The use of bleomycin in model systems to study the pathogenesis of interstitial pulmonary fibrosis, J. S. Lazo et al . The pulmonary toxicity of nitrosoureas, A. C. Smith. Index.

A kinetic investigation of the pulmonary metabolism of dopamine in rats shows marked differences compared with noradrenaline

The aim of this study was to investigate the deamination of dopamine in the intact pulmonary circulation of isolated lungs of the rat. The first part of the study showed that dopamine is not converted to noradrenaline by dopamine-beta-hydroxylase (DBH) when dopamine is perfused through isolated lung preparations with monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited. Hence, it was not necessary to inhibit DBH in subsequent experiments. The metabolite profile for deamination of dopamine in the lungs was examined by determining whether MAO and semicarbazide-sensitive amine oxidases (SSAO) contribute to the deamination of dopamine (and noradrenaline), and by determining the activity of MAO (kMAO) for the metabolism of dopamine. Lungs were perfused with 1 nmol/l 3H-dopamine or 3H-noradrenaline with COMT inhibited and, in experiments to determine the contribution of SSAO to deamination, with MAO inhibited. Inhibition of MAO reduced the deamination of dopamine and noradrenaline by 99.8% and 98.6%, respectively, indicating that MAO, and not SSAO, was responsible for deamination of the catecholamines in the lungs. The kMAO value for deamination of dopamine was 3.89 min-1. Further experiments were carried out to determine the contributions of MAO-A and MAO-B to the deamination of dopamine in lungs perfused with 1 nmol/l 3H-dopamine and 100 nmol/l lazabemide or 300 nmol/l Ro41-1049, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for saturation of catechol-O-methyltransferase by low concentrations of noradrenaline in perfused lungs of rats.

Previous studies on the pulmonary removal and metabolism of catecholamines in rat lungs have shown that, when the lungs are perfused with a low concentration (1 nmol/l) of noradrenaline, the amine is metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), but is predominantly O-methylated, and the activities of COMT and MAO are 0.357 min-1 and 0.186 min-1, respectively. The aim of the present study was to examine the changes in the metabolic profile of noradrenaline in rat lungs over a range of concentrations, and to examine the kinetics of the pulmonary O-methylation of noradrenaline and adrenaline. In isolated lungs perfused with 3H-noradrenaline, there was a progressive decrease in the proportion of O-methylated metabolites and a corresponding increase in the proportion of deaminated metabolites, as the noradrenaline concentration in the perfusion solution was increased from 1 to 10 to 100 to 1000 nmol/l. Experiments designed to determine the rate of uptake of noradrenaline in lungs perfused with 1 nmol/l 3H-noradrenaline, under conditions of MAO inhibited, COMT inhibited and COMT and MAO inhibited, showed that the results were compatible with co-existence of COMT and MAO in the pulmonary endothelial cells. Hence, it appeared that the changing metabolic profile with amine concentration in the previous series of experiments was not due to saturation of noradrenaline uptake into cells that contained COMT but not MAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary and blood enzyme kinetics as predictors of pulmonary metabolism of esters

The enzymatic hydrolysis of four aliphatic esters of biphenylacetic acid by rat lung homogenate and blood was investigated. The log V max K m ratios derived in both tissues were parabolically related to lipophilicity, similar trends were also observed for log V max values against lipophilicity. K m values could not be related to lipophilicity. The pulmonary and blood intrinsic clearances were linearly related, suggesting blood could be used to predict the pulmonary metabolism of esters. Pulmonary extraction ratios, predicted from the intrinsic clearance using the 'well-stirred' model, were negligible.

Comparison of the metabolism of 7-ethoxycoumarin and coumarin in precision-cut rat liver and lung slices

The metabolism of 7-ethoxycoumarin and [3- 14C] coumarin was compared in precision-cut rat liver and lung slices. The lung slices were prepared using an agarose gel instilling technique enabling the production of tissue cylinders followed by lung slices employing a Krumdieck tissue slicer. Both 50μM 7-ethoxycoumarin and 50μM [3- 14C]coumarin were metabolized by rat liver and lung slices. 7-Ethoxycoumarin was converted to 7-hydroxycoumarin (7-HC) which was conjugated with both d-glucuronic acid and sulfate. 7-HC sulfate was the major metabolite formed by both liver and lung slices. [3- 14C]Coumarin was metabolized by rat liver and lung slices to both polar products and to metabolite(s) that bound covalently to tissue slice proteins. The polar products included unidentified metabolites and 3-hydroxylation pathway products, with only very small quantities of 7-HC being formed. These results demonstrate that precision-cut lung slices area useful model in vitro system for studying the pulmonary metabolism of xenobiotics. Moreover, the precision-cut tissue slice technique may be employed for comparisons of hepatic and extrahepatic xenobiotic metabolism.

Norepinephrine Infusion Following Cardiopulmonary Bypass: Effect of Infusion Site

The placement of left atrial catheters following cardiopulmonary bypass (CPB) allows accurate monitoring of left ventricular filling pressures, as well as access for the infusion of vasoactive drugs. While the left atrial administration of norepinephrine (NE) is thought to provide higher systemic arterial NE levels while minimizing any pulmonary vasoconstriction, no study critically compares central venous and left atrial NE infusion following cardiopulmonary bypass. A canine model was used to compare central venous and left atrial NE infusion at three dosages (0.2, 0.4, and 0.6 μg/kg/min) both prior to CPB and following 2 hr of hypothermic CPB at 27°C. Prior to CPB, there was no difference in the hemodynamic efficacy of central venous and left atrial NE infusion at any dosage. The pulmonary circulation metabolized 16-29% of circulating NE. Only at the 0.2 μg/kg/min dose was there a difference in the arterial NE level between central venous (3474 ± 486 pg/ml) and left atrial (5504 ± 751 pg/ml, P = 0.019) NE administration. Above this dose, no difference in the arterial NE level was identified. Following 2 hr of CPB, the pulmonary endothelium metabolized a significantly higher percentage of circulating NE (3542%). Despite this increased extent of pulmonary metabolism, there was no difference in the hemodynamic efficacy or the resulting arterial NE level of central venous and left atrial NE infusion at a given dose. In conclusion, the results demonstrate: (1) increased pulmonary NE uptake following CPB, and (2) no difference in hemodynamic efficacy between central venous and left atrial NE infusion over a wide range of three doses in a model with normal lungs.