Rat Lung Model Research Articles

Effects of the twin-arginine translocase on secretion of virulence factors, stress response, and pathogenesis.

A novel secretion pathway originally found in plants has recently been discovered in bacteria and termed TAT, for "twin-arginine translocation," with respect to the presence of an Arg-Arg motif in the signal sequence of TAT-secreted products. However, it is unknown whether the TAT system contributes in any way to virulence through the secretion of factors associated with pathogenesis or stress response. We found that the opportunistic pathogen Pseudomonas aeruginosa produces several virulence factors that depend on the TAT system for proper export to the periplasm, outer membrane, or extracellular milieu. We identified at least 18 TAT substrates of P. aeruginosa and characterized the pleiotropic phenotypes of a tatC deletion mutant. The TAT system proved essential for the export of phospholipases, proteins involved in pyoverdine-mediated iron-uptake, anaerobic respiration, osmotic stress defense, motility, and biofilm formation. Because all these traits have been associated with virulence, we studied the role of TAT in a rat lung model. A tatC mutant did not cause the typical multifocal pulmonary abscesses and did not evoke a heavy inflammatory host response compared with wild type, indicating that tatC mutant cells are attenuated for virulence. Because the TAT apparatus is well conserved among important bacterial pathogens yet absent in mammalian cells, it represents a potential target for novel antimicrobial compounds.

Cyclic nucleotides phosphodiesterase activity in a rat lung model of asthma

OBJECTIVE: To assess the change of cGMP-PDE and cAMP-PDE activity in a rat lung model of asthma. METHODS: cGMP-PDE and cAMP-PDE activity were determined by HPLC. RESULTS: Both cAMP-PDE activity and cGMP-PDE activity in the lung tissue of antigen-challenged rats were higher than that from the normal rats (P <0.05). CONCLUSION: In the rat lung model of asthma, cyclic nucleotides phosphodiesterase activity was elevated. This may be significant in the pathogenesis of asthma.

High airway-to-blood transport of an opioid tetrapeptide in the isolated rat lung after aerosol delivery

The airway-to-blood absorption of the μ-selective opioid tetrapeptide agonist Tyr-D-Arg-Phe-Phe-NH2 (MW 631) was investigated in the isolated, perfused, and ventilated rat lung model. The lung metabolism of the peptide was compared after airway and vascular delivery. The concentrations of the parent tetrapeptide and five of its metabolites in the perfusate and in bronchoalveolar lavage fluid were analyzed by LC-MS.The metabolism of the peptide was higher after delivery to the airways compared to vascular delivery. However, the tetrapeptide was highly transported from the air-to-blood side to an extent of 47.8 ± 10.7% in 2 h. In conclusion, the results prompt investigations of the pulmonary route as a successful alternative to parenteral delivery for this tetrapeptide.

NMDA ALTERS THE DEVELOPMENT OF HYPOXIC PULMONARY VASOCONSTRICTION AND NITRIC OXIDE SYNTHETASE ACTIVITY IN THE ISOLATED PERFUSED RAT LUNG

Using an isolated salt-perfused rat lung model, the authors investigated whether N-methyl-D-aspartate (NMDA) (1 mM) in the pulmonary circulation effects the pulmonary vascular responses to an acute stimulus of hypoxic insult under baseline, nitric oxide synthetase (NOS)-blocked conditions (N- Ω -nitro-L arginine methyl ester; L-NAME, 2 mM), and with an NMDA receptor blocker, MK-801 (0.3 μ M) added. NOS activityat baseline, and in response tohypoxia, NMDA, L-NAME, and a combination of these stimuli were also assessed. NMDA did not in itself alter hypoxic pulmonary vasoconstriction (HPV), but did significantly attenuate HPV during NOS blockade. This effect of NMDA was erased by MK-801. Assessment of NOS activity showed that hypoxia alone caused a doubling of NO production within the lung. This effect was erased by the addition of L-NAME. NMDA alone caused a significant, 3-fold increase in NOS activity, which was not further affected by hypoxic challenge. L-NAME did not depress NOS activity in the hypoxia + NMDA group. These data suggest that NMDA receptor activation results in increased NOS activity and presumably increased production of NO. The increased NOS activity induced by NMDA receptor stimulation is resistant to the blockade effect of L-NAME. The actions of NMDA receptor activation may represent a natural protective mechanism, at least within the pulmonary vasculature, in face of acute, abnormal stimuli such as hypoxia.

Efficacies of ABT-773, a new ketolide, against experimental bacterial infections.

ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 microg/ml and an area under the concentration-time curve (AUC) of 12.03 microg. h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.

Evaluation of Pulmonary Edema: Stereological versus Gravimetrical Analysis

Assessment of lung edema by gravimetrical analysis is a standard method to evaluate the severity of experimentally induced ischemia/reperfusion (IR) injury. The aim of this study was to compare gravimetrical assessment of pulmonary edema with a stereological approach which allows for qualitative and quantitative distinction between intravascular and edematous fluids by light microscopy. Eight experimental groups which differed in mode of preservation, ischemic storage and pharmacological treatments were studied in an extracorporeal rat lung model. Analysis of the pooled data showed that the wet/dry ratio values mainly reflected the amount of intra-alveolar edema (r_s = 0.442; p = 0.0057) but only stereological assessment of edema formation revealed differences depending on the treatment used. Only stereological data correlated significantly with oxygen tension measured at the end of reperfusion (r_s = –0.530; p = 0.0009). We conclude that gravimetry is of minor functional importance compared to assessment by stereological methods which prove to be a reliable and efficient tool for the evaluation of IR injury in the different experimental settings.

Optimal alveolar oxygen concentration for cold storage of the lung.

Ischemia of the lung is different from that of solid organs because the lung contains gas in the alveoli. However, the optimal gas composition in the alveoli during cold storage remains uncertain. We investigated the relationship between the alveolar oxygen concentration and reperfusion injury. The lungs inflated with 0% O2, 5% O2, room air, 50% O2, or 100% O2 were reperfused after 8 hR storage at 4 degrees C and pulmonary functions were measured for 120 min using an ex vivo rat lung model. The levels of high-energy phosphate and lipid peroxidation of the lung were analyzed after a PA flush, preservation, and reperfusion. Additionally, respiration of the mitochondria in the lungs was measured after preservation. The pulmonary functions were significantly superior in the 5% O2 group than those in the 0% O2, 50% O2, and 100% O2 groups. Pulmonary edema developed in the 0% O2, 50% O2, and 100% O2 groups, but not in the 5% O2 group. After preservation, the energy level in the lungs decreased only in the 0% O2 group. Although lipid peroxidation of the lungs did not increase in any group after preservation, significant increases were observed in the room air, 50% O2 and 100% O2 groups after reperfusion. State 3 and 4 ratios of the mitochondrial respiration significantly decreased in the lungs of the room air, 50% O2 and 100% O2 groups. Although the cold-preserved lungs require oxygen, hyperoxygenation induced mitochondrial dysfunction and increased lipid peroxidation and led to deleterious lung function after reperfusion. Therefore, hypoxic conditions that can maintain the energy level of the lung during cold storage would be optimal.

Heat stress attenuates ventilator-induced lung dysfunction in an ex vivo rat lung model.

Our laboratory has previously shown decreased mortality rates and the attenuation of lung injury in rats exposed to heat stress (H) 18 h prior to induction of sepsis. In the present study, we examined the hypothesis that heat stress would protect lungs against ventilator-induced lung injury. Male Sprague-Dawley rats were anesthetized and randomly allocated to receive either sham treatment or exposure to heat (rectal temperature 41 degrees C, for 15 min). The lungs were harvested 18 h later, a pressure-volume (P- V) curve was constructed, and the lungs were either lavaged for cytokine and surfactant analyses (preventilation data) or were mechanically ventilated with VT 40 ml/kg in a warmed, humidified chamber. After 2 h of mechanical ventilation, another P-V curve was constructed and the lungs were lavaged for cytokine and surfactant analyses (postventilation data). Mechanical ventilation in control lungs produced a 47% decrease in chord compliance, an increase in lung lavage levels of tumor necrosis factor (TNF)-alpha (722 +/- 306 pg/ml), interleukin (IL)-1beta (902 +/- 322 pg/ml), and macrophage inflammatory protein-2 (MIP-2) (363 +/- 104 pg/ml) as compared with low levels of cytokines detected in preventilation data, and no change in percentage of surfactant large aggregates (LA). In contrast, in mechanically ventilated lungs from animals that were exposed to heat stress we observed a smaller decrease in chord compliance (17%), a significant attenuation in cytokine levels (TNF-alpha 233 +/- 119 pg/ml; IL-1beta 124 +/- 53 pg/ml; MIP-2 73 +/- 52 pg/ml; p < 0.05) and a significant increase in percentage LA compared with control animals. We conclude that exposing animals to heat stress confers protection against the effects of an injurious form of mechanical ventilation, by a mechanism that may involve attenuation of cytokines and preservation of some surfactant properties.

A rat lung model of instilled liquid transport in the pulmonary airways.

When a liquid is instilled in the pulmonary airways during medical therapy, the method of instillation affects the liquid distribution throughout the lung. To investigate the fluid transport dynamics, exogenous surfactant (Survanta) mixed with a radiopaque tracer is instilled into tracheae of vertical, excised rat lungs (ventilation 40 breaths/min, 4 ml tidal volume). Two methods are compared: For case A, the liquid drains by gravity into the upper airways followed by inspiration; for case B, the liquid initially forms a plug in the trachea, followed by inspiration. Experiments are continuously recorded using a microfocal X-ray source and an image-intensifier, charge-coupled device image train. Video images recorded at 30 images/s are digitized and analyzed. Transport dynamics during the first few breaths are quantified statistically and follow trends for liquid plug propagation theory. A plug of liquid driven by forced air can reach alveolar regions within the first few breaths. Homogeneity of distribution measured at end inspiration for several breaths demonstrates that case B is twice as homogeneous as case A. The formation of a liquid plug in the trachea, before inspiration, is important in creating a more uniform liquid distribution throughout the lungs.

Mitochondrial Respiration as an Early Marker of Viability in Cardiac-Arrested Rat Lungs

Background. To evaluate the possibility of using pulmonary mitochondrial respiratory functions as early markers of ischemic lung viability in non-heart-beating donors, we investigated the roles of the mitochondria in ischemia–reperfusion injury of cardiac-arrested rat lungs.Materials and methods. Male Lewis rats were exposed to various periods of postmortem warm ischemia (0, 1, and 2 h at 21°C). After a pulmonary artery flush and cold preservation (1 h at 4°C), the rat lungs were reperfused using an isolated rat lung model. Each experimental group consisted of three subgroups (n = 7 in each subgroup) to examine pulmonary functions and biochemical measurements.Results. The pulmonary functions after reperfusion were exacerbated after a 1-h postmortem warm ischemia and worsened after a 2-h warm ischemia following cardiac arrest. The mitochondrial respiratory control ratios already significantly decreased after a 1-h warm ischemia compared with nonischemic rat lungs, at which time the value was almost equivalent to that after a 2-h ischemia. There were no significant changes in the state 3 and 4 respiration of the mitochondria, the pulmonary lactate levels, or the lipid peroxide levels in the lung tissues and mitochondria during the first 1-h period of warm ischemia. The adenine nucleotide levels significantly decreased with the prolongation of the period of warm ischemia, but did not seem to be practical, because their determination required a much longer time than that of the mitochondrial respiratory control ratio.Conclusion. These results suggested that the mitochondrial respiratory control ratio may be a useful early marker for lung viability after cardiac arrest.

Keratinocyte growth factor attenuates hydrostatic pulmonary edema in an isolated, perfused rat lung model.

Hydrostatic pulmonary edema is a common complication of congestive heart failure, resulting in substantial morbidity and mortality. Keratinocyte growth factor (KGF) is a mitogen for type II alveolar epithelial and microvascular cells. We utilized the isolated perfused rat lung model to produce hydrostatic pulmonary edema by varying the left atrial and pulmonary capillary pressure. Pretreatment with KGF attenuated hydrostatic edema formation. This was demonstrated by lower wet-to-dry lung weight ratios, histological evidence of less alveolar edema formation, and reduced alveolar accumulation of intravascularly administered FITC-labeled large-molecular-weight dextran in rats pretreated with KGF. Thus KGF attenuates injury in this ex vivo model of hydrostatic pulmonary edema via mechanisms that prevent increases in alveolar-capillary permeability.

Acute versus subacute haemorrhagic shock evaluated in an isolated perfused rat lung model

Volume resuscitation of haemorrhagic shock (HS) may lead to delayed apparition of shock lung. We compared acute versus subacute grade IV HS with and without volume resuscitation in an isolated blood-perfused and ventilated lung rat model.

Pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model.

We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy. In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain: (1) a straight P-t curve (constant compliance, minimal stress); (2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P = a. tb +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O. The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found. The predictive power of coefficient b to predict noninjurious ventilatory strategy in a model of acute lung injury is high.

Dexamethasone and pentastarch produce additive attenuation of ischaemia/reperfusion lung injury

The choice of an intravenous solution for the attenuation of ischaemia/reperfusion (I/R) lung injury is still a difficult one. Although 10% (w/v) pentastarch has been used in ICU settings, its use in I/R lung injury has not been well explored. We hypothesized that this synthetic colloid substance, which maintains colloid osmotic pressure and potentially 'seals' capillary leaks, in combination with an anti-inflammatory agent (i.e. dexamethasone), would ameliorate I/R lung injury. After 60 min of lung ischaemia in an isolated rat lung model, lungs were reperfused for 60 min in a closed circulating system with one of the following solutions: (1) NS (0.9% normal saline), (2) NS+Dex (dexamethasone), (3) NS+Penta (pentastarch), or (4) NS+Penta+Dex. Haemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (K(fc)) and lung pathology were analysed. Results showed significantly lower values of K(fc) and LWG in pentastarch- or dexamethasone-perfused groups as compared with those in the NS group. Dexamethasone as an additive to NS+Penta further decreased K(fc) and LWG. Histopathological studies showed similar decreases in injury profiles. We conclude that reperfusion with dexamethasone and pentastarch can attenuate I/R lung injury, and that dexamethasone and pentastarch have additive effects. Our data thus suggest that the combination of a colloid substance with 'sealing effects' and an anti-inflammatory agent may provide a better reperfusion solution for patients with I/R lung injury or for lungs stored for transplant.

Keratinocyte growth factor prevents ventilator-induced lung injury in an ex vivo rat model.

Mechanical ventilation has been shown to produce lung injury characterized by noncardiogenic pulmonary edema. Keratinocyte growth factor (KGF) is a heparin-binding growth factor that causes alveolar type II pneumocyte hyperplasia. KGF pretreatment and the resultant pneumocyte hyperplasia reduce fluid flux in models of lung injury. We utilized the isolated perfused rat lung model to produce lung injury by varying tidal volume and the level of positive end-expiratory pressure during mechanical ventilation. Pretreatment with KGF attenuated ventilator-induced lung injury (VILI). This was demonstrated by lower wet-to-dry lung weight ratios and less lung water accumulation in the KGF group. Further, KGF prevented the decline in dynamic compliance and alveolar protein accumulation in VILI. KGF pretreatment reduced alveolar accumulation of intravascularly administered fluorescein isothiocyanate-labeled high-molecular-weight dextran. Thus, pretreatment with KFG attenuates injury in this ex vivo model of VILI via mechanisms that prevent increases in permeability.

Use of anti-(tumour necrosis factor-α) antibody or 3-deaza-adenosine as additives to promote protection by University of Wisconsin solution in ischaemia/reperfusion injury

Experimental interventions that reduce ischaemia/reperfusion (I/R) lung injury can be used to improve the properties of preservation solutions. We attempted to increase the attenuation of I/R injury by University of Wisconsin solution (UW) by adding an antibody against tumour necrosis factor-alpha (TNF-alpha), to neutralize TNF-alpha, and/or by adding 3-deaza-adenosine (c3-Ado), to inhibit leucocyte adhesion and the biosynthesis of ICAM-1 (intercellular cell-adhesion molecule 1). We examined I/R injury using an isolated rat lung model. Six different solutions were perfused individually, followed by evaluation of I/R injury: (1) 0.9% NaCl (normal saline; NS), (2) NS+anti-TNF-alpha antibody, (3) UW alone, (4) UW+anti-TNF-alpha, (5) UW+c3-Ado and (6) UW+anti-TNF-alpha+c3-Ado. Haemodynamic changes, lung weight gain, capillary filtration coefficient, TNF-alpha levels and lung pathology were analysed in order to evaluate I/R injury. Compared with lungs perfused with NS, lungs treated with NS+anti-TNF-alpha showed less I/R injury. The addition of anti-TNF-alpha and/or c3-Ado to UW reduced I/R injury compared with unmodified UW. Among the six solutions tested, UW containing anti-TNF-alpha antibody reduced I/R injury to the greatest extent. We conclude that addition of anti-TNF-alpha antibody or c3-Ado protects against I/R lung injury when using UW. Further investigation of the improved properties of modified UWs would be beneficial with regard to lung transplantation research.

Use of anti-(tumour necrosis factor-α) antibody or 3-deaza-adenosine as additives to promote protection by University of Wisconsin solution in ischaemia/reperfusion injury

Experimental interventions that reduce ischaemia/reperfusion (I/R) lung injury can be used to improve the properties of preservation solutions. We attempted to increase the attenuation of I/R injury by University of Wisconsin solution (UW) by adding an antibody against tumour necrosis factor-α (TNF-α), to neutralize TNF-α, and/or by adding 3-deaza-adenosine (c3-Ado), to inhibit leucocyte adhesion and the biosynthesis of ICAM-1 (intercellular cell-adhesion molecule 1). We examined I/R injury using an isolated rat lung model. Six different solutions were perfused individually, followed by evaluation of I/R injury: (1) 0.9% NaCl (normal saline; NS), (2) NS+anti-TNF-α antibody, (3) UW alone, (4) UW+anti-TNF-α, (5) UW+c3-Ado and (6) UW+anti-TNF-α+c3-Ado. Haemodynamic changes, lung weight gain, capillary filtration coefficient, TNF-α levels and lung pathology were analysed in order to evaluate I/R injury. Compared with lungs perfused with NS, lungs treated with NS+anti-TNF-α showed less I/R injury. The addition of anti-TNF-α and/or c3-Ado to UW reduced I/R injury compared with unmodified UW. Among the six solutions tested, UW containing anti-TNF-α antibody reduced I/R injury to the greatest extent. We conclude that addition of anti-TNF-α antibody or c3-Ado protects against I/R lung injury when using UW. Further investigation of the improved properties of modified UWs would be beneficial with regard to lung transplantation research.

Platelet activating factor acetylhydrolase decreases lung reperfusion injury

Background. Ischemia-reperfusion injury involves free radical production, polymorphonuclear neutrophil chemotaxis/degranulation, and production of proteolytic enzymes, complement components, coagulation factors, and cytokines. Activated polymorphonuclear neutrophils, endothelial cells, and macrophages produce platelet activating factor, which further promotes these inflammatory reactions. The recently cloned plasma form of platelet activating factor-acetylhydrolase (PAF-AH) demonstrates antiinflammatory effects by degrading platelet activating factor. We evaluated the effects of PAF-AH in an isolated perfused rat lung model by adding it to the flush solutions or to the reperfusion blood. Methods. Rat lungs were isolated, flushed with Euro-Collins (EC) or University of Wisconsin (UW) solution, stored at 4°C for 6 or 12 hours, and reperfused using a cross-circulating syngeneic support rat. During reperfusion, oxygenation, compliance, and capillary filtration coefficient were calculated. There were four groups in the study; group I (control) had no PAF-AH added, group II had PAF-AH added to the flush solution, group III had PAF-AH added to reperfusion blood, and group IV had PAF-AH added to both flush solution and reperfusion blood. Results. After 6 hours of storage, oxygenation, compliance, and capillary filtration coefficient significantly improved for EC in group IV. For UW, oxygenation improved in group IV whereas compliance improved in groups II, III, and IV. After 12 hours of storage, compliance improved for EC in group IV and capillary filtration coefficient improved in groups III and IV. For UW, oxygenation and compliance improved in groups II and IV, whereas capillary filtration coefficient improved in group IV. Conclusions. Addition of PAF-AH to intracellular organ preservation solutions and to the blood reperfusate significantly improves postreperfusion oxygenation and compliance, and reduces lung capillary permeability.

Early phase collagen synthesis in lungs of rats exposed to bleomycin

Skin wound healing exhibits type III collagen synthesis occurring transiently as early as 10 h after injury, with subsequent synthesis of type I to form a scar. We hypothesized that similar collagen type switching also occurred in the bleomycin model of lung fibrosis in the rat. We could measure elevated lung collagen synthesis rates as early as 4 days after administration of bleomycin. Collagen type I:III ratios in whole lung remained constant for the first 7 days at the control level of 2:1, then increased to as high as 5:1 at day 21. Procollagen mRNA content, expressed as a ratio of type I:III mRNAs, was consistent with the protein synthesis data and the observed ratio of collagen types being made by the lungs at the various time points evaluated. We conclude that a transient increase in type III relative to type I collagen does not occur in the bleomycin rat lung model. Therefore, the sequence of type-specific collagen expression and deposition in the skin wound healing model is not entirely analogous to this widely used animal model of pulmonary fibrosis.

Ropivacaine attenuates pulmonary vasoconstriction induced by thromboxane A2 analogue in the isolated perfused rat lung

Background and Objectives: Thromboxane A2 (TXA2) activation is involved in several pathophysiological states in producing pulmonary hypertension. Local anesthetics (LA) inhibit signaling of TXA2 receptors expressed in cell models. Therefore, we hypothesized that LA may inhibit pulmonary vasoconstriction induced by the TXA2 analogue U 46619 in an isolated lung model. Methods: Isolated rat lungs were perfused with physiological saline solution and autologous blood with or without the LA lidocaine, bupivacaine, ropivacaine, or the permanently charged lidocaine analogue QX 314 (all 1 μg/mL) as a pretreatment. Subsequently, pulmonary vasoconstriction was induced by 3 concentrations of U 46619 (25, 50, and 100 ng/mL) and the change in pulmonary artery pressure (Pa) was compared with each LA. In a second experiment, Pa responses to angiotensin II (0.1 μg), hypoxic pulmonary vasoconstriction (HPV, 3% O2 for 10 minutes), or phenylephrine (0.1 μg) were assessed to determine the specificity of ropivacaine effects on TXA2 receptors. Finally, reversibility of pulmonary vasoconstriction was determined by adding ropivacaine to the perfusate after pulmonary vasoconstriction was established with U 46619. Results: Ropivacaine, but not bupivacaine, lidocaine, or QX 314 significantly attenuated pulmonary vasoconstriction induced by 50 ng/mL U 46619 (35.9%, P < .003) or 100 ng/mL U 46619 (45.2%, P < .001). This effect of ropivacaine was likely to be specific for the thromboxane receptor because pulmonary vasoconstriction induced by angiotensin II, HPV, or phenylephrine was not altered. Ropivacaine did not reverse vasoconstriction when it was administered after U 46619. Conclusions: Ropivacaine, but not lidocaine, bupivacaine, or QX 314 at 1 μg/mL, attenuates U 46619–induced pulmonary vasoconstriction in an isolated perfused rat lung model. These results support evidence that the clinically used enantiomer S(-)-ropivacaine may inhibit TXA2 signaling. Reg Anesth Pain Med 2000;25:187-194.