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Lungs from rabbits sensitized to ovalbumin or bovine gamma-globulin were isolated and perfused with autologous blood. The response to antigen challenge via the perfusate was immunologically specific and characterized by a marked increase in perfusion resistance, a moderate increase in airway resistance and a small decrease in lung compliance. The response could also be elicited by specific antigen challenge in lungs from sensitized rabbits perfused with blood from normal rabbits and in lungs from normal rabbits perfused with blood or plasma from sensitized rabbits. The magnitude of the response was greater when blood or plasma from sensitized animals was used as the perfusate. Therefore, blood and/or plasma factors appear to be the major contributors to the response.

We examined the influence of the size of emboli on the vascular volume (QL) and extravascular volume (Qev) accessible to 3HOH during a single pass through an isolated dog lung lobe using the double indicator-dilution method with 125I-human serum albumin as the vascular indicator. As successively more beads of a given diameter (58, 548, or 3,175 microns) were introduced into a lung lobe, a linear relationship between QL and Qev was obtained as they both decreased. The slope of the graph of QL vs. Qev with progressive embolism was directly proportional to the bead diameter. This suggested an approach for estimating the total vascular volume in vessels smaller than the diameter of the beads before embolization, referred to as Qm. If it is assumed that most of the transvascular diffusional exchange of 3HOH occurs in vessels smaller than the smallest beads (mainly capillaries) and that vessel obstruction does not change the ratio of Qev to the perfused capillary volume, the slope of the plot of QL vs. Qev is an estimate of the fraction, Qm/QL, of the total vascular volume in vessels smaller than the bead diameter. In the dog lung lobes studied, Qm/QL was approximately 0.64 for 58-microns vessels, 0.75 for 548-microns vessels, and 0.82 for 3,175-microns vessels. The results suggest that, with occlusion of vessels greater than or equal to 58 microns, 3HOH does not diffuse significantly into unperfused regions.(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred strains were referred to us for identification because they apparently could not be identified satisfactorily with the API 20E system (appareils et procédés d'identification). The inability to identify 31 strains was due primarily to failure to follow the manufacturer's instructions. Twenty six further strains were found to have been correctly identified by the sender's own API 20E results, so that only the remaining 43 strains definitely fell into the category for which our identification service was intended. Eighteen of the 43 strains not identified by the sender were identified by us using the API 20E system, and several possible reasons are given to explain the differences in these results. The remaining 25 strains either could not be identified by us on the API 20E system or, in the case of 13, they could not be identified by our conventional system and therefore no comparison could be made. The average interlaboratory probability of errors for the API 20E tests was 6.1%.

Given the pH dependence of enzymes in general and the potential importance of a blood and alveolar gas composition dependency on the interpretation of changes in the hydrolysis of angiotensin-converting enzyme (ACE) substrates by pulmonary endothelial ACE, we examined the influence of Pco2 and Po2 on the hydrolysis of a synthetic ACE substrate (benzoyl-phenylalanyl-alanyl-proline, BPAP) on passage through isolated rabbit lungs. Perfusate pH values of about 7.1, 7.4, and 7.9 were obtained by ventilating the lungs with gas containing different CO2 concentrations and Po2 values of approximately 110 and approximately 10 Torr were obtained by varying the concentration of O2 in the ventilating gas mixture. In the range studied neither acidosis nor alkalosis produced any significant changes in BPAP hydrolysis or in the kinetic parameters, Vmax and Km, for the hydrolysis process. On the other hand, a reduction in BPAP hydrolysis was detected when the Po2 was reduced from 110 to 10 Torr. The Vmax for BPAP hydrolysis by the lung was inversely correlated with the magnitude of the hypoxic vasoconstriction that occurred, suggesting that the reduced BPAP hydrolysis with hypoxia was due to the loss of perfused surface area due to the vasoconstriction. The results suggest that correlations between Pco2 and/or pH and whole-lung ACE activity that might occur in diseased lungs do not imply causalty. The hemodynamic consequences of changing Po2 (i.e., hypoxic vasoconstriction) may alter whole-organ ACE activity in the sense of changing the perfused surface area (i.e., the amount of ACE in contact with flowing perfusate).

To determine the influence of pulmonary vasoconstriction on lung tissue perfusion, we examined the effects of hypoxia, sympathetic nerve stimulation, and histamine on vascular resistance, blood, and extravascular volumes, weight, and the distribution of vascular transit times in dog left lower lung lobes perfused in situ. Hypoxia, sympathetic stimulation, and histamine increased pulmonary vascular resistance by 1.96, 1.42, and 2.02 times and increased the relative dispersion of the transit time distributions by 1.49, 1.30, and 1.71 times the control values, respectively. Hypoxia and sympathetic stimulation tended to decrease the blood volume accessible to indocyanine green dye and the lobe weight. On the other hand, histamine infusion, which also decreased the volume accessible to the dye, increased the lobe weight. Despite this increase in weight, histamine infusion resulted in a decrease in the extra-vascular volume accessible to 3HOH. These results indicate that these vasoconstrictor stimuli increased the heterogeneity of transit times through the lung lobe and decreased the flowing blood volume. In addition, histamine decreased the size of the perfused microvascular bed, indicating that pulmonary vasoconstriction can influence the local pattern of microvascular perfusion.

Previously we found that raising cerebrospinal fluid pressure (PCSF) caused pulmonary vasoconstriction mediated by adrenal catecholamines. To localize the site of this vasoconstriction we used the outflow occlusion technique to divide changes in the pulmonary arteriovenous pressure gradient (Pa-v) into upstream and downstream pressure drops. Experiments were conducted in 10 dogs in which the animal's left lower lung lobe was denervated and perfused at constant flow and outflow pressure with blood pumped from the dog's pulmonary artery. Raising PCSF to 218 Torr caused Pa-v to rise from 9.0 to 12.5 Torr. Most (83%) of this increase resulted from an increase in the downstream pressure drop. Previous studies have indicated that changes in the upstream and downstream pressure drops, as measured by this technique, are highly correlated with changes in the resistance of the arterial and venous sides of the vascular bed. Thus, it appears that elevated PCSF caused primarily pulmonary venoconstriction. Similar results were obtained with norepinephrine and epinephrine infusion. This is consistent with previous studies, indicating that adrenal catecholamines are responsible for the increase in Pa-v in response to PCSF in this preparation.

We examined the influence of glass bead embolization and oleic acid, dextran, and imipramine infusion on the pulmonary uptake of trace doses of [3H]serotonin and the extravascular volume accessible to [14C]antipyrine in anesthetized dogs. Embolization and imipramine decreased serotonin uptake by 53 and 61%, respectively, but no change was observed with oleic acid or dextran infusion. The extravascular volume accessible to the antipyrine was reduced by 77% after embolization and increased by 177 and approximately 44% after oleic acid and dextran infusion, respectively. The results suggest that when the perfused endothelial surface is sufficiently reduced, as with embolization, the uptake of trace doses of serotonin will be depressed. In addition, decreases in serotonin uptake in response to imipramine in this study and in response to certain endothelial toxins in other studies suggest that serotonin uptake can reveal certain kinds of changes in endothelial function. However, the lack of a response to oleic acid-induced damage in the present study suggests that serotonin uptake is not sensitive to all forms of endothelial damage.

The arterial and venous pressure curves obtained after occluding the venous outflow from a dog lung lobe perfused with constant flow contain information about the intralobar longitudinal distribution of vascular resistance (R) and compliance (C). To utilize this information, a lumped model consisting of four parallel C's separated by three serial R's was used. Solutions of the governing differential equations yield a nonlinear system of four algebraic equations in the seven unknowns and the measured data. Three of the equations form a linear subsystem in which the unknowns are the three R's and the coefficients are functions of the four C's. This is an underdetermined system, but when nonnegativity and boundedness constraints are adjoined, the solution set falls within a narrow band of distributions of cumulative R relative to cumulative C. The shape of this band changes when data are obtained from lobes influenced by various vasoactive stimuli revealing the changes in the longitudinal distribution of the vascular resistance relative to the vascular compliance.

The present study was carried out to begin to evaluate the saturable kinetics of the hydrolysis of a synthetic substrate, benzoyl-phenylalanyl-alanyl-proline (BPAP), for angiotensin-converting enzyme (ACE), by the pulmonary endothelium of the dog using a multiple indicator dilution method. In the experiments, isolated dog lung lobes were perfused with a salt solution containing 5% bovine serum albumin. Boluses containing [3H]BPAP, and various amounts of unlabeled BPAP were injected into the lobar artery, and timed samples of venous effluent were collected. The samples were analyzed to determine the fractional hydrolysis of the injected BPAP. The BPAP hydrolysis on passage through the lungs exhibited the saturable behavior and the relative insensitivity to changing flow rate previously described. Since we have described previously that BPAP behaves as if it exists in two forms, one of which is virtually unhydrolyzable on a single pass through the lungs, a model was formulated to include the influence of the unhydrolyzable form, as well as the saturable hydrolysis of the hydrolyzable form, on the fractional hydrolysis of the injected BPAP. This model provides a new method for estimating the kinetic parameters of BPAP hydrolysis by pulmonary endothelial ACE, and it explains the observation that the fractional BPAP hydrolysis does not vary with flow rate and transit time to the extent predicted by previous models.

Intrapulmonary instillation of proteins into rabbit lungs with BCG-induced granulomatous inflammation results in greater transport of these molecules into the blood, and the primary route is probably the pulmonary lymphatics. In addition, rabbits with inflamed lungs develop a more potent systemic immune response when exposed to soluble antigens as an aerosol. The current study was done to further study the mechanisms of this phenomenon using the Jerne plaque technique. Intrapulmonary immunization with soluble antigens (solubilized SRBCs and HSA) resulted in a greater PFC response to both antigens when the lungs exhibited BCG-induced granulomatous inflammation. A previous study demonstrated that more antigen administered intratracheally was found in the HLNs when the lungs displayed granulomatous inflammation. However, in the present study, we did not observe an enhanced PFC response in HLN cells when antigens were introduced into inflamed lungs. When rabbits with BCG-inflamed lungs were immunized i.v., they did not develop an enhanced PFC response in the spleen. Immunization into the respiratory tract of normal rabbits with large doses (300 micrograms) of soluble antigens also resulted in a substantial PFC response in the spleen that was quantitatively greater than that induced by the same i.v. dose. These data indicate that (1) administration of antigens into inflamed lung results in an enhanced systemic immune response, (2) although larger quantities of soluble antigens administered by the pulmonary route accumulate in the HLN when lungs are inflamed, cells from this tissue do not exhibit an enhanced PFC response, and (3) large doses of soluble antigens instilled into normal lungs induce a greater systemic immune response that the same doses administered i.v. This study further demonstrates the importance of pulmonary inflammation and the immune response to inhaled antigens and provides insight as to how individuals with chronic inflammatory lung disease can react in an augmented fashion to environmental antigens.

The objectives of this study were to develop a surgical procedure that would allow for bilateral isolated lung perfusion in vivo as a means of delivering organ-specific chemotherapy and to evaluate the influence of the procedure on certain pulmonary physiologic parameters. The sterile surgical procedure that was carried out in dogs involved the setting up of two separate perfusion circuits. Once standard systemic cardiopulmonary bypass was established, a second circuit was devised to perfuse the lungs by placing an inflow cannula into the main pulmonary artery and collecting venous effluent in the left atrium. Cross-contamination between perfusion circuits was determined in acute studies with labeled plasma protein or red blood cells and was found to be in an acceptable range if the aorta was cross-clamped and the heart arrested. Only about 0.4 ml/min of pulmonary perfusate leaked into the systemic circulation, indicating that systemic toxicity should not be a major concern when chemotherapy agents are added to the pulmonary perfusate. Chronic studies demonstrated that hemodynamic parameters, lung water, pulmonary endothelial serotonin extraction, and histologic findings all showed minimal changes after 50 minutes of isolated lung perfusion. Five days after perfusion, lung dynamic compliance and peak serotonin extraction showed significant decreases. However, all of the measured parameters had returned toward baseline levels by the end of the 8-week postoperative study period. The procedure offers significant advantages over the previously described single lung perfusion and may provide a method of delivering immediate high-concentration adjuvant chemotherapy to coincide with resection of primary or metastatic lung tumors.

Fractional hydrolysis (M) of the synthetic angiotensin-converting enzyme (ACE) substrate [3H]benzoyl-Phe-Ala-Pro (BPAP) on passage through the isolated dog lung lobe was found to be relatively independent of flow rate and transit time (t). The most commonly expressed explanation for this kind of observation is that recruitment of ACE-containing surface area occurs when flow is increased. To test this, as well as other hypotheses that might explain the behavior of this substrate, we compared M obtained after the first pass of a BPAP-containing bolus through isolated rabbit lungs with that obtained after two sequential passes through the lungs. In this way, we could double t with no change in flow or vascular pressure. We found that, when the second pass occurred within a few seconds of the first, M after both the first and second pass was only slightly larger than that after the first pass alone. If the time between passes was increased to a few minutes, M after the second pass was substantially increased. These results are contrary to the recruitment hypothesis and suggest that this substrate may exist in alternative forms that are in slow equilibrium relative to the capillary t. When albumin was present in the perfusate, an albumin-bound fraction appeared to be one such alternative form. However, experiments carried out using protein-free perfusate suggest the possibility that conformational variants of the substrate may also exist.

The ether- and dye-dilution methods were used to estimate the arterial, capillary, and venous volumes and compliances in isolated dog lung lobes. In the range of arterial pressure from approximately 7 to 14.5 Torr and venous pressure of 1.4 to 10.8 Torr, the total lobar blood volume ranged from approximately 2 to approximately 2.6 ml/kg body wt. About 19% of the lobar vascular volume was in the arteries, approximately 59% was in the capillaries, and approximately 22% was in the veins. The lobar vascular compliance was approximately 0.065 ml.Torr-1.kg body wt-1 with an arterial-capillary-venous distribution of approximately 30:49:21. These results suggest that the largest fractions of the intralobar blood volume and compliance are in the capillary bed. The segmental compliances along with outflow occlusion data were used to place lower and upper bounds on the arterial, capillary, and venous resistances. These bounds were 13.6 and 61.4% of the total vascular resistance for the arteries, 0 and 59.4% for the capillaries, and 5.5 and 64.9% for the veins, respectively. These bounds are rather broad, but they help to put the information content of the occlusion data under the conditions of these experiments into perspective.

The first pass uptake of fentanyl in the human lung was studied in two groups of patients using a double indicator dilution technique. A bolus containing fentanyl and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of fentanyl taken up by the lung during the first pass and the instantaneous extraction of fentanyl at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. In patients who had been receiving no other drugs prior to the experiment, the total first pass uptake (mean +/- SE) of fentanyl was 82.6% +/- 1.4% of the injected dose. In patients who had been receiving 30-120 mg/day of propranolol the total first pass uptake (mean +/- SE) of fentanyl decreased to 52.8% +/- 6.3% of the injected dose. In one patient on 120 mg of propranolol per day, first pass uptake of fentanyl was only 20.3% of the injected dose. Additional studies in a rat isolated perfused lung preparation coperfused with fentanyl and propranolol also demonstrated that one basic lipophilic amine (propranolol) could inhibit the pulmonary uptake of a second basic lipophilic amine (fentanyl). The high first pass uptake of fentanyl in the human lung limits the rate of entry of this drug into the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

We previously presented a model from which the kinetic parameters Km and Vmax for serotonin uptake by the lung can be obtained from multiple indicator-dilution data. The purpose of the present study was to determine whether experimentally induced changes in lung endothelial function would be revealed in the kinetic parameters calculated using the model. In experiments using isolated dog lung lobes, embolization with 550-microns glass beads was used to reduce the vascular volume and perfused surface area. Imipramine was used to inhibit the serotonin uptake mechanism. In addition, we studied the influence of the vasodilator papaverine, which in previous studies had been used to block the serotonin-induced vasoconstriction. Embolization, imipramine, and papaverine all significantly reduced percentage uptake of serotonin. The kinetic analysis revealed a significant decrease in the maximum serotonin uptake rate (Vmax) with all three experimental manipulations. In addition, imipramine significantly increased Km. The results indicate that the kinetic parameters obtained from the model do respond to transport inhibition and changes in endothelial surface area, further supporting their usefulness as indexes of endothelial function.

This study was performed to determine whether the lung histological changes which occur in rabbits following intravenous injection of killed Bacilli Calmette-Guérin (BCG) are accompanied by measurable changes in pulmonary function. We measured pulmonary function in New Zealand white rabbits 3 weeks after intravenous injection of BCG and in normal rabbits. After a tracheostomy and carotid artery catheterization was performed, each anesthetized rabbit was placed in a body plethysmograph for pulmonary function testing. Following the measurements, the lungs were removed for weighing and histological evaluation. In the BCG-treated rabbits, the lung weight/body weight ratios were 152% greater, the pulmonary resistance was 104% higher, dynamic compliance was 45% lower, minute ventilation was 28% greater, and the delta AaPO2 gradient was 13 torr higher than in the normal control rabbits. Histological evaluation of the BCG-treated animals revealed diffuse pulmonary involvement with non-caseating granulomas.

Isolated perfused rabbit lungs were insufflated with 125I-labeled bovine serum albumin (125I-BSA) and the accumulation of radioactive BSA and its breakdown products was measured in the blood. The addition of anti-BSA serum to the blood caused a 4- to 6-fold reduction in the amount of 125I-BSA which appeared in the blood following the insufflation. To determine whether this reduction was the result of inhibition of absorption or the reuptake of 125I-BSA antigen-antibody complexes formed in the blood, we infused the 125I-BSA into the anti-BSA containing blood perfusing the lungs. Virtually none of the radioactivity was taken up by the lungs, indicating that the reduced blood levels following insufflation were the result of reduced absorption through the lung resulting from antigen-antibody interaction within the alveolocapillary membrane or the bronchoalveolar secretions.

In this study, we investigated the possibility that the adrenal gland contributes to nicotine-induced pulmonary hypertension using a canine left lower lung lobe (LLL) preparation that was pump-perfused with mixed venous blood at constant flow and outflow pressure. Main pulmonary artery, left atrial, and LLL arterial pressures were monitored to assess the responses of the animal's intact right lung and isolated LLL. With the adrenal venous return intact, injection of 10-26 micrograms/kg nicotine into the left ventricle or ascending aorta resulted in a 42% increase in LLL arterial pressure and a 70% increase in the pulmonary arterial-left atrial pressure gradient (Ppa-Pla). When the adrenal venous return was interrupted, the increases in LLL arterial pressure and Ppa-Pla were reduced to 6 and 10%, respectively. The LLL response could be eliminated by alpha-adrenergic receptor blockade, suggesting that adrenal catecholamines may contribute to the pulmonary hypertension induced by nicotine infusion.

In this study we investigated the possibility that a circulating vasoactive agent contributes to the pulmonary hypertension elicited by elevated cerebrospinal fluid pressure (PCSF) using a denervated canine left lower lung lobe (LLL) preparation that was pump perfused with mixed venous blood at constant flow and venous pressure. Raising the PCSF to an average 190 Torr resulted in a 34.3% increase in LLL inflow pressure. This response was eliminated by adrenal venous occlusion and also by alpha-blockade of the LLL. The results indicated that adrenal catecholamines were responsible for the LLL response. The passively induced elevation of left atrial pressure (Pla) that occurs in the intact animal during elevated PCSF was stimulated in the LLL by raising the outflow pressure. This maneuver attenuated the increase in LLL vascular resistance and suggested that the elevation in Pla seen in the intact animal could mask humorally mediated responses of the magnitude we observed.

The single-pass, bolus-injection method was used to study the effect of serotonin (5-HT) concentration on the extraction of 5-HT by isolated perfused rabbit lungs. The extraction pattern suggested that an uptake model, which includes multiple parallel uptake processes, provided a better representation of the data than the simple Michaelis-Menten equation, which has commonly been used to fit the saturable uptake data in previous studies. In particular, the rabbit lung data could be fit with two such parallel pathways. Since the 5-HT uptake could virtually be completely blocked by imipramine, both pathways can be considered to be carrier-mediated processes. The high-affinity pathway was saturable within the range of concentrations studied, with a Km and Vmax of approximately 0.84 microM and 0.21 nmol.s-1.g wet lung wt-1. The Km for the low-affinity pathway was larger than concentrations for which accurate uptake measurements are practical in the perfused organ. Thus, for the low-affinity pathway, only Vmax/Km was identifiable. Vmax/Km values for the high- and low-affinity pathways were approximately 2.87 and 0.35 ml/s, respectively. The results suggest that it will be worthwhile to investigate the behavior of these uptake parameters in response to changes in lung physiology and endothelial function in future studies.

Rapid occlusion of the venous outflow from a lung lobe perfused with constant flow causes the arterial and venous pressure to increase with time. Pressure values obtained by linear extrapolation of the nearly linear portions of the resulting arterial and venous pressure versus time curves back to the instant of occlusion provide data which can be used to place limits on the actual unknown distribution of resistance versus compliance. This has been proven deductively for the case of compartmental models having a small number of resistances and compliances. For compartmental models having a large number of resistances and compliances approaching a continuous distribution, an inductive approach was used in which a large number of simulations indicated that the actual continuous distribution is confined by the experimental data to the same limits as those for the small number of resistances and compliances.

The kinetics of the pulmonary endothelial uptake of serotonin (5-HT) were evaluated in isolated dog lung lobes using three methods. In method A serotonin was infused at various constant rates to provide a range of capillary concentrations that included Km. The arterial and venous concentrations measured by high-performance liquid chromatography were then used to determine the effect of concentration on the rate of 5-HT uptake. In method B trace doses of 5-[3H]HT and a reference indicator (indocyanine green dye) were injected during each constant infusion of unlabeled 5-HT to provide a measure of unidirectional 5-HT uptake at each background concentration. In method C boluses containing different amounts of unlabeled 5-HT, along with the 5-[3H]HT and the dye, were injected such that each bolus resulted in a range of concentrations and provided a measure of the unidirectional uptake at each concentration. Each method provided the data needed to calculate the maximum uptake rate (Vmax) and the concentration at Vmax/2 (Km), assuming that the uptake kinetics can be represented by the Michaelis-Menten equation. However, the mathematical model underlying each method involved different assumptions about the returning flux of the 5-HT which entered the endothelial cell and the heterogeneity of vascular transit times. The results obtained, considered in light of the different assumptions involved, indicate that all three methods can provide reasonable estimates of the mass transfer kinetic constants if the constant infusions of 5-HT are of short duration and/or the boluses are adequately dispersed prior to reaching the capillary bed.

Serotonin extraction following a bolus injection of serotonin and a nonpermeating indicator into the pulmonary artery can be evaluated using a model that represents the saturable uptake of serotonin by Michaelis-Menten kinetics. By use of this model Km, Vmax, and a perfusion parameter, alpha, can be determined by multiple linear regression analysis of the time-concentration data. Kinetic and perfusion parameters were obtained using data from isolated dog lung lobes in which plasma flow rate was changed by changing the pump flow rate in blood- or plasma-perfused lobes or by keeping the pump flow rate constant and removing the blood cells. The calculated Vmax was reproducible and flow independent over the range of flow rates used in the study. The calculated Km was more sensitive than Vmax to small variations in experimental data and was independent of flow at flow rates greater than about one-half the normal cardiac output per gram of lung tissue. The perfusion parameter alpha was lower in the plasma-perfused lobes, reflecting more homogeneous perfusion in the absence of cells. The results suggest that this approach will be useful for separating changes in the kinetics of serotonin uptake by endothelial cells from effects of changes in flow and perfusion heterogeneity.

The systemic appearance of radioiodinated proteins (125I-OA and 131I-HSA) administered via the respiratory route was studied in normal rabbits and in rabbits with BCG-induced chronic granulomatous pulmonary inflammation. The proteins were administered by i.t. injection into intact rabbits and into rabbits with tracheal cannulas or as an aerosol into isolated perfused lungs. The results showed that radioactivity appeared in the circulation as two fractions, one that was precipitables with 5% TCA and therefore protein-bound and one that was soluble in TCA. In both intact and tracheostomized animals, significantly more protein-;ound radioactive iodine was detected in the circulation of BCG-treated animals than in normal animals as early as 15 min after i.t. injection, and the differences persisted from 2 to 4 hr. However, in the isolated perfused lung, in which the only route for protein uptake into the circulation was the alveolocapillary barrier, only minimal differences in blood protein levels were observed as compared to normal BCG-inflamed lungs. This study suggests that chronic pulmonary inflammation promotes the absorption of i.t.-injected protein into the circulation, and that the route of enhanced uptake into blood is not the alveolocapillary membrane.

We found that when 15-keto-PGE1 was added to cat blood, it was converted to 13, 14-dihydro-15-keto-PGE1 (dihydro-keto-PGE1) by a NADH-dependent enzyme associated with some formed element(s) in the blood. When PGE1 was injected into the pulmonary artery of blood-perfused lungs, the only metabolite detectable in the pulmonary venous blood was the dihydro-keto-PGE1. However, when the lungs were perfused with an artificial perfusate containing no blood cells, a small amount of 15-keto-PGE1 was detected in the venous effluent. Therefore it would appear that a blood-borne delta13 reductase was partially responsible for the conversion of PGE1 to dihydro-keto-PGE1 on passage through blood-perfused cat lungs.

Apnoeic left lower lobes of dog lungs were inflated by increasing alveolar pressure or decreasing pleural pressure, or the lobes were collapsed and exposed to decreasing pleural pressure with the bronchus occluded. Under each of these conditions the lobe could be made 'hypoxic' by perfusion with mixed venous blood or 'normoxic' by perfusion with systemic arterial blood. Inflation of the lobes diminished the hypoxic presor response. The relative influence of decreasing pleural pressure on inflated and collapsed lobes was such that at low pleural pressures resistance to flow through the hypoxic atelectatic lobe was no greater than that through the inflated normoxic lobe. The results indicated that the level of lung inflation can alter the effectiveness of the hypoxic pressor response in reducing perfusion to underventilated regions.

We have examined the influence of hypoxia on the longitudinal distribution of vascular resistance and intravascular pressure in isolated cat lungs using the low-viscosity bolus technique. Hypoxia increased total vascular resistance, decreased total lung blood volume, and moved the maximum local resistance downstream away from the main pulmonary artery. The circumference of the main pulmonary artery was increased and the extravascular lung water (double indicator dilution technique) was decreased by hypoxia. Thus, it would appear that distension of the large pulmonary arteries and a decrease in the amount of lung tissue perfused contributed to the change in resistance distribution brought about by hypoxia.

A multiple indicator dilution technique was used to study inactivation of [14C]prostaglandin E1 (PGE1) by isolated cat lungs. A bolus containing [2-14C]PGE1, indocyanine green dye and 3HOH was rapidly introduced into the blood entering the pulmonary artery. Sequential samples of the venous effluent were collected and analyzed for 3H, dye, and 14C. The 14C-labelled compounds were separated by thin-layer chromatography, and the quantity of PGE1 and its metabolites contained in each sample was determined (radiochromatogram scanning). Recovery of the dye and 3H was complete within the sampling period. However, only 79% of the injected 14C emerged from the lung within this period, 36% as [14C]PGE1, and 43% as two less polar metabolites. The mean transit times (including connecting tubing) for the unmetabolized [14C]PGE1 and the dye were 9.1 and 8.7 s, respectively. The apparent mean transit times for 14C in the metabolites were considerably longer, 12.4 and 14.3 s. The 3HOH mean transit time was 10.7 s. These data are compatible with an extraluminal site for PGE1 metabolism.

The pulmonary uptake of 1-alpha-acetylmethadol (LAAM) and methadone was studied during a single pass through the isolated perfused rat lung (IPL). The IPL was perfused for 10 min with perfusate containing various concentrations of one of the radiolabeled drugs, followed by a 30-min drug-free perfusion and the amount of radioactivity in the pulmonary venous effluent was used to estimate uptake and efflux of the drugs with time. Both drugs were extensively taken up by the IPL; however, LAAM uptake was significantly greater than that of methadone. The amount of each drug taken up was a nonlinear function of concentration in the perfusate, suggesting saturability of the major uptake processes. During drug-free perfusion LAAM and methadone previously accumulated were released from the lung at two different efflux rates; however, a third, more rapid efflux process for methadone was also evident. The total venous effluent collected during the drug-free perfusion contained a significantly greater fraction of the accumulated methadone as compared to LAAM. Calculation of the total amount of each drug effluxable at the observed rates indicated that another pool for both drugs existed in the lung that did not efflux at an observable rate. The accumulated LAAM remaining in this "slowly effluxable pool" was significantly greater than methadone. These data demonstrate a greater pulmonary uptake and tissue sequestration of LAAM as compared to methadone, and may be one of the contributing factors in the persistence of LAAM and its active metabolites in the body.

Isolated cat lungs were perfused with constant blood flow. During control conditions (Pa02, 100 Torr), pulmonary artery pressure increased as the lungs were inflated. Hypoxia (Pa02, 22 Torr) increased arterial pressure. However, as the lungs were inflated arterial pressure fell. Thus, the magnitude of the hypoxic pressor response was reduced by inflation. During control conditions, arterial volume (ether bolus method) increased with increasing transpulmonary pressure. Hypoxia decreased arterial volume, and the increase in arterial volume with inflation was somewhat less than that during control conditions. When the influences of vascular and transpulmonary pressures were examined independently by changing one while holding the other constant, increasing transpulmonary pressure increased arterial volume beyond that which could be accounted for by changes in the differences between arterial and pleural pressure. However, this influence of transpulmonary pressure did not appear to be altered by hypoxia. Thus, while hypoxia decreased arterial volume at all levels of lung inflation, it had relatively little effect on the influence of interdependence between the pulmonary arterial bed and the surrounding lung tissue.

In this paper we present two methods which can be used to numerically deconvolve indicator dilution curves to obtain vascular transport functions. In the first method, direct algebraic deconvolution is made stable and practical by the damped least squares method. The second method involves a time-shift of the output curve which is based on the first and second moments of the input and output curves. This method is stable, computationally simple and can provide reasonable estimates of the transport function.

Angiotensin-converting enzyme (ACE) activity of the cerebral microcirculation of anesthetized dogs was measured from cerebral venous outflow curves after bolus injection of a synthetic ACE substrate, [3H]benzoyl-phenylalanyl-alanylproline ([3H]BPAP), into a common carotid artery. Cerebral BPAP metabolism was quantified by measuring the concentration of [3H]benzoyl-phenylalanine (the product of BPAP hydrolysis by ACE) in blood samples from the sagittal sinus after occlusion of the lateral sinuses with bone wax. Instantaneous BPAP metabolism in each sample increased as a function of time after injection, suggestive of perfusion heterogeneity, and averaged 59 +/- 4% (n = 8) over a single pass during normoxia and normocapnia. The ratio of Vmax (the maximal rate of cerebral BPAP metabolism) to Km (the concentration at Vmax/2), was calculated from instantaneous outflow curves using a model based on first-order kinetics. Increases in cerebral blood flow during either hypoxia or hypercapnia significantly reduced BPAP metabolism to 33 +/- 3 (n = 7) and 24 +/- 3% (n = 5), respectively; however, Vmax/Km of ACE activity (0.19 +/- 0.03 ml/s) was not affected by either condition. The lack of change in apparent kinetics of ACE activity (i.e., in Vmax/Km) during hypoxia or hypercapnia suggests that recruitment of cerebral capillaries was not a quantitatively significant factor in controlling BPAP metabolism with this degree of either hypoxia or hypercapnia.

We examined the influence of changing outflow pressure, P out, on the vascular and extravascular volumes (QV and QEV, respectively, as measured by indicator dilution) and on the outflow occlusion pressures in isolated dog lung lobes perfused with constant flow. Changing P out had a substantial effect on QV, but not on QEV, whether P out was less than or greater than alveolar pressure, PA. Since QEV did not change with QV, recruitment of previously unperfused vessels did not appear to contribute substantially to the increases in QV when P out was increased. The rapid jump in P out immediately following outflow occlusion was virtually independent of the difference between PA and P out suggesting that the alveolar vessels were an important volume storage site when P out was low relative to PA. We conclude that, over a certain range of pressures, alveolar vessel volume can be controlled by venous pressure even when the change in venous pressure has little effect on arterial pressure (zone 2). Further, we conclude that in zone 3 and within the transition from zone 2 to zone 3 increases in the intralobar blood volume occurring within the alveolar vessels may not require recruitment in the sense of opening of previously unperfused vessels.

Certain substrates are rapidly taken up and/or metabolized by pulmonary endothelial cells in a saturable process. When such a substrate and a reference indicator are included in a bolus which is injected into the blood flowing into the lung, the extraction ratio, E(t), curves measured in the pulmonary venous outflow are asymmetric with respect to the reference indicator curve. If a sufficient quantity of substrate is included in the bolus, the extraction curves are concave upward. The shapes of the E(t) curves contain information regarding the chemical-physical processes which govern the fate of the substrate during its single passage through the lung. To interpret the shapes, computer simulations are used to illustrate separately the effects of the uptake of substrate into the cell, the returning flux of the substrate from the cell, the saturation phenomena of the extraction process, and the perfusion heterogeneity of the capillaries. Lastly, a simple analytical method for estimating the organ kinetic parameters of the extraction process is presented.

Six hundred and twenty one strains (555 Enterobacteriaceae, 46 Vibrionaceae, and 20 Acinetobacter) were examined in the Mast system. The results were consulted in the code book supplied by the manufacturer and those not listed were processed through the manufacturer's full database held on an Apricot microcomputer in our laboratory. The proportion of strains correctly identified was 88%, with 9% not identified, and 3% incorrectly identified.

The influence of plasma albumin binding of the synthetic angiotensin-converting enzyme (ACE) substrate [3H]benzoyl-phenylalanyl-alanyl-proline (BPAP) on BPAP hydrolysis by pulmonary endothelial ACE was studied in isolated rabbit lungs perfused with a salt solution containing either 5% bovine serum albumin (BSA) or 5% dextran. The single-pass indicator-dilution method was used to measure the fraction (M) of [3H]BPAP hydrolyzed. Lung M was greater with albumin-free perfusate than when BSA was present. M decreased as the time (ti) that the BPAP was in contact with the BSA before reaching the lung was increased, suggesting that some BSA binding sites for BPAP were not in equilibrium during bolus transit through the lungs. The M vs. ti data were correlated using a model incorporating both rapid and slow binding kinetics of BPAP and BSA. For the slow BPAP-BSA interaction, the dissociation rate constant was approximately 0.015 s-1, and the fraction of the BPAP bound to these slowly equilibrating sites at equilibrium was approximately 22%. The results indicate that transient plasma protein binding kinetics can affect lung BPAP hydrolysis.

The first pass uptake of fentanyl, meperidine, and morphine in human lung was studied in patients using a double indicator dilution technique. A bolus containing one of the drugs and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia for surgery. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of drug taken up by the lung during the first pass and the instantaneous extraction of drug at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. The total uptake (mean +/- SE) during the first pass through the human lung for fentanyl and meperidine was 75.2 +/- 3.2% and 64.7 +/- 7.8% of the injected dose, respectively. The pulmonary uptake of morphine was very small, with 96.5 +/- 7.1% of the injected dose recovered in arterial blood after the first pass through the lung. The arterial blood concentration of drug and dye versus time showed a slight delay of the fentanyl and meperidine peaks compared to ICG. It was also observed that greater than 90% of these drugs were extracted from the blood in the early part of the first pass, but the extraction decreased with time during the first pass through the lung. These findings indicate that some of the drug taken up by the lung can diffuse back out into the blood.2+off

We have attempted to evaluate some approaches for estimating pulmonary capillary pressure from the transient pressure data obtained from the tip of the Swanz-Ganz catheter after inflation of the balloon. To this end experiments were carried out in anesthetized dogs in which pulmonary vasoconstriction was induced by infusion of histamine, serotonin, or norepinephrine or by hypoxia. In a group of closed chest dogs, the time course for the fall in the catheter tip pressure toward the wedge pressure was different for the different vasoconstrictors. For example, during histamine infusion the fall in pressure was slow, whereas during serotonin infusion it was rapid. To evaluate the information in the decay curves, a group of dogs was studied with open thorax to permit the simultaneous occlusion of both the artery and vein of one lung lobe (double occlusion) as well as occlusion of the lobar artery alone (arterial occlusion). The pattern of response to the various vasoconstrictors observed with lobar arterial occlusion was similar in these animals to the closed chest animals. The equilibrium pressure after double occlusion (the double occlusion pressure), expressed as a fraction of the mean arterial-venous pressure difference before occlusion, was correlated with the mean decay time of the arterial pressure curve after arterial occlusion. We also found significant correlations between the double occlusion pressure and the estimates of capillary pressure based on model interpretations of the pressure decay curve after arterial occlusion. However, there was wide scatter in the individual comparisons.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the influence of stellate ganglion stimulation, hypoxia, and the infusion of norepinephrine, PGF2alpha, serotonin, and histamine on the longitudinal distribution of vascular resistance and intravascular pressures in an isolated left lower lobe of the dog lung using the low-viscosity bolus technique. Sympathetic stimulation, norepinephrine, serotonin, PGF2alpha, and hypoxia increased total pulmonary vascular resistance by increasing the resistance, primarily on the arterial or upstream side of the volume midpoint, whereas histamine increased the resistance near the venous end of the lobar vascular bed. Hypoxia increased the volume upstream from the site of maximum resistance, suggesting that the larger lobar arteries were distended by the elevated lobar artery pressure. Sympathetic stimulation, norepinephrine, PGF2alpha, and serotonin, on the other hand, had little effect on the volume upstream from the maximum resistance, suggesting that these vasomotor stimuli prevented distension of the larger arteries.

Changes in perfusion pressure in response to graded doses of prostaglandin F 2 alpha (PGF 2 alpha) were measured during both forward and retrograde perfusion of isolated cat lungs perfused at a constant flow rate. During forward perfusion, PGF 2 alpha produced a dose-dependent increase in pulmonary artery pressure and a decrease in lung fluid volume. During retrograde perfusion, PGF 2 alpha also produced a dose-dependent increase in perfusion pressure; however, the dose required was fivefold greater than that needed to produce an identical change in pressure during forward perfusion. In addition, during retrograde perfusion, the lung fluid volume increased in response to PGF 2 alpha. These results suggest that the major site of activity of PGF 2 alpha is on the arterial side of the pulmonary vascular bed and that inactivation of PGF 2 alpha by the lung occurs primarily distal to this arterial site of vasomotion. The changes in perfusion pressure in response to PGF 2 alpha were markedly dependent on pH and oxygen tension (Po-2), being abolished by severe alkalosis and potentiated by both acidosis and hypoxia. In contrast, neither serotonin nor norepinephrine exhibited such a pH or Po-2 dependency. Since the ratio of the forward response to the retrograde response was not decreased by alterations of pH or Po-2, their influence on the responses appears to be through interaction at the site of vascular activity rather than through alteration of the rate of prostaglandin inactivation.

When dog lung lobes were perfused at constant arterial inflow rate, occlusion of the venous outflow (VO) produced a rapid jump in venous pressure (Pv) followed by a slower rise in both arterial pressure (Pa) and Pv. During the slow rise Pa(t) and Pv(t) tended to converge and become concave upward as the volume of blood in the lungs increased. We compared the dynamic vascular volume vs. pressure curves obtained after VO with the static volume vs. pressure curves obtained by dye dilution. The slope of the static curve (the static compliance, Cst) was always larger than the slope of the dynamic curve (the dynamic compliance, Cdyn). In addition, the Cdyn decreased with increasing blood flow rate. When venous occlusion (VO) was followed after a short time interval by arterial occlusion (AO) such that the lobe was isovolumic, both Pa and Pv fell with time to a level that was below either pressure at the instant of AO. In an attempt to explain these observations a compartmental model was constructed in which the hemodynamic resistance and vascular compliance were volume dependent and the vessel walls were viscoelastic. These features of the model could account for the convergence and upward concavity of the Pa and Pv curves after VO and the pressure relaxation in the isovolumic state after AO, respectively. According to the model analysis, the difference between Cst and Cdyn and the flow dependence of Cdyn are due to wall viscosity and volume dependence of compliance, respectively. Model analysis also suggested ways of evaluating changes in the viscoelasticity of the lobar vascular bed. Hypoxic vasoconstriction that increased total vascular resistance also decreased Cst and Cdyn and appeared to increase the vessel wall viscosity.