BioInnovate Ireland--fostering entrepreneurial activity through medical device innovation training.

In the midst of a rich environment for medical device development and manufacturing, universities can play a critical role by developing relevant training programs to produce entrepreneurs who can be efficient and successful in creating early stage companies by understanding deeply the issues involved in creating a useful device, how to raise money, designing early clinical studies and locating manufacturing partners.

Detection of changes in lung tissue properties with multiple-indicator dilution.

We evaluated the potential utility of a group of indicators, each of which targets a particular tissue property, as indicators in the multiple-indicator dilution method to detect and to identify abnormalities in lung tissue properties resulting from lung injury models. We measured the pulmonary venous outflow concentration vs. time curves of [14C]diazepam, 3HOH, [14C]phenylethylamine, and a vascular reference indicator following their bolus injection into the pulmonary artery of isolated perfused rabbit lungs under different experimental conditions, resulting in changes in the lung tissue composition. The conditions included granulomatous inflammation, induced by the intravenous injection of complete Freund's adjuvant (CFA), and intratracheal fluid instillation, each of which resulted in similar increases in lung wet weight. Each of these conditions resulted in a unique pattern among the concentration vs. time outflow curves of the indicators studied. The patterns were quantified by using mathematical models describing the pulmonary disposition of each of the indicators studied. A unique model parameter vector was obtained for each condition, demonstrating the ability to detect and to identify changes in lung tissue properties by using the appropriate group of indicators in the multiple-indicator dilution method. One change that was particularly interesting was a CFA-induced change in the disposition of diazepam, suggestive of a substantial increase in peripheral-type benzodiazepine receptors in the inflamed lungs.

Structure-function relationships in the pulmonary arterial tree.

Knowledge of the relationship between structure and function of the normal pulmonary arterial tree is necessary for understanding normal pulmonary hemodynamics and the functional consequences of the vascular remodeling that accompanies pulmonary vascular diseases. In an effort to provide a means for relating the measurable vascular geometry and vessel mechanics data to the mean pressure-flow relationship and longitudinal pressure profile, we present a mathematical model of the pulmonary arterial tree. The model is based on the observation that the normal pulmonary arterial tree is a bifurcating tree in which the parent-to-daughter diameter ratios at a bifurcation and vessel distensibility are independent of vessel diameter, and although the actual arterial tree is quite heterogeneous, the diameter of each route, through which the blood flows, tapers from the arterial inlet to essentially the same terminal arteriolar diameter. In the model the average route is represented as a tapered tube through which the blood flow decreases with distance from the inlet because of the diversion of flow at the many bifurcations along the route. The taper and flow diversion are expressed in terms of morphometric parameters obtained using various methods for summarizing morphometric data. To help put the model parameter values in perspective, we applied one such method to morphometric data obtained from perfused dog lungs. Model simulations demonstrate the sensitivity of model pressure-flow relationships to variations in the morphometric parameters. Comparisons of simulations with experimental data also raise questions as to the "hemodynamically" appropriate ways to summarize morphometric data.

Accounting for the heterogeneity of capillary transit times in modeling multiple indicator dilution data.

To mathematically model multiple indicator dilution (MID) data for the purpose of estimating parameters descriptive of indicator-tissue interactions, it is necessary to account for the effects of the distribution of capillary transit times, h(c)(t). In this paper, we present an efficient approach for incorporating h(c)(t) in the mathematical modeling of MID data. In this method, the solution of the model partial differential equations obtained at different locations along the model capillary having the longest transit time provides the outflow concentrations for all capillaries. When weighted by h(c)(t), these capillary outflow concentrations provide the outflow concentration versus time curve for the capillary bed. The method is appropriate whether the available data on capillary dispersion are in terms of capillary transit time or relative flow distributions, and whether the dispersion results from convection time differences among heterogeneous parallel pathways or axial diffusion along individual pathways. Finally, we show that the knowledge of a relationship among the moments of h(c)(t), rather than h(c)(t) per se, is sufficient information to account for the effect of h(c)(t) in the mathematical modeling interpretation of MID data. This relationship can be determined by including a flow-limited indicator in the injected bolus, thus providing an efficient means for obtaining the experimental data sufficient to account for capillary flow and transit time heterogeneity in MID modeling.

Transit time dispersion in the pulmonary arterial tree.

Knowledge of the contributions of arterial and venous transit time dispersion to the pulmonary vascular transit time distribution is important for understanding lung function and for interpreting various kinds of data containing information about pulmonary function. Thus, to determine the dispersion of blood transit times occurring within the pulmonary arterial and venous trees, images of a bolus of contrast medium passing through the vasculature of pump-perfused dog lung lobes were acquired by using an X-ray microfocal angiography system. Time-absorbance curves from the lobar artery and vein and from selected locations within the intrapulmonary arterial tree were measured from the images. Overall dispersion within the lung lobe was determined from the difference in the first and second moments (mean transit time and variance, respectively) of the inlet arterial and outlet venous time-absorbance curves. Moments at selected locations within the arterial tree were also calculated and compared with those of the lobar artery curve. Transit times for the arterial pathways upstream from the smallest measured arteries (200-micron diameter) were less than approximately 20% of the total lung lobe mean transit time. Transit time variance among these arterial pathways (interpathway dispersion) was less than approximately 5% of the total variance imparted on the bolus as it passed through the lung lobe. On average, the dispersion that occurred along a given pathway (intrapathway dispersion) was negligible. Similar results were obtained for the venous tree. Taken together, the results suggest that most of the variation in transit time in the intrapulmonary vasculature occurs within the pulmonary capillary bed rather than in conducting arteries or veins.

Ascorbate-mediated transplasma membrane electron transport in pulmonary arterial endothelial cells.

Pulmonary endothelial cells are capable of reducing certain electron acceptors at the luminal plasma membrane surface. Motivation for studying this phenomenon comes in part from the expectation that it may be important both as an endothelial antioxidant defense mechanism and in redox cycling of toxic free radicals. Pulmonary arterial endothelial cells in culture reduce the oxidized forms of thiazine compounds that have been used as electron acceptor probes for studying the mechanisms of transplasma membrane electron transport. However, they reduce another commonly studied electron acceptor, ferricyanide, only very slowly by comparison. In the present study, we examined the influence of ascorbate [ascorbic acid (AA)] and dehydroascorbate [dehydroascorbic acid (DHAA)] on the ferricyanide and thiazine reductase activities of the bovine pulmonary arterial endothelial cell surface. The endothelial cells were grown on microcarrier beads so that the reduction of ferricyanide and methylene blue could be studied colorimetrically in spectrophotometer cuvettes and in flow-through cell columns. The ferricyanide reductase activity could be increased 80-fold by adding DHAA to the medium, with virtually no effect on methylene blue reduction. The DHAA effect persisted after the DHAA was removed from the medium. AA also stimulated the ferricyanide reductase activity but was less potent, and the relative potencies of AA and DHAA correlated with their relative rates of uptake by the cells. The results are consistent with the hypothesis that AA is an intracellular electron donor for an endothelial plasma membrane ferricyanide reductase and that the stimulatory effect of DHAA is the result of increasing intracellular AA. Adding sufficient DHAA to markedly increase extracellular ferricyanide reduction had little effect on the plasma membrane methylene blue reductase activity, suggesting that pulmonary arterial endothelial cells have at least two separate transplasma membrane electron transport systems.

Feldkamp and circle-and-line cone-beam reconstruction for 3D micro-CT of vascular networks.

Detailed morphometric knowledge of the microvascular network is needed for studies relating structure to haemodynamic function in organs like the lung. Clinical volumetric CT is limited to millimetre-order spatial resolution. Since evidence suggests that small arterioles (50 to 300 micrometres) dominate pulmonary haemodynamics, we built a micro-CT scanner, capable of imaging excised lungs in 3D with 100 microm resolution, for basic physiology research. The scanner incorporates a micro-focal (3 microm) x-ray source, an xyz theta stage and a CCD-coupled image intensifier detector. We imaged phantoms and contrast-enhanced rat lungs, reconstructing the data with either the Feldkamp or the circle-and-line cone-beam reconstruction algorithm. We present reconstructions using 180 views over 360 degrees for the circular trajectory, augmented with views from a linear scan for the circle-and-line algorithm. Especially for platelike features perpendicular to the rotation axis and remote from the midplane, the circle-and-line algorithm produces superior reconstructions compared with Feldkamp's algorithm. We conclude that the use of nonplanar source trajectories to perform micro-CT on contrast-enhanced, excised lungs can provide data useful for morphometric analysis of vascular trees, currently down to the 130 microm level.

Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung.

We measured the pulmonary venous concentration vs. time curves for [3H]alfentanil, [14C]lidocaine, and [3H]codeine after the bolus injection of each of these lipophilic amine compounds (LAC) and a vascular-reference indicator (fluorescein isothiocyanate-dextran) into the pulmonary artery of isolated perfused rabbit lungs. A range of flows and perfusate albumin concentrations was studied. To evaluate the information content of the data, we developed a kinetic model describing the pulmonary disposition of these LAC that was based on indicator dilution theory, and we sought a robust approach for interpreting the estimated model parameters. We found that the distribution of the kinetic model rate constants of the lipophilic amine-tissue interactions can be described by alpha, H, and psi, where alpha is a measure of the capacity of the rapidly equilibrating interactions between the lipophilic amine and the tissue; H is a measure of the equilibrium capacity of the slowly equilibrating interactions between the lipophilic amine and the tissue; and psi is the mean sojourn time. The values of alpha, H, and psi were 0.8 +/- 0.1 (SE), 0.6 +/- 0.1, and 1.6 +/- 0.5 s; 1.9 +/- 0.1, 5.3 +/- 0.4, and 5.6 +/- 0.5 s; and 1.1 +/- 0.1, 9.8 +/- 0.4, and 4.7 +/- 0.2 s for alfentanil, lidocaine, and codeine, respectively. These values for alpha, H, and psi reveal the relative dominance of the slowly equilibrating interactions for lidocaine and codeine in comparison with alfentanil. This approach to data analysis may have utility for the potential use of LAC to reveal and to quantify changes in lung tissue composition associated with lung disease.

Anatomic distribution of pulmonary vascular compliance.

Previously, the pressure changes after arterial and venous occlusion have been used to characterize the longitudinal distribution of pulmonary vascular resistance with respect to vascular compliance using compartmental models. However, the compartments have not been defined anatomically. Using video microscopy of the subpleural microcirculation, we have measured the flow changes in approximately 40-micron arterioles and venules after venous, arterial, and double occlusion maneuvers. The quasi-steady flows through these vessels after venous occlusion permitted an estimation of the compliance in three anatomic segments: arteries > 40 microns, veins > 40 microns, and vessels < 40 microns in diameter. We found that approximately 65% of the total pulmonary vascular compliance was in vessels < 40 microns, presumably mostly capillaries. The transient portions of the pressure and flow data after venous, arterial, and double occlusion were consistent with most of the arterial compliance being upstream from most of the arterial resistance and most of the venous compliance being downstream from most of the venous resistance.

Kinetics of plasma membrane electron transport in a pulmonary endothelial cell-column.

Thiazine dyes such as toluidine blue O (TBO) are reduced at the luminal endothelial surface. The purpose of this study was to determine the rate of this reaction in endothelial cells in culture. A multiple indicator dilution method was used to measure the reaction kinetics during transient passage of a TBO-containing bolus through a chromatographic column filled with bovine pulmonary arterial endothelial cells grown on microcarrier beads (cell-column). A bolus containing TBO and an inert extracellular reference indicator (FITC-Dextran) was injected upstream of the cell-column, and the indicator concentrations were measured downstream using on-line photodetection. The effects of column flow rate, PO2, and TBO concentration were studied. The fraction of TBO reduced upon passage through the cell-column decreased with increasing flow indicating that the reaction rate rather than TBO delivery controlled TBO reduction. The fraction of TBO reduced did not change with PO2 or dose in the ranges studied. TBO reduction was about 10 times that for steady state TBO sequestration by these cells which, along with the lack of a PO2 effect indicates that the rapid rate of reduction is not the rate-limiting step in steady state sequestration.

Flow-induced vasodilation in the ferret lung.

To examine the possibility that shear stress may be a pulmonary vasodilator stimulus, we studied the effect of changing blood flow on the diameters of small pulmonary arteries in isolated perfused ferret lung lobes. The arteries studied were in the approximately 0.3- to 1.3-mm-diameter range, and the diameters were measured by using microfocal X-ray imaging. The diameters were measured at two flow rates, 10 and 40 ml/min, with the intravascular pressure in the measured vessels the same at the two flow rates as the result of venous pressure adjustment. The response to a change in flow was studied under both normoxic and hypoxic conditions. Hypoxia was used to elevate pulmonary arterial tone to increase the likelihood of detecting a vasodilator response. Under normoxic conditions, changing flow had little effect on the arterial diameters, but under hypoxic conditions the arteries were consistently larger at the higher flow than at the lower flow, even though the distending pressure was the same at the two flow rates. The results are consistent with the hypothesis that shear stress is a pulmonary vasodilator stimulus.

Pulmonary endothelial thiazine uptake: separation of cell surface reduction from intracellular reoxidation.

The objective of this study was to further evaluate the hypothesis that the accumulation of thiazine dyes, such as methylene blue, by cultured bovine pulmonary arterial endothelial cells involves reduction on the cell surface, followed by diffusion of the lipophilic reduced form of the dye into the cells and intracellular reoxidation to the relatively membrane-impermeant hydrophilic form. The specific question addressed was whether inhibition of methylene blue uptake by cyanide and azide is via inhibition of extracellular reduction or inhibition of intracellular reoxidation. We used the cell membrane-impermeant ferricyanide ion as a secondary electron acceptor to measure the extracellular reduction of methylene blue independently from its uptake by the cells. In addition, toluidine blue O, incorporated into an acrylamide polymer so that it could not permeate the cells in either its reduced or oxidized forms, was used to examine the effects of cyanide and azide on the extracellular reduction. Microscopic observations of the effect of the inhibitors on the intracellular accumulation of methylene blue were also made. The results indicate that the reduction and intracellular sequestration are separate processes and that, in doses that inhibited intracellular reoxidation, and therefore uptake and sequestration, neither cyanide nor azide had an inhibitory effect on extracellular reduction. The intracellular distribution of the observable oxidized form of the dye was consistent with oxidation of the reduced dye within subcellular organelles. The demonstration that extracellular reduction and intracellular sequestration are separate events is consistent with the hypothesized sequence of events.

Regional perfusion parameters from pulmonary microfocal angiograms.

An indicator-dilution model was developed to describe transport of vascular contrast medium through an organ during acquisition of vascular dynamic contrast images. The model provides the theoretical basis for methods of determining regional blood flow, blood volume, and mean transit time from time-absorbance curves acquired from the images of tissue regions of interest (ROI) distal from the inlet site. The robustness of these methods was evaluated using a computer-simulated vessel network, which simulated the passage of a bolus of contrast medium through arterioles, networks of capillaries, and venules. The network was used to evaluate the reliability of ROI parameter estimation methods when the underlying model assumptions are violated. The shape of the ROI inlet concentration curve and moderate amounts of random noise did not affect the ability of the method to recover accurate parameter estimates. The estimates of ROI flow and transit time were degraded in the presence of significant dispersion of the inlet concentration curve as it traveled through arteries upstream from the microvascular ROI or when the flow was redistributed within the ROI. The estimates of ROI volume were relatively robust. The method was applied to image data of the dog pulmonary vasculature obtained using microfocal X-ray angiography to show that the results obtained from the simulations are consistent with actual data.

Effects of physical parameters on the cylindrical model for volume measurement by conductance.

Despite its undisputed utility for determining changes in ventricular pressure-volume relationships, the conductance catheter technique has not been proven reliable for measuring absolute volume. This limitation is due to violations of the assumptions inherent in the cylindrical model on which the method is based (i.e., homogeneous electric field and no leakage current). The purpose of this investigation was to relate cylindrical model correction factors to the physical environment of the catheter and to the cylindrical equation. Physical measurements of saline-filled, nonconductive cylinders using a four-electrode conductance catheter were compared with a three-dimensional finite element model of the physical apparatus. These measurements were incorporated into a parallel conductance model to relate physical parameters to corrections in the cylindrical equation for volume measurement. Excellent agreement between measured and modeled data was found. Results demonstrated a nonlinear relationship between the field nonhomogeneity correction factor (alpha) and cylinder diameter. The relationship between alpha and diameter was consistent with a theoretical extrapolation of cylinder diameter toward infinity. An inverse relationship between alpha and the parallel conductance volume (Vp) was also clarified. The parallel conductance model was able to demonstrate opposite effects of the physical presence of the catheter body and electrodes, which tended to cancel out any net effect on measured conductance. Results of this investigation and the developed finite element model clarify the nature of the correction terms in the cylindrical model and may lead to greater application of the conductance technique.

In vitro and finite-element model investigation of the conductance technique for measurement of aortic segmental volume.

This investigation examined the feasibility of applying the conductance catheter technique for measurement of absolute aortic segmental volume. Aortic segment volume was estimated simultaneously in vitro by using the conductance catheter technique and sonomicrometer crystals. Experiments were performed in five isolated canine aortas. Vessel diameter and pressure were altered, as were the conductive properties of the surrounding medium. In addition, a three-dimensional finite-element model of the vessel and apparatus was developed to examine the electric field and parallel conductance volume under different experimental conditions. The results indicated that in the absence of parallel conductance volume, the conductance catheter technique predicted absolute changes in segmental volumes and segmental pressure-volume relationships that agreed closely with those determined by sonomicrometry. The introduction of parallel conductance volume added a significant offset error to measurements of volume made with the conductance catheter that were nonlinearly related to the conductive properties of the surrounding medium. The finite-element model was able to predict measured resistance and parallel conductance volume, which correlated strongly with those measured in vitro. The results imply that absolute segmental volume and distensibility may be determined only if the parallel conductance volume is known. If the offset volume is not known precisely, the conductance catheter technique may still be applied to measure absolute changes in aortic segmental volume and compliance.

An interpretation of 14C-urea and 14C-primidone extraction in isolated rabbit lungs.

We measured the venous concentration versus time curves of 14C-urea and 14C-primidone after rapid bolus injections of a vascular reference indicator, fluorescein isothiocyanate dextran, and one of the two 14C-labeled indicators in isolated rabbit lungs perfused with Krebs-Ringer bicarbonate solution containing 4.5% bovine serum albumin at flow rates (F) of 6.67, 3.33, 1.67, and 0.83 ml/sec and with nearly constant microvascular pressure and total lung vascular volume. When we calculated the permeability-surface area product, PS, from the 14C-urea and 14C-primidone outflow curves using the Crone model, the estimates of the PS product were directly proportional to F. However, the fractional change in the PS with flow was different for the two indicators. We also estimated the PS from the same 14C-urea and 14C-primidone data using an alternative model that includes perfusion heterogeneity, estimated in a previous study, and flow-limited and barrier-limited extravascular volumes accessible to both urea and primidone. This model was able to fit the outflow curves of either 14C-urea or 14C-primidone at all four flows studied with one flow-independent PS for each indicator. The ability of the new model to explain the 14C-urea and 14C-primidone data with no flow-dependent change in PS suggests that a change in PS with F estimated using other models such as the Crone model is not sufficient for capillary surface area recruitment.

Impact of angiotensin-converting enzyme substrate conformation on fractional hydrolysis in lung.

We examined the hydrolysis kinetics of benzoyl-phenylalanyl-glycyl-proline (BPGP) in the isolated perfused lung and in vitro for evidence of preferential hydrolysis of the trans isomer by angiotensin-converting enzyme (ACE). Nuclear magnetic resonance spectroscopy showed that BPGP exists as cis and trans isomers in a ratio of 44:56. After a single pass through the perfused rabbit lung over a wide range of infused BPGP concentrations, 42% of the BPGP was not hydrolyzed. In single-pass bolus-injection studies, 41% of the injected BPGP was not hydrolyzed, and very little further hydrolysis occurred in a second passage of the bolus through the lungs. In rat lung recirculation and in vitro studies of BPGP hydrolysis by ACE, approximately 60% of the substrate was hydrolyzed rapidly compared with the remaining approximately 40%, and the peptidyl-prolyl cis-trans isomerase cyclophilin increased the rate of the slower phase of the reaction in both kinds of experiments. We conclude that the rapid hydrolysis phase represents primarily the hydrolysis rate of the trans isomer and the slower phase the cis-trans isomerization rate, suggesting that the trans isomer of BPGP is preferentially hydrolyzed by ACE in the perfused lung and in vitro.

Subpleural pulmonary microvascular pressures in the dog lung.

The reported values for the pressure difference between lobar artery and subpleural arteriole and between subpleural venule and lobar vein as a fraction of the total arterial-to-venous pressure drop across the dog lung have varied considerably. We carried out the present study to provide an additional set of measurements and to determine whether it is likely that differences in venous pressure or transpulmonary pressure between studies might make a substantial contribution to variations between studies. We measured the lobar arterial pressure (Pa) to subpleural arteriole (22-60 microns diam) pressure (Pma) to subpleural venule (30-80 microns diam) pressure (Pmv) to lobar venous pressure (Pv) distribution over a range of alveolar pressures (PA; 2.5-13.1 mmHg) and venous pressures (0-24.2 mmHg) in isolated dog lung lobes using the micropuncture servo-null technique. On average, near functional residual capacity (PA = 3 mmHg) and venous pressure equal to PA, (Pa-Pma)/(Pma-Pmv)/(Pmv-Pv) was 37:30:33%. Under zone 3 conditions, there was a small positive correlation between the fractional Pa-to-Pma pressure difference and PA and Pv, but dependence of the Pmv-to-Pv fraction on PA and Pv was not consistent. The overall effects of PA and Pv on the fractional pressure drops were not sufficient to account for differences between previous studies. Under zone 2 conditions as the venous pressure was varied, the changes in Pmv were nearly equal to the changes in Pv, whereas Pma was relatively insensitive to Pv. Thus, the zone 2 results were consistent with a capillary location for the flow-limiting segment under zone 2 conditions.

Reduction of thiazine dyes by bovine pulmonary arterial endothelial cells in culture.

The uptake of methylene blue (MB), and toluidine blue O (TBO) by bovine pulmonary arterial endothelial cells grown on microcarrier beads was detected as a decrease in the concentration of dye in the medium after these thiazine dyes were added to the medium surrounding the cells. Because the reduced forms of these dyes are much more lipophilic than the oxidized forms, we considered the possibility that reduction of the dyes at the cell surface might have preceded the uptake by the cells. Therefore, we studied the ability of the cells to reduce a toluidine blue O-polyacrylamide polymer (TBOP), which was too large to enter the cells in either the oxidized or reduced form. The TBO moieties of the polymer were reduced by the cells, indicating that the dyes did not have to enter the cells to be reduced and that reduction can occur at, or near, the cell surface. The rate of TBOP reduction was about the same as the rate of uptake of the monomeric dyes, indicating that the cell surface reduction mechanism had a sufficient capacity to account for the monomer uptake by the cells. We also found that ferricyanide ion, which also did not permeate the cells, was reduced by the cells and that external ferricyanide inhibited the monomeric MB uptake. Thus the results with ferricyanide were also consistent with the concept that the monomeric thiazine dyes are reduced at the cell surface before the more lipophilic reduced forms are taken up by the endothelial cells.

Estimation of the pulmonary capillary transport function in isolated rabbit lungs.

Recently, we presented a method for estimating the pulmonary capillary volume and transport function based on the use of a reference indicator and two or more indicators that rapidly equilibrate (radially) with the tissue (i.e., the concentrations in the vascular and extravascular spaces at a given axial location are in equilibrium) during transit through the capillaries in a bolus-injection indicator dilution method (S. H. Audi, G. S. Krenz, J. H. Linehan, D. A. Rickaby, and C. A. Dawson. J. Appl. Physiol. 77:332-351, 1994). The objectives of the present study were 1) to determine whether [14C]diazepam and [3H]alfentanil equilibrate sufficiently rapidly between the vascular space and tissue and with sufficiently different pulmonary extra-vascular mean residence times to be used in a single bolus to estimate the pulmonary capillary volume and transport function using this method and 2) to estimate the pulmonary capillary volume and transit time distribution in isolated perfused rabbit lungs. Both [14C]diazepam and [3H]alfentanil were found to be rapidly equilibrating indicators by the criteria that, over a wide range of flow rates, their respective venous effluent concentration curves were nearly congruent on a time scale normalized to the lung mean transit time for the reference indicator (fluorescein isothiocyanate dextran). In addition, at a given plasma albumin concentration, [14C]diazepam had a significantly longer extravascular mean residence time than [3H]alfentanil, e.g., at 6% plasma albumin concentration, the extravascular mean residence time of [14C]diazepam was more than twice that of [3H]alfentanil. On average, the estimated pulmonary capillary volume for a 2.7-kg was approximately 4.2 ml or approximately 44% of the total pulmonary vascular volume (9.5 ml). The relative dispersion of the pulmonary capillary transport function of the rabbit was approximately 90%.