Blood flow switching among pulmonary capillaries is decreased during high hematocrit.

Pulmonary capillary perfusion within a single alveolar wall continually switches among segments, even when large-vessel hemodynamics are constant. The mechanism is unknown. We hypothesize that the continually varying size of plasma gaps between individual red blood cells affects the likelihood of capillary segment closure and the probability of cells changing directions at the next capillary junction. We assumed that an increase in hematocrit would decrease the average distance between red blood cells, thereby decreasing the switching at each capillary junction. To test this idea, we observed 26 individual alveolar capillary networks by using videomicroscopy of excised canine lung lobes that were perfused first at normal hematocrit (31-43%) and then at increased hematocrit (51-62%). The number of switches decreased by 38% during increased hematocrit (P < 0.01). These results support the idea that a substantial part of flow switching among pulmonary capillaries is caused by the particulate nature of blood passing through a complex network of tubes with continuously varying hematocrit.     

Leukocyte kinetics in the microcirculation

The transport of leukocytes in the microcirculation is specific for the type, size, and the rheological and adhesive properties, the microanatomy of the host organ, and the hemodynamics. The adhesion to the endothelium is determined largely by the degree of activation via chemotactic factors. Leukocyte motion differs from that of red cells or platelets in several respects. When granulocytes enter into capillaries, they are deformed just like red cells. Under normal flow conditions, the time to deform at the entry to capillaries is typically 1,000 times larger than for the red cell, leading to temporary obstruction of the capillaries. After entry, granulocytes move with lower velocity than red cells which causes a cell train formation inside the capillary. At the venular side, the granulocyte is displaced from the center stream toward the endothelium by faster moving red cells. This process leads to systematic attachment of the granulocytes to the endothelium. At a reduced perfusion pressure or in the presence of locally elevated levels of chemotactic factors, the granulocytes may not be able to pass through the capillary network, which leads to microvascular obstruction. Organs with a narrow capillary network may thereby become filters for circulating granulocytes. This event is accompanied in many situations with damage to the host organ.     

Red cell distribution and the recruitment of pulmonary diffusing capacity.

The distribution of red blood cells in alveolar capillaries is typically nonuniform, as shown by intravital microscopy and in alveolar tissue fixed in situ. To determine the effects of red cell distribution on pulmonary diffusive gas transport, we computed the uptake of CO across a two-dimensional geometric capillary model containing a variable number of red blood cells. Red blood cells are spaced uniformly, randomly, or clustered without overlap within the capillary. Total CO diffusing capacity (DLCO) and membrane diffusing capacity (DmCO) are calculated by a finite-element method. Results show that distribution of red blood cells at a fixed hematocrit greatly affects capillary CO uptake. At any given average capillary red cell density, the uniform distribution of red blood cells yields the highest DmCO and DLCO, whereas the clustered distribution yields the lowest values. Random nonuniform distribution of red blood cells within a single capillary segment reduces diffusive CO uptake by up to 30%. Nonuniform distribution of red blood cells among separate capillary segments can reduce diffusive CO uptake by >50%. This analysis demonstrates that pulmonary microvascular recruitment for gas exchange does not depend solely on the number of patent capillaries or the hematocrit; simple redistribution of red blood cells within capillaries can potentially account for 50% of the observed physiological recruitment of DLCO from rest to exercise.     

Direct observation of epicardial coronary capillary hemodynamics during reactive hyperemia and during adenosine administration by intravital video microscopy

Using high-resolution intravital charge-coupled device video microscopy, we visualized the epicardial capillary network of the beating canine heart in vivo to elucidate its functional role under control conditions, during reactive hyperemia (RH), and during intracoronary adenosine administration. The pencil-lens video-microscope probe was placed over capillaries fed by the left anterior descending artery in atrioventricular-blocked hearts of open-chest, anesthetized dogs paced at 60-90 beats/min (n = 17). In individual capillaries under control conditions, red blood cell flow was predominant during systole or diastole, indicating that the watershed between diastolic arterial and systolic venous flows is located within the capillaries. Capillary flow increased during RH and reached a peak flow velocity (2.1 +/- 0.6 mm/s), twice as high as control (1.2 +/- 0.5 mm/s), with enhancement of intercapillary cross-connection flow and enlargement of diameter (by 17%). With adenosine, capillary flow velocity significantly increased (1.8 +/- 0.7 mm/s). However, the increase in volumetric capillary flow with adenosine estimated from red blood cell velocity and diameter was less than the increase in arterial flow, whereas that during RH was nearly equivalent to the increase in arterial flow. There was a time lag of approximately 1.5 s for refilling of capillaries during RH, indicating their function as capacitance vessels. In conclusion, the coronary capillary network functions as 1) the major watershed between diastolic-dominant arterial and systolic-dominant venous flows, 2) a capacitor, and 3) a significant local flow amplifier and homogenizer of blood supply during RH, but with adenosine the increase in capillary flow velocity was less than the increase in arterial flow.     

Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics

To assess O2 delivery to tissue by a new surface-modified, polyethylene glycol-conjugated human hemoglobin [MP4; Po2 at 50% saturation of hemoglobin (P50); 5.4 mmHg], we studied microcirculatory hemodynamics and O2 release in golden Syrian hamsters hemodiluted with MP4 or polymerized bovine hemoglobin (PolyBvHb; P50 54.2 mmHg). Comparisons were made with the animals' hemodiluted blood with a non-O2 carrying plasma expander with similar solution properties (Dextran-70). Systemic hemodynamics (arterial blood pressure and heart rate) and acid-base parameters were not correlated with microhemodynamics (arteriolar and venular diameter, red blood cell velocity, and flow). Microscopic measurements of Po2 and the O2 equilibrium curves permitted analysis of O2 release in precapillary and capillary vessels by red blood cells and plasma hemoglobin separately. No significant differences between the groups of animals with respect to arteriolar diameter, flow, or flow velocity were observed, but the functional capillary density was significantly higher in the MP4-treated animals (67%) compared with PolyBvHb-treated animals (37%; P < 0.05) or dextran-treated animals (53%). In the PolyBvHb-treated animals, predominant O2 release (both red blood cells and plasma hemoglobin) occurred in precapillary vessels, whereas in MP4 animals most of the O2 was released from both red blood cells and plasma hemoglobin in capillaries. Base excess correlated directly with capillary O2 release but not systemic O2 content or total O2 release. Higher O2 extraction of both red blood cell and plasma hemoglobin in capillaries represents a new mechanism of action of cell-free hemoglobin. High O2 affinity appears to be an important property for cell-free hemoglobin solutions.     

Pulmonary capillaries are recruited during pulsatile flow.

Capillaries recruit when pulmonary arterial pressure rises. The duration of increased pressure imposed in such experiments is usually on the order of minutes, although recent work shows that the recruitment response can occur in <4 s. In the present study, we investigate whether the brief pressure rise during cardiac systole can also cause recruitment and whether the recruitment is maintained during diastole. To study these basic aspects of pulmonary capillary hemodynamics, isolated dog lungs were pump perfused alternately by steady flow and pulsatile flow with the mean arterial and left atrial pressures held constant. Several direct measurements of capillary recruitment were made with videomicroscopy. The total number and total length of perfused capillaries increased significantly during pulsatile flow by 94 and 105%, respectively. Of the newly recruited capillaries, 92% were perfused by red blood cells throughout the pulsatile cycle. These data provide the first direct account of how the pulmonary capillaries respond to pulsatile flow by showing that capillaries are recruited during the systolic pulse and that, once open, the capillaries remain open throughout the pulsatile cycle.     

Red blood cell mechanics and capillary blood rheology.

Blood contains a high vol fraction of erythrocytes (red blood cells), which strongly influence its flow properties. Much is known about the mechanical properties of red cells, providing a basis for understanding and predicting the rheological behavior of blood in terms of the behavior of individual red cells. This review describes quantitative theoretical models that relate red cell mechanics to flow properties of blood in capillaries. Red cells often flow in single file in capillaries, and rheological parameters can then be estimated by analyzing the motion and deformation of an individual red cell and the surrounding plasma in a capillary. The analysis may be simplified by using lubrication theory to approximate the plasma flow in the narrow gaps between the cells and the vessels walls. If red cell shapes are assumed to be axisymmetric, apparent viscosities are predicted that agree with determinations in glass capillaries. Red cells flowing in microvessels typically assume nonaxisymmetric shapes, with cyclic "tank-treading" motion of the membrane around the interior. Several analyses have been carried out that take these effects into account. These analyses indicate that nonaxisymmetry and tank-treading do not significantly influence the flow resistance in single-file or two-file flow.     

The flow of sickle-cell blood in the capillaries.

Oxygen tension levels and red cell velocities for the flow of sickle-cell blood in the capillaries are determined by using the Krogh model for oxygen transport and lubrication theory for the cell motion. The coupling and interaction between these arises from the red cell compliance, which is assumed to vary with the oxygen concentration. Microsieving data is used to establish an upper bound for this relationship. Calculations are carried out for a range of capillary sizes, taking into account the rightward shift of the oxyhemoglobin dissociation curve and the reduced hematocrit of sickle-cell blood, and are compared to, as a base case, the flow of normal blood under normal pressure gradient. The results indicate that under normal pressure gradients the oxygen tensions and cell velocities for sickle blood are considerably higher than for normal blood, thus acting against the tendency for cells to sickle, or significantly change their rheological properties, in the capillaries. Under reduced pressure gradients, however, the concentrations and velocities drop dramatically, adding to the likelihood of such shape or flow property changes.     

Red blood cell mechanics and capillary blood rheology

Blood contains a high vol fraction of erythrocytes (red blood cells), which strongly influence its flow properties. Much is known about the mechanical properties of red cells, providing a basis for understanding and predicting the rheological behavior of blood in terms of the behavior of individual red cells. This review describes quantitative theoretical models that relate red cell mechanics to flow properties of blood in capillaries. Red cells often flow in single file in capillaries, and rheological parameters can then be estimated by analyzing the motion and deformation of an individual red cell and the surrounding plasma in a capillary. The analysis may be simplified by using lubrication theory to approximate the plasma flow in the narrow gaps between the cells and the vessel walls. If red cell shapes are assumed to be axisymmetric, apparent viscosities are predicted that agree with determinations in glass capillaries. Red cells flowing in microvessels typically assume nonaxisymmetric shapes, with cyclic “tank-treading” motion of the membrane around the interior. Several analyses have been carried out that take these effects into account. These analyses indicate that nonaxisymmetry and tank-treading do not significantly influence the flow resistance in single-file or two-file flow.     

Regression of capillary network in atrophied soleus muscle induced by hindlimb unweighting.

Little is known about the mechanisms responsible for the adaptation and changes in the capillary network of hindlimb unweighting (HU)-induced atrophied skeletal muscle, especially the coupling between functional and structural alterations of intercapillary anastomoses and tortuosity of capillaries. We hypothesized that muscle atrophy by HU leads to the apoptotic regression of the capillaries and intercapillary anastomoses with their functional alteration in hemodynamics. To clarify the three-dimensional architecture of the capillary network, contrast medium-injected rat soleus muscles were visualized clearly using a confocal laser scanning microscope, and sections were stained by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) and with anti-von Willebrand factor. In vivo, the red blood cell velocity of soleus muscle capillaries were determined with a pencil-lens intravital microscope brought into direct contact with the soleus surface. After HU, the total muscle mass, myofibril protein mass, and slow-type myosin heavy chain content were significantly lower. The number of capillaries paralleling muscle fiber and red blood cells velocity were higher in atrophied soleus. However, the mean capillary volume and capillary luminal diameter were significantly smaller after HU than in the age-matched control group. In addition, we found that the number of anastomoses and the tortuosity were significantly lower and TUNEL-positive endothelial cells were observed in atrophied soleus muscles, especially the anastomoses and/or tortuous capillaries. These results indicate that muscle atrophy by HU generates structural alterations in the capillary network, and apoptosis appears to occur in the endothelial cell of the muscle capillaries.     

A computational study of the effect of capillary network anastomoses and tortuosity on oxygen transport

The objective of this study was to investigate the effects of capillary network anastomoses and tortuosity on oxygen transport in skeletal muscle, as well as the importance of muscle fibers in determining the arrangement of parallel capillaries. Countercurrent flow and random capillary blockage (e.g. by white blood cells) were also studied. A general computational model was constructed to simulate oxygen transport from a network of blood vessels within a rectangular volume of tissue. A geometric model of the capillary network structure, based on hexagonally packed muscle fibers, was constructed to produce networks of straight unbranched capillaries, capillaries with anastomoses, and capillaries with tortuosity, in order to examine the effects of these geometric properties. Quantities examined included the tissue oxygen tension and the capillary oxyhemoglobin saturation. The computational model included a two-phase simulation of blood flow. Appropriate parameters were chosen for working hamster cheek-pouch retractor muscle. Our calculations showed that the muscle-fiber geometry was important in reducing oxygen transport heterogeneity, as was countercurrent flow. Tortuosity was found to increase tissue oxygenation, especially when combined with anastomoses. In the absence of tortuosity, anastomoses had little effect on oxygen transport under normal conditions, but significantly improved transport when vessel blockages were present.     

Red blood cell orientation in pulmonary capillaries and its effect on gas diffusion.

When alveoli are inflated, the stretched alveolar walls draw their capillaries into oval cross sections. This causes the disk-shaped red blood cells to be oriented near alveolar gas, thereby minimizing diffusion distance. We tested these ideas by measuring red blood cell orientation in histological slides from rapidly frozen rat lungs. High lung inflation did cause the capillaries to have oval cross sections, which constrained the red blood cells within them to flow with their broad sides facing alveolar gas. Low lung inflation stretched alveolar walls less and allowed the capillaries to assume a circular cross section. The circular luminal profile permitted the red blood cells to have their edges facing alveolar gas, which increased the diffusion distance. Using a finite-element method to calculate the diffusing capacity of red blood cells in the broad-side and edge-on orientations, we found that edge-on red blood cells had a 40% lower diffusing capacity. This suggests that, when capillary cross sections become circular, whether through low-alveolar volume or through increased microvascular pressure, the red blood cells are likely to be less favorably oriented for gas exchange.     

High viscosity plasma expanders: Volume restitution fluids for lowering the transfusion trigger

Hemorheological studies lead to the axiom that high plasma viscosity is detrimental and that it is beneficial to lower blood viscosity, a precept embodied in the practice of hemodilution, where improved perfusion is attributed to the lowering of blood viscosity. Hemodilution is limited by the transfusion trigger, hemoglobin content of blood of about 7-8 g/dl, which indicates when further volume replacements must restore oxygen carrying capacity with red blood cells (RBC). However, oxygen consumption and delivery are not compromised upon passing this landmark. The reduced blood viscosity does not transmit adequate pressure to the capillaries, causing functional capillary density (FCD) to decrease, jeopardizing organ function through the inadequate extraction of products of metabolism from the tissue by the capillaries. Studies in hemorrhagic shock show that survival is primarily determined by the maintenance of FCD and secondarily by tissue oxygenation. FCD is maintained as hematocrit is reduced beyond the transfusion trigger by increasing plasma viscosity, which transmits systemic pressure to the capillaries and induces vasodilatation through the increased shear stress dependent release of vasodilators. Consequently the transfusion trigger is also a "viscosity trigger" indicating when blood and plasma viscosity are too low. In this condition increasing plasma viscosity is beneficial and extends the transfusion trigger reducing the use of blood transfusions.     

Impaired capillary hemodynamics in skeletal muscle of rats in chronic heart failure.

Skeletal muscle blood flow is reduced and O(2) extraction is increased at rest in chronic heart failure (CHF). Knowledge of red blood cell (RBC) flow distribution within the capillary network is necessary for modeling O(2) delivery and exchange in this disease. Intravital microscopy techniques were used to study the in vivo spinotrapezius muscle microcirculation in rats with CHF 7 wk after myocardial infarction and in sham-operated controls (sham). A decrease in mean muscle fiber width from 51.3 +/- 1.9 microm in sham to 42.6 +/- 1.4 microm in CHF rats (P < 0.01) resulted in an increased lineal density of capillaries in CHF rats (P < 0.05). CHF reduced (P < 0.05) the percentage of capillaries supporting continuous RBC flow from 87 +/- 5 to 66 +/- 5%, such that the lineal density of capillaries supporting continuous RBC flow remained unchanged. The percentage of capillaries supporting intermittent RBC flow was increased in CHF rats (8 and 27% in sham and CHF, respectively, P < 0.01); however, these capillaries contributed only 2.3 and 3.3% of the total RBC flux in sham and CHF rats, respectively. In continuously RBC-perfused capillaries, RBC velocity (252 +/- 20 and 144 +/- 9 microm/s in sham and CHF, respectively, P < 0.001) and flux (21.4 +/- 2.4 and 9.4 +/- 1.1 cells/s in sham and CHF, respectively, P < 0.01) were markedly reduced in CHF compared with sham rats. Capillary "tube" hematocrit remained unchanged (0.22 +/- 0.02 and 0.19 +/- 0.02 in sham and CHF, respectively, P > 0.05). We conclude that CHF causes spinotrapezius fiber atrophy and reduces the number of capillaries supporting continuous RBC flow per fiber. Within these capillaries supporting continuous RBC flow, RBC velocity and flux are reduced 45-55%. This decreases the potential for O(2) delivery but enhances fractional O(2) extraction by elevating RBC capillary residence time. The unchanged capillary tube hematocrit suggests that any alterations in muscle O(2) diffusing properties in CHF are mediated distal to the RBC.     

The intraorganic lymphatic bed of the mucous membrane of the tongue

The intraorganic lymphatic bed of the canine tongue mucous membrane is presented by the superficial and deep capillary networks and by the plexuses of the intraorganic lymphatic vessels. The capillaries of the superficial network in the thickness of the mucous membrane of the dorsal surface of the lingual tip, body and root form the lymphatic bed of the mechanical and gustatory papillas. The diameter of the capillaries in the both networks and in the intraorganic lymphatic vessels is greater in the mucous membrane of the ventral surface of the tip and of the lateral surfaces of the lingual body, and density of their arrangement is higher in the mucous membrane on the dorsal surface of the lingual tip, body and root. The capillaries of the superficial network in all areas of the lingual mucous membrane are thinner than those of the deep network, and the loops formed by the capillaries of the superficial network are less than the loops of the deep network.     

Fine structure of the epidermis of the mudskipper,Periophthalmus modestus (Gobiidae)

The ultra-structure of the epidermis of the mudskipper,Periophthalmus modestus, was examined by both light and transmission electron microscopies. The epidermis is exceptionally not well endowed with mucous or granular cells. Filament-containing cells occur in three distinct layers of the surface, middle and basal epidermis. The surface layer is further subdivided into two layers, an outermost and less superficial one. Two different cell types were identified in the epidermis. Type I cells are fiat cells in a single stratum. Type II cells are enormous cells, characterized by having a large vacuole in the cytoplasm. The outermost layer is composed of a free surface of Type I cells and numerous microridges covered with a fuzzy, fibrillar substance. The “fuzz” forms a cuticule-like structure, but keratinization as found in terrestrial animals does not occur. The superficial layer contains Type I cells and intraepithelial blood capillaries. When Type I cells become senescent, numerous intercellular spaces are formed in the plasma membranes of adjacent cells, with the senescent cells finally falling off. Just beneath these cells, however, young cells of Type I are always found. The blood capillaries are usually reinforced with young Type I cells. A large volume of oxygen may be absorbed through the skin using the blood capillary network. The middle layer contains several strata of Type II cells. The special corky structure of these cells seems to play an important role in thermal insulation and protection against ultraviolet light in relation to life out of water. However, by comparison with terrestrial animals, the histological design of the epidermis of this goby appears incomplete, so as to reduce desiccation on land, owing to the epidermis lacking a keratinized stratum. The differentiation of the epidermis seems to be an adaptation for a terrestrial habit in this species.     

Dynamical clustering of red blood cells in capillary vessels

We have modeled the dynamics of a 3-D system consisting of red blood cells (RBCs), plasma and capillary walls using a discrete-particle approach. The blood cells and capillary walls are composed of a mesh of particles interacting with harmonic forces between nearest neighbors. We employ classical mechanics to mimic the elastic properties of RBCs with a biconcave disk composed of a mesh of spring-like particles. The fluid particle method allows for modeling the plasma as a particle ensemble, where each particle represents a collective unit of fluid, which is defined by its mass, moment of inertia, translational and angular momenta. Realistic behavior of blood cells is modeled by considering RBCs and plasma flowing through capillaries of various shapes. Three types of vessels are employed: a pipe with a choking point, a curved vessel and bifurcating capillaries. There is a strong tendency to produce RBC clusters in capillaries. The choking points and other irregularities in geometry influence both the flow and RBC shapes, considerably increasing the clotting effect. We also discuss other clotting factors coming from the physical properties of blood, such as the viscosity of the plasma and the elasticity of the RBCs. Modeling has been carried out with adequate resolution by using 1 to 10 million particles. Discrete particle simulations open a new pathway for modeling the dynamics of complex, viscoelastic fluids at the microscale, where both liquid and solid phases are treated with discrete particles. Figure A snapshot from fluid particle simulation of RBCs flowing along a curved capillary. The red color corresponds to the highest velocity. We can observe aggregation of RBCs at places with the most stagnant plasma flow.     

Numerical Simulation of Blood Flow Through Microvascular Capillary Networks

A numerical method is implemented for computing blood flow through a branching microvascular capillary network. The simulations follow the motion of individual red blood cells as they enter the network from an arterial entrance point with a specified tube hematocrit, while simultaneously updating the nodal capillary pressures. Poiseuille’s law is used to describe flow in the capillary segments with an effective viscosity that depends on the number of cells residing inside each segment. The relative apparent viscosity is available from previous computational studies of individual red blood cell motion. Simulations are performed for a tree-like capillary network consisting of bifurcating segments. The results reveal that the probability of directional cell motion at a bifurcation (phase separation) may have an important effect on the statistical measures of the cell residence time and scattering of the tube hematocrit across the network. Blood cells act as regulators of the flow rate through the network branches by increasing the effective viscosity when the flow rate is high and decreasing the effective viscosity when the flow rate is low. Comparison with simulations based on conventional models of blood flow regarded as a continuum indicates that the latter underestimates the variance of the hematocrit across the vascular tree.     

Microvascular and capillary perfusion following glycocalyx degradation.

Systemic parameters and microvascular and capillary hemodynamics were studied in the hamster window chamber model before and after hyaluronan degradation by intravenous injection of Streptomyces hyaluronidase (100 units, 40-50 U/ml plasma). Glycocalyx permeation was estimated using fluorescent markers of different molecular size (40, 70, and 2,000 kDa), and electrical charge. Systemic parameters (blood pressure, heart rate, blood gases) and microhemodynamics (vascular tone, velocity, and blood flow) remained statistically unchanged after injection of hyaluronidase, compared with inactivated hyaluronidase. Conversely, capillary hemodynamics were drastically affected. Functional capillary density, the capillaries perfused with red blood cells (RBCs), decreased by 35%, capillary Hct of the remaining functional capillaries increased from 16 to 27%, and penetration of 70-kDa fluorescent marker increased. Furthermore, plasma-only perfused capillaries statistically increased 30 min after hyaluronidase. The decrease in functional capillary density accounted for an increased RBC flux in the remainder of the capillaries, since the same number of RBCs had to traverse a reduced number of capillaries. Flux balances showed a reduction from baseline of 11% for the RBC flux and 20% for the plasma flux after treatment. These discrepancies are within the margin of error of the techniques used and could be explained by accounting for RBC over-velocity compared with plasma. These findings suggest that the decrease in the glycocalyx leads to capillary perfusion impairments.     

Red Blood Cells: Centerpiece in the Evolution of the Vertebrate Circulatory System

All vertebrates except cold-water ice fish transport oxygenvia hemoglobin packaged in red blood cells (RBCs). VertebrateRBCs vary in size by thirtyfold. Differences in RBC size havebeen known for over a century, but the functional significanceof RBC size remains unknown. One hypothesis is that large RBCsare a primitive character. Agnathans have larger RBCs than domammals. However, the largest RBCs are found in urodele amphibianswhich is inconsistent with the hypothesis that large RBCs areprimitive. Another possibility is that small RBCs increase bloodoxygen transport capacity. Blood hemoglobin concentration ([Hb])and mean RBC hemoglobin concentration (MCHC) increase from Agnathato birds and mammals. However, the changes in [Hb] and MCHCdo not parallel changes in RBC size. In addition, RBC size doesnot affect blood viscosity. Thus, there is no clear link betweenRBC size and oxygen transport capacity. We hypothesize thatRBC size attends changes in capillary diameter. This hypothesisis based on the following observations. First, RBC width averages25% larger than capillary diameter which insures cell deformationduring capillary flow. Functionally, RBC deformation minimizesdiffusion limitations to gas exchange. Second, smaller capillariesare associated with increased potential for diffusive gas exchange.However, smaller capillaries result in higher resistances toblood flow which requires higher blood pressures. We proposethat the large capillary diameters and large RBCs in urodelesreflect the evolutionary development of a pulmonary vascularsupply. The large capillaries reduced systemic vascular resistancesenabling a single ventricular heart to supply blood to two vascularcircuits, systemic and pulmonary, without developing high pressureson the pulmonary side. The large RBCs preserved diffusive gasexchange efficiency in the large capillaries.