Changes In Microvascular Pressure Research Articles

Effects of perfusion rate on permeability of frog and rat mesenteric microvessels to sodium fluorescein.

The permeability, P(S), to sodium fluorescein (Stokes-Einstein radius = 0.45 nm) has been measured in single mesenteric capillaries of pithed frogs and anaesthetised rats as perfusion velocity, U, was varied over a range from 400 up to 2000-10,000 microm s(-1). P(S) increased linearly with U. In 20 frog capillaries, mean (+/- S.E.M.) P(S) (in microm s(-1)) = 9.35 (+/- 1.55)U x 10(-5) + 0.244 (+/- 0.0291). Similarly, in nine rat venules, mean P(S) = 1.62 (+/- 0.385)U x 10(-4) + 0.375 (+/- 0.025). The flow-dependent component of permeability could be reversibly abolished in frog capillaries by superfusing with 100 microM noradrenaline and by superfusing rat venules with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (20 microM). It was shown that changes in microvascular pressure accompanying changes in U during free perfusion could account for only 15 % of the changes in P(S), i.e. 85 % of the changes in P(S) were changes in the permeability coefficient itself. A comparison between the changes in P(S) with U and the previously described changes in microvascular permeability to K(+) with U, suggest that if the flow-dependent component of permeability is modelled as a population of pores of constant size, these have radii of 0.8 nm. Such a pathway would limit flow-dependent permeability to small hydrophilic molecules and have minimal effect on net fluid exchange.

Inhibition of nitric oxide synthesis augments pulmonary oedema in isolated perfused rabbit lung

The role of nitric oxide (NO) in precipitating pulmonary oedema in acute lung injury remains unclear. We have investigated the mechanism of involvement of NO in the maintenance of liquid balance in the isolated rabbit lung. Thirty pairs of lungs were perfused with colloid for up to 6 h, during which pulmonary vascular resistance (PVR) and capillary pressure (PCP) were measured frequently, and time to gain 5 g in weight (t5) was recorded. Four protocols with different perfusate additives were studied: (i) none (control, n = 11); (ii) 10 mmol NG-nitro-L-arginine methyl ester (L-NAME) (n = 6); (iii) 10 mmol L-NAME with 100 mumol lodoxamide, an inhibitor of mast cell degranulation (n = 7); (iv) 10 mmol L-NAME with 10 mumol 8-bromo-3',5'-cyclic guanosine monophosphate (8Br-cGMP), an analogue of cGMP that may reduce vascular permeability by relaxing contractile elements in endothelial cells (n = 6). Neither PVR nor PCP differed between protocols. L-NAME markedly reduced t5 from 248 (27) min (mean (SEM)) in protocol (i) to 144 (5) min in protocol (ii) (P < 0.05). Both lodoxamide (t5 = 178 (7) min) and 8Br-cGMP (t5 = 204 (10) min) substantially corrected the effect of L-NAME (P < 0.005). Results suggest that maintenance of a low permeability by NO may involve mast cell stabilization and endothelial cell relaxation.

Changes in Vessel Pressure and Interstitial Fluid Pressure of Normal Subcutis and Subcutaneous Tumor in Rats Due to Angiotensin II

To elucidate the mechanism of enhancement of transport of anticancer drugs into tumor tissue due to angiotensin II (AII), changes in microvascular pressure (MVP) and interstitial fluid pressure (IFP) due to AII were measured in normal subcutis and subcutaneous tumor in rats. TWO different tumor cell lines AH109A and AH272 were used. MVP and IFP were measured using a microocclusion method and a diffusion chamber method, respectively. Insignificant changes in the pressure of normal venous vessels and the IFP of normal subcurtis were brought about by AII-induced hypertension. In both AH109A and AH272, the IFP of the same region within the tumor increased with enlargement of tumor volume. The IFP of AH109A tumor (tumor volume = 1.8-2.2 cm 3) increased slightly due to AII, but the tumor MVP of AH109A and AH272 increased markedly. Though both tumor IFP and MVP increased significantly due to AII, the increase in the tumor MVP was much larger than that of tumor IFP. We conclude that AII increases the hydrostatic pressure difference between tumor vascular and interstitial spaces and leads to enhancement of the efficiency of filtration from tumor vessels to tumor tissue, which is one of the mechanisms of enhancement of drug delivery to tumor tissue due to AII.

Fluid restitution and shift of blood volume in anesthetized rabbits subject to cyclic hemorrhage

We investigated the effect of a 10% cyclic blood volume change with a period of 2 or 4 min to study the short-term control of blood volume. In experiments with pentobarbital-anesthetized rabbits, the blood density variation over a 2-min cycle is 0.94 +/- 0.04 (SE) g/l, and the plasma density variation is 0.17 +/- 0.04 g/l. The plasma density variation could result from a fluid restitution from the extravascular space (with a density 1,005 g/l), with a volume equal to 14% of the withdrawn blood volume. This restitution cannot account, however, for the entire observed density change in arterial blood. Because of the Fahraeus effect in microvascular flow, a shift in blood volume from the microvasculature is another mechanism that could lead to a decrease in the density of arterial blood. An analysis of the blood and plasma density variations indicates that a blood volume (49% of the shed volume) is shifted from the micro- to macrocirculation. This volume compensation by fluid restitution and volume shift acts to minimize the effect of hemorrhage on the filling of the venous system. We found that the blood density waveform parallels the change in blood volume. When the blood volume change reverses its direction, the density change also reverses direction with a time delay less than 8 s. The blood density variations are not altered by bilateral vagotomy or its combination with hexamethonium (a sympathetic ganglionic blocker). These observations of anesthetized rabbits indicate that the short-term compensation is primarily due to the volume shift from the microcirculation and is not regulated by humoral or neural mechanisms but by local mechanisms such as autoregulation and the passive response due to changes in microvascular pressure.

Role of protein kinase C in bradykinin-induced increases in microvascular permeability.

The goal of this study was to determine whether protein kinase C mediates bradykinin-induced increases in microvascular permeability. Permeability of the hamster cheek pouch was evaluated using intravital fluorescent microscopy and fluorescein isothiocyanate (FITC)-dextran (MW 70,000). We examined effects of sphingosine, a protein kinase C inhibitor, on bradykinin-induced increases in permeability. Increases in permeability were quantitated by counting the number of leaky sites and calculating the clearance of FITC-dextran. During bradykinin (10(-6) M), leaky sites increased from 0 to 40 +/- 4 (mean +/- SEM) sites/0.11 cm2, and clearance increased from 1.7 +/- 1.0 to 22 +/- 9 ml/sec x 10(-6). The bradykinin type-2 receptor antagonist D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin virtually abolished formation of leaky sites in response to bradykinin. To determine whether changes in microvascular pressure contribute to the increase in leaky sites, venular pressure was measured using a micropipette and survo-null device. Increases in cheek pouch venular pressure were similar during application of bradykinin and adenosine, which increased permeability, and isoproterenol, which did not increase permeability in the cheek pouch. Thus, increases in permeability were not linked to changes in microvascular pressure. The protein kinase C inhibitor, sphingosine (10(-6) M), markedly attenuated responses to bradykinin. Leaky sites increased from 0 to only 2 +/- 1 sites/0.11 cm2, and clearance increased from 3.9 +/- 1.4 to only 6.7 +/- 2.2 ml/sec x 10(-6). To test the specificity of sphingosine, we examined effects of adenosine (10(-6) M). Sphingosine did not significantly alter increases in microvascular permeability in responses to adenosine. We also examined effects of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), another protein kinase C inhibitor, on responses to bradykinin and adenosine. H-7 greatly attenuated formation of leaky sites during stimulation with bradykinin and did not alter the number of leaky sites produced during adenosine. The findings suggest that protein kinase C may mediate increases in vascular permeability in response to bradykinin.

Analysis of noninvasive macromolecular transport measurements in the lung.

Several groups of investigators are measuring transcapillary protein flux in the lung using noninvasive methods. Results from these studies are reported using several different protein transport indexes, including pulmonary transvascular transfer coefficient, relative extravascular protein, pulmonary transcapillary escape rate, protein leak index, lung transferrin index, slope index, and lung-to-heart count ratios. The purpose of this study is to discover the relationships between these indexes by employing a two-compartment theory of protein transcapillary transport in the lung. We found that all the above indexes can be related to a single index, which we call the normalized slope index. This index is the time rate of change of radioactivity originating from protein in lung interstitium divided by radioactivity arising from protein in lung plasma, normalized by this ratio at time 0, and corrected for blood volume changes. In particular the normalized slope index is shown to be the same as pulmonary transcapillary escape rate under normal sampling conditions and is relatively unaffected by changes in interstitial volume. The response of the normalized slope index to changes in microvascular pressure and microvascular permeability is explored by applying a two-pore model of the microvascular barrier. Results indicate that the normalized slope index is relatively insensitive to changes in microvascular pressure but is greatly affected by changes in microvascular permeability (i.e., changes in large-pore size or number). Since all published leak indexes are related, we would encourage all investigators in the field to adopt a single leak index. We recommend that when a two-compartment model is applied to external detection data, the results be expressed as pulmonary transcapillary escape rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of crystalloid on lung fluid balance after smoke inhalation.

Inhalation injury occurs in 21% of flame burn victims who require large fluid volumes for resuscitation and have a mortality rate greater than 30%. This study was done to determine how vulnerable the smoke-injured lung is to fluid accumulation when crystalloids are infused rapidly. Mongrel dogs were exposed to smoke and 10% body-weight Ringer's lactate in three groups: (I) fluid only, (II) smoke only, and (III) smoke and fluid. The increase in wet-dry lung weight ratio was 2% in Group I, 28% in Group II, and 42% in Group III, consistent with pulmonary edema present only in Group III. The decrease in colloid oncotic pressure was similar in both of the groups that were given fluid, and the rise in the surface tension minimum of lung extracts was similar in both of the groups that were exposed to smoke. The smoke-injured lung loses the ability to protect itself when challenged with fluid. Reduced oncotic pressure is not responsible. Changes in microvascular pressure, endothelial and epithelial damage, and surfactant inactivation interact to cause this increase in extravascular lung water.

Pulmonary microvascular exchange: An analog computer simulation

An analog computer simulation of human pulmonary microvascular exchange was programmed and tested. This model of blood-to-lymph transport is based on a compartmental analysis of the lungs and has the capacity to describe fluid volumes, plasma protein content, flows and pressures for both normal and perturbed conditions. Normal conditions were predicted and shown to be in agreement with the literature. The trends in the response of the lungs to changes in microvascular pressure is shown also to agree with the literature both for steady state and transient predictions. The results of a sensitivity analysis, which demonstrates the response of the lungs to a variety of perturbations, is also reported. The simulation predicts reasonable results for normal, transient, and perturbed conditions in human lungs.

Effects of histamine and increased venous pressure on transmicrovascular protein transport

Histamine administered locally into canine forelimbs increases lymph flow, lymph protein concentration, and lymph protein transport. In this study we examined the time course of these changes and compared them to the changes produced by mechanically increasing venous pressure alone and during the infusion of histamine or acetylcholine. Intrabrachial infusion of histamine at 4 μg base/min produced 25- and 45-fold increases in lymph flow and protein transport, respectively, and a 50% increase in lymph protein concentration. These effects, however, waned with time. Qualitatively similar changes were seen with histamine infused at 16 and 64 μg base/min. Increased venous pressure alone produced 8- and 5-fold increases in lymph flow and protein transport, respectively, and decreased total protein concentration. Increasing venous pressure during histamine infusion further increased lymph flow and protein transport, which then waned with time. However, protein transport during histamine plus increased venous pressure was always greater than with the infusion of histamine alone. Increasing venous pressure during acetylcholine infusion increased lymph flow but decreased lymph protein concentration, resulting in only a small increase in total protein transport. These data indicate that the effects of histamine on protein transport are much greater than during increased venous pressure alone but that they wane with time. Increasing venous pressure during histamine infusion further increases protein transport relative to histamine alone. Histamine appears to increase microvascular efflux of protein, at least in part, through a mechanism which is sensitive to changes in microvascular pressure.

Transcapillary protein leakage and fluid movement: Effect of venous pressure

The effect of elevating venous pressure ( ΔP v) on the transcapillary escape of albumin ( Q T) in control and papverinized gracilis muscles perfused at constant flow was determined by means of direct monitoring of the rate of accumulation of tissue 125I-labeled albumin radioactivity. Simultaneously, transcapillary fluid movement (FM) was assessed volumetrically. Under control isovolumetric conditions, Q T = 2.25 mg/min · 100 g. In addition to causing an FM of 0.03 ml/min · 100 g · mm Hg, increasing P v enhanced Q T by 0.06 mg/min · 100 g · mm Hg. Papverinization itself decreased Q T to 2.0 mg/min · 100 g and affected FM only slightly. However, the superposition of P v elevation caused a FM of 0.008 ml/min · 100 g · mm Hg and resulted in Q T increasing by 0.29 mg/min · 100 g · mm Hg. The results of this study indicate that Q T is sensitive to changes in microvascular hemodynamics, and thus changes in microvascular pressure may affect FM in two ways, first by increasing the transcapillary pressure gradient and second by augmenting Q T which may superimpose an oncotic adjunct to FM.