THE GRADIENT OF VASCULAR PERMEABILITY : III. THE GRADIENT ALONG THE CAPILLARIES AND VENULES OF FROG SKIN

A steeply mounting gradient of permeability is demonstrable along the meshwork of capillaries which connects the arterioles and venules of the skin of the frog. The venules incorporated in the meshwork are even more permeable than the capillary meshes giving into them. The presence of the gradient under such differing conditions as exist along frog and mammalian capillaries enables one to rule out certain factors which might be invoked to explain it; and it is not explainable in terms of those influences generally recognized as conditioning exchange between the blood and tissues. Not improbably it results from a structural differentiation along the capillary.     

THE RELATION OF HYDROSTATIC PRESSURE TO THE GRADIENT OF CAPILLARY PERMEABILITY

The gradient of permeability along the capillaries of voluntary muscle and the capillaries and venules of skin exists independently of the hydrostatic conditions, though influenced by them. Its presence cannot be explained by a graded tonic contraction of the capillaries. The evidence,—like that of previous papers,—points to local differences in the barrier offered by the wall of these vessels as responsible for the gradient.     

THE GRADIENT OF VASCULAR PERMEABILITY : II. THE CONDITIONS IN FROG AND CHICKEN MUSCLE,AND IN THE MAMMALIAN DIAPHRAGM

A mounting gradient of permeability exists along the capillaries of frog muscle. In chicken muscle on the other hand none has been demonstrated; but the close-knit vascularization is arranged in duplicate in such manner that the blood runs in opposite directions through the capillaries of nearly adjacent fibres. In a flight muscle of the pigeon there exists in addition to this artifice what appears to be a special collecting system of venous capillaries. In the mammalian diaphragm indications of such a system are also to be found, and a gradient of capillary permeability like that in the other skeletal muscles is probably present. These vascular conditions are briefly considered in terms of function.     

THE GRADIENT OF VASCULAR PERMEABILITY

The permeability of the capillaries in the skeletal muscles of mammals increases progressively along their course and is greatest where they pass into the least venules. The gradient of permeability is so largely independent of functional states as to give grounds for the view that it is determined by inherent local differences. Through the gradient opportunity is equalized along the capillary. In the liver lobule this object is accomplished by an artifice of arrangement whereby the blood flow past the cells is increased with their distance from the source of supply. In the urinary bladder the interlacing of capillaries, their progressive widening, and a consequent gradual slowing of the blood flow act to achieve the same end. Here a gradient of permeability has not been demonstrable. Where cells of different sorts are served by a slender capillary, their differing requirements may render unnecessary any provision to equalize their opportunities; but where shortcomings in local maintenance will reduce the efficiency of an entire fabric, as the muscle fibre, and where cells of like character live competitively along the same channel, as in the liver, some arrangement must exist to ensure an even distribution of the services rendered by the blood. In situations of the kind last mentioned the immediate environment of the individual cell, the "milieu interne" of Bernard, is not only kept as constant as possible but it must be the same, by and large, for all of the cells. The task of serving voluntary muscle is not strictly limited to the capillaries. The intrafascicular arterioles and venules act so effectively to sustain the tissue about them that where they run no capillaries are supplied.     

THE RELATIVE PRESSURES WITHIN CUTANEOUS LYMPHATIC CAPILLARIES AND THE TISSUES

The pressure in the cutaneous lymphatic capillaries of normal mice anesthetized with nembutal ranged between 0.0 and 2.7 cm. of water. Measurements of the interstitial pressure in the tissue immediately next the lymphatics showed that, in more than half the instances studied, there was a slight gradient of pressure from the tissues to the lymph. In nearly all the other instances the pressures inside and outside the lymphatic capillaries were approximately equal. In two cases in which lymph flow in the capillaries was rapid, the lymph pressure may have been negative. Under these circumstances there must have been a considerable gradient of pressure from the tissues to the lymph. In skin which was rapidly becoming, or had recently become, edematous as result of the application of xylol or of heat, the intralymphatic capillary pressure generally was increased, yet when compared with the pressure prevailing in the edema fluid outside of the capillaries it was usually found to be relatively much lower, at times by as much as 5.9 cm. of water. The findings indicate that a pressure gradient is an important factor in lymph formation under normal and pathological circumstances.     

THE GRADIENT OF PERMEABILITY OF THE SKIN VESSELS AS INFLUENCED BY HEAT,COLD, AND LIGHT

The mounting gradient of permeability along the small vessels of the corium is essentially unaltered by active hyperemia produced by heat, cold, or light. Only when the vascular walls are so damaged that rapid leakage ensues, as shown by the development of edema, does the permeability of the capillary web as a whole approximate that of the venules. It is plain that the normal gradient of vascular permeability depends upon the integrity of the vessel wall. The method of experiment described can be utilized for a study of the functional changes which result in the lesions due to burning and freezing.     

THE INFLUENCE OF THE PLASMA COLLOIDS ON THE GRADIENT OF CAPILLARY PERMEABILITY

The influence of osmotic conditions on the gradient of capillary permeability disclosed by the distribution into mammalian muscle of vital dyes has been tested experimentally. The percentage of circulating blood proteins was increased in rabbits by the injection of compatible plasma, or of compatible serum concentrate obtained by means of a new method of ultrafiltration which has proved both rapid and effective. It was found that when this had been done and the circulatory conditions had stabilized themselves, the gradient of capillary permeability still existed, though its effective extent was less than under normal circumstances. When the percentage of circulating blood proteins was reduced, on the other hand, by repeated bleedings with return of the cells, either as such or suspended in the protein-free fluid obtained by dialysis of serum, the extent of the gradient of capillary permeability was broadened and dye passed out into the tissue more readily than usual from the capillary as a whole. In contrast to these findings injection of a very hypertonic dextrose solution during the period when dye was escaping had no perceptible effect on the gradient of capillary permeability. The observed phenomena cannot be explained by a flow of dye-stained fluid into or out of the blood vessels. The gradient of capillary permeability exists independently of osmotic conditions, though its extent can be markedly influenced by altering the amount of circulating blood proteins. A considerable proportion of the dye used to study the gradient is adsorbed upon these proteins, as subsidiary experiments have shown. This happening provides a sufficient cause for the differences observed in the extent of the gradient when the percentage of proteins is increased or diminished. The evidence like that of previous papers indicates that the cause for the gradient is to be found in a structural differentiation along the capillary, such that the barrier offered by its wall progressively diminishes on the way to the venule. Most current estimates of the effective osmotic pressure of the blood proteins fail to take into account the existence of local differences in permeability along the capillary.     

Polyarteritis nodosa complicated by antiphospholipid syndrome

Polyarteritis nodosa is a necrotizing vasculitis of small and medium-sized arteries that spares the smallest blood vessels (arterioles, venules, and capillaries). Antiphospholipid syndrome is an autoimmune disorder characterized by venous or arterial thrombosis and/or by fetal losses, associated with antiphospholipid antibodies. The association of both diseases is infrequent. This case report discusses a male patient with a diagnosis of polyarteritis nodosa who, after 7 years of being diagnosed with vasculitis, showed ischemic lesions in his legs associated with high titers of anticardiolipin antibodies, along with angiographic and histologic evidence of thrombosis. Despite immunosuppressive and anticoagulant therapy, his lesions progressed, and both legs had to be amputated.     

THE LIBERATION OF RENIN BY PERFUSION OF KIDNEYS FOLLOWING REDUCTION OF PULSE PRESSURE

1. Isolated dogs'' kidneys have been perfused with defibrinated blood under hemodynamic conditions similar to those in the body. Under these circumstances blood flow, urine secretion, and oxygen consumption are well maintained, but urea clearance is low. Renal venous blood collected initially and at the end of 3 or more hours of perfusion exhibited no difference in vasoconstriction properties when perfused along with renin or renin-activator through an isolated rabbit''s ear. 2. Reduction of pulse pressure by constricting the renal artery may be performed without reducing mean pressure significantly. Impairment of urea clearance and rate of urine secretion follow, and oxygen consumption is slightly reduced. 3. After an hour or more of perfusion with reduced pulse pressure, gradual rise in mean renal arterial pressure distal to the clamp and reduction of blood flow occur. 4. Renal venous blood collected after about one hour of perfusion with reduced pulse pressure differs from that collected before reduction of pulse pressure in that it causes intense vasoconstriction when perfused with renin-activator through an isolated rabbit''s ear. 5. Perfusion of a dog''s hind leg under similar circumstances does not cause this change in the venous blood to occur.     

EVIDENCE FOR A BLOOD-THYMUS BARRIER USING ELECTRON-OPAQUE TRACERS

In order to verify the existence of a blood-thymus barrier to circulating macromolecules, the permeability of the vessels of the thymus was analyzed in young adult mice using electron opaque tracers of different molecular dimensions (horseradish peroxidase, cytochrome c, catalase, ferritin, colloidal lanthanum). Results show that although blood-borne macromolecules do penetrate the thymus, their parenchyma] distribution is limited to the medulla of the lobe by several factors: (a) the differential permeability of the various segments of the vascular tree; (b) the spatial segregation of these segments within the lobe; (c) the strategic location of parenchymal macrophages along the vessels. The cortex is exclusively supplied by capillaries, which have impermeable endothelial junctions. Although a small amount of tracer is transported by plasmalemmal vesicles through the capillary endothelium, this tracer is promptly sequestrated by macrophages stretched out in a continuous row along the cortical capillaries and it does not reach the intercellular clefts between cortical lymphocytes and reticular cells. The medulla contains all the leaky vessels, namely postcapillary venules and arterioles. Across the walls of the venules, large quantities of all injected tracers escape through the clefts between migrating lymphocytes and endothelial cells; also the arterioles have a small number of endothelial junctions which are permeable to peroxidase, but do not allow passage of tracers of higher molecular weight. The tracers released by the leaky vessels penetrate the intercellular clefts of the medulla, but they never reach the cortical parenchyma, even at long time intervals after the injection. Therefore, a blood-thymus barrier to circulating macromolecules does exist, but is limited to the cortex. Medullary lymphocytes are freely exposed to blood-borne substances.     

Pressure-flow relationships of the pulmonary circulation during endotoxin infusion in intact dogs.

BACKGROUND AND METHODS: We aimed to characterize the effects of an endotoxin insult (Escherichia coli 0127:B8) on the relationships between pulmonary vascular pressure and flow in intact dogs. To achieve this goal, multipoint plots of total pressure gradient, arterial pressure gradient, and venous pressure gradient vs. flow were generated by graded inflation of a right atrial balloon, which was used to vary flow. The partitioning of the total pressure decrease across the pulmonary vasculature (total pressure gradient = pulmonary arterial pressure-pulmonary artery occlusion pressure [PAOP]) into gradients across pulmonary arterial (arterial pressure gradient = pulmonary arterial pressure--effective capillary pressure) and pulmonary venous (venous pressure gradient = effective capillary pressure--PAOP) regions was assessed by a waveform mathematical analysis of the pulmonary arterial pressure profile during arterial occlusion, with computation of both PAOP and effective pulmonary capillary pressures. Slopes and extrapolated pressure intercepts from linear regression fits to the pulmonary vascular pressure/flow plots were determined in seven dogs after a 2-hr endotoxic infusion interval and were compared with the corresponding values that characterized a similar group of sham-operated dogs. RESULTS: Under normal conditions, the extrapolated pressure intercept for pulmonary arterial pressure gradient was virtually 0 mm Hg; for total pulmonary arterial pressure gradient and pulmonary venous pressure gradient, the mean extrapolated pressure intercepts were substantially positive: 2.4 +/- 0.2 and 2.1 +/- 0.3 mm Hg, respectively. Endotoxin infusion at 0.25 micrograms/kg/min significantly increased the pressure intercepts from 2.4 to 8.7 and from 2.1 to 8.3 mm Hg of total pressure gradient and venous pressure gradient vs. flow, respectively. This infusion produced a minor, nonsignificant change in the intercept of arterial pressure gradient vs. flow, whereas it increased its slope significantly (p less than .05) from 0.036 to 0.081 mm Hg/mL/min/kg. CONCLUSIONS: These data suggest that endotoxin's effects on vascular resistance are exerted at two different loci such that these effects are additive. These endotoxin-induced effects consisted of increased vascular resistance of the arterial segment and appearance of a Starling resistor at the venous side of the pulmonary circulation, which acted as the relevant back-pressure to flow.     

BLOOD MICROCIRCULATION IN THE LYMPH NODE DURING THE PRIMARY IMMUNE RESPONSE

Microangiography performed after total blood replacement with contrast material provided complete visualization of the vascular structures of the lymph node. Starting of the 2nd day, there is capillary redistribution throughout the cortex of the lymph node. The previously rather avascular nodules dissolve, and the cortical lymphoid tissue becomes uniformly vascular. Beginning on the 2nd day and reaching its peak on the 5th day, there is a significant increase in diameter and density of the subcapsular and medullary cord capillaries. 15 days after the antigenic stimulus, the appearance of the microvasculature returns to normal. The postcapillary venules (the microvascular structures which follow the capillaries) are widely distributed throughout. Histologically, only a fraction of these venules have a high endothelial lining (HE venules). Therefore, it is suggested that among the postcapillary venules, those with high endothelial lining should be specifically denoted. Great individual variation in the number of HE venules was observed, and no correlation with the timing of the immune response could be established. Whether the microvascular changes described lead to cellular change or are mere expressions of it cannot definitely be stated. However, the significant hypervascularity along the intranodal lymph pathways and the diffuse, even redistribution of the capillaries and postcapillary structures could greatly facilitate the humoral and cellular exchange between the circulating blood, the circulating lymph, and the tissues of the lymph node.     

Changes in the cardiac hemodynamics and coronary blood flow in acute myocardial infarction due to perftoran

One hundred and twenty patients with acute myocardium infarction, who were receiving perftoran, were analyzed within the case study. The microcirculation condition was determined by biomicroscopy of the eye conjunctiva capillaries. Changes in capillaries were evaluated by the Ditzel classification. Hemostasis was evaluated by coalugram. The condition of the myocardium was examined by electrocardiography and Echo-cardiography. The contractive ability of the myocardium was assessed by a shortening degree of the anterior-posterior size and by the ejection fraction. According to the study results, the administration of perftoran increased the number of functioning capillaries, decreased the venous congestion and reduced the diameter of arterioles and venules. Hypercoagulation was significantly decreasing. The general evaluation of the contractive ability of myocardium was satisfactory in all patients.     

CONDITION OF THE CAPILLARIES IN HISTAMINE SHOCK

1. Histamine exerts a local dilator effect upon capillaries and upon the smallest arterioles and venules which border the capillary system. There occurs also an opening up of large numbers of capillaries of which no trace can be seen before the application of histamine. 2. When injected intravenously in amounts sufficient to produce shock, histamine causes a quickly progressive dilatation of both the visible and the occult capillaries and of their immediately adjacent arterioles and venules, all of which become engorged with blood that moves through them in a strikingly sluggish manner. The circulatory failure which characterizes histamine shock results from the dilatation of the peripheral vascular bed.     

Factor XIII and wound healing

In addition to those wounds with increasing fragility of capillaries during impaired healing, there are especially long lasting diabetic wounds or calf ulcerations due to chronic venous insufficiency or postthrombotic syndrome that show a failure of endothelial barrier function with an increased permeability as an important part of its pathophysiological situation. The possibility of controlling this increased permeability is of great therapeutical interest and may give distinct benefit for wound healing. In the close past, clinical as well as experimental studies revealed the plasma transglutaminase (factor XIIIa) as potential new strategy in treatment of increased vascular permeability.     

Die Beeinflussung des in situ gemessenen extravasalen Proteingehaltes durch Änderung der Gefäßpermeabilität

The extravascular protein contents in the perivascular connective tissue of a rat's mesenterial plate was measured ultramicrospectrophotometrically in situ and in vivo after changing the hydrostatic and colloidosmotic pressures of the blood. We analized the perivascular area of the different microcirculatory vessels, arterioles, capillaries and venules. The perivascular protein contents, which corresponds besides arterioles to 40% and besides venules to 59% in comparison to the intravascular blood plasma, decreased in a comparison group under the osmotic influence of the perfusion liquid on the mesenterial plate. An injection of an isotonic saline solution is followed only by small fluctuations of the perivascular protein contents during one hour. After blood loss a transitional increase of extravascular protein at the perivenular area was observed indicating the mobilisation of protein depots. Around arterioles the extravascular protein contents did not change significantly. An intravenous injection of albumin solution was followed by a short-termed increase of tissue protein around the arterioles. Around the venules after 50 minutes the extravascular protein contents increased significantly. Within one hour after the changes of the permeability conditions the maximal induceable protein movements in the perivascular space were calculated as +/- 1.35 g% plasma protein concentration corresponding to a maximun protein exchange of +/- 3.1 mg ml(-1) tissue.     

肝静脉压力梯度测定对食管静脉曲张套扎术后早期再出血的预测价值

目的研究肝静脉压力梯度(HVPG)对食管静脉曲张套扎术(EVL)后早期再出血的预测价值。方法选取该院2014年1月-2015年1月收治的120例EVL后早期再出血患者作为研究对象,收集其各项临床重要参数,并进行HVPG测量,采用Logistic回归分析的方法对评估阈值进行分析。结果饮酒、早期出血、胆红素、心率、输血量、Child-Pugh评分和自终末期肝病模型(MELD)评分组间比较差异有统计学意义(P0.05);HVPG=16.98 mm Hg,为预测再出血的阈值,且在该时间内的预测准确性最高。结论 HVPG对EVL术后早期再出血具有预测价值。     

FACTORS INFLUENCING THE INTERMITTENT PASSAGE OF LOCKE'S SOLUTION INTO LIVING SKIN

Minute amounts of Locke''s or Tyrode''s solution have been brought into contact with the interstitial connective tissue of the skin of the living mouse, at atmospheric pressure, in such a manner that the blood or lymphatic vessels are not entered directly. Under such circumstances these absorbable fluids enter the tissue spontaneously. Entrance is strikingly intermittent, not continuous, and so too when very slight pressures are brought to bear on the fluids (1). Hyperemia of the tissues, with accompanying dilatation of the blood vessels, increases the entrance of fluids at atmospheric pressure but it is still intermittent. By contrast, venous obstruction leads to intermittent backflow into the apparatus, but reflex hyperemia, following release of the obstruction, is attended by an increase of flow into the tissues in spite of the great reactive dilatation of vessels. The inflow is also intermittent. If the skin is deprived of circulation, fluid does not enter it at all at atmospheric pressure, though it moves in regularly and continuously if slight pressure is put upon it. Edema-forming fluids, described in the text, also enter in a continuous manner when forced into the skin of either living or dead animals. So too do serum and sperm oil. The findings indicate that the passage of interstitial fluid into the blood vessels may be intermittent under normal circumstances and its escape from them as well. The observed occurrence of intermittent flow in the blood vessels of several tissues (9, 15–25) will go far to account for the intermittent entrance of fluid into the skin.     

Pressure-dependent factors in edema formation in canine forelimbs.

Acetycholine (10 mug/min) infused intra-arterially for 30 minutes into naturally perfused forelimbs increased forelimb weight 23 g. largely due to edema formation. The weight gain was associated with markedly elevated skin and skeletal muscle blood flows and small vein pressures, suggesting that the edema was attributable, in part, to a rise in microvascular pressures. Mechanically increasing venous pressure and blood flow to similar levels for 30 minutes in pump-perfused forelimbs produced a weight gain of 27 g. The rate of weight gain for the acetylcholine and mechanical alterations was nearly identical. Acetylcholine and mechanical alterations both increased forelimb lymph flow rate but failed to increase lymph total protein concentration significantly. These studies indicate that in the dog forelimb elevated microvascular pressures result in edema formation by increasing the transcapillary hydrostatic pressure gradient without producing an important decrease in the transcapillary colloid osmotic pressure gradient. Increased pressure is not associated with a large increase in microvascular permeability to plasma proteins as is seen with the administration of high doses of histamine and bradykinin.     

Subpleural microvascular flow velocities and shear rates in normal and septic mechanically ventilated rats

Changes in pulmonary microhemodynamics are important variables in a large variety of pathological processes. We used in vivo fluorescent videomicroscopy of the subpleural microvasculature in mechanically ventilated rats to directly monitor microvascular flow velocity (FV) and shear rate in pulmonary arterioles, capillaries, and venules in healthy rats and in septic rats 20 h after cecal ligation and puncture (CLP). Observations were made through a small thoracotomy after injection of fluorescent microspheres (D = 1 microm) into the systemic circulation. The FVs were calculated off-line by frame-by-frame measurements of the distance covered by individual microspheres per unit of time. In healthy rats, inspiratory FV were 1322 +/- 142 microm/s in subpleural arterioles and 599 +/- 25 microm/s in capillaries. The highest FV was found in venules (1552 +/- 132 microm/s). The calculated shear rates were 547 +/- 62/s in arterioles and 619 +/- 19/s in capillaries. The highest shear rates were detected in venules (677 +/- 59/s). No significant changes in FV and shear rates were observed throughout the 1-h observation period in any of the microvascular compartments. Pulmonary microvascular FV and shear rates found in sham-operated rats in the CLP experiments were not significantly different from values of healthy rats. The CLP caused a significant increase in leukocyte sequestration in the lungs and a mean of 27% to 34% decrease in FV in all sections of the pulmonary microvasculature (P < 0.001 in capillaries and P < 0.05 in venules). Also, CLP caused a 23% decrease in capillary shear rate that reached only borderline statistical significance (P < 0.06) and a significant 35% decrease in mean shear rate in venules (P < 0.05). Fluorescent videomicroscopy is offered as a stable and reproducible method for in vivo determinations of pulmonary microhemodynamics in clinically relevant models of sepsis.