[Changes in the permeability induced by calcium. I. Influence of calcium on capillary permeability to Evans-blue].
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OBJECTIVE: To study the regulation of antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP) in obese and lean women with a swelling syndrome. PATIENTS: Thirty-four obese women and 12 lean women with a swelling syndrome and an abnormal isotopic test of capillary permeability to albumin were investigated. MEASUREMENTS: After 10 nocturnal hours of fluid restriction, subjects were asked at 8am to ingest a tap water load of 20 ml/kg within 10 min and to remain strictly recumbent until twelve noon on the first day, and to remain standing and to walk around until twelve noon on the second day. Free water clearance and the cGMP/creatinine and albumin/creatinine ratios were determined hourly in the morning. RESULTS: The total 4 h-urinary volume/ingested water volume ratio was significantly lower on the second day both in the lean and the obese patients, the differences being slightly larger in the obese patients. The increase in free water clearance was significantly less on the second day in the obese patients. The increase in cGMP/creatinine ratio was also significantly lower on the second day in the obese patients. The maximum level of the urinary albumin/creatinine ratio was significantly higher on the second day in the obese patients. CONCLUSION: In obese women with a swelling syndrome: (1) The higher increase in the urinary albumin excretion rate after water loading followed by a sustained upright position suggests a widespread alteration in capillary function, which is also indicated by the isotopic test of capillary permeability to albumin. (2) The water load-induced inhibition of ADH secretion and stimulation of ANP secretion or ANP activity, more defective in the upright position than in the recumbent one, is probably another major contributing factor to orthostatic oedema.
To study the possibility of enhancing the delivery of antineoplastic agents to tumor tissue, we conducted an experimental study using induced hypertension with angiotensin II in rats with experimental brain tumors. Drug delivery was evaluated by measuring local cerebral blood flow (LCBF) and regional cerebral capillary permeability with quantitative autoradiography. There was no significant difference of LCBF in the central region of tumor tissue between the control group and the induced hypertension group. LCBF in the peripheral region of tumor tissue in the induced hypertension group was significantly higher than that in the control group. On the other hand, despite induced hypertension, no significant changes in the regional cerebral capillary permeability were observed between the groups. These results indicate that delivery of the lipid-soluble antineoplastic agents, which depend upon cerebral blood flow, can be enhanced by induced hypertension.
The effect of altered alveolar-capillary permeability on angiotensin converting enzyme (ACE) activity in serum (SACE) was studied in 45 patients with sarcoidosis and 21 healthy controls. In sarcoidosis increased albumin concentrations in the bronchoalveolar lavage fluid (L albumin) and increased ratios of L albumin to albumin in serum (S albumin) indicated an increased permeability of the alveolar-capillary membrane. ACE activity in the lavage fluid (LACE) was correlated with the number of alveolar macrophages in controls, indicating that it may come from these cells. LACE was high in active sarcoidosis while in inactive disease it was similar to that in controls. SACE in sarcoidosis was significantly increased. Ninety per cent of patients with increased L albumin had increased SACE. SACE activity was significantly correlated with concentrations of L albumin and with LACE activity. The relationships between signs of increased membrane permeability and SACE and between LACE and SACE suggest that excess SACE in sarcoidosis may, at least partly, originate in the alveolar space.
We developed a new method by which capillary permeability changes secondary to gram-negative sepsis can be easily monitored. In a preliminary trial, ten dogs were injected intravenously with live Escherichia coli. Progressive extravasation of fluorescein from the retinal capillary bed was demonstrated by retinal angiography, thus indicating "capillary leak." In a subsequent trial, fluorophotometry facilitated direct quantitation of this leak. Three control and three septic dogs underwent continuous hemodynamic and physiologic monitoring. Hourly retinal fluorophotometric measurements were recorded. The control group demonstrated no capillary leak nor any change in hemodynamic and physiologic status. In the septic group, there was a dramatic increase in extravascular fluorescein concentration two to four hours after E coli infusion, correlating well with hemodynamic and physiologic parameters typical of gram-negative shock.
Experiments were performed in 10 cats of either sex to ascertain the effects of postprandial arterial plasma concentrations of neurotensin (NT) on intestinal capillary permeability and blood flow. NT was infused intra-arterially into an isolated perfused loop of terminal ileum to produce a 182 +/- 15 (SE) pM plasma NT concentration. Intestinal lymph (L) and plasma (P) protein concentrations were measured at various venous pressures under control conditions and during NT infusion. The osmotic reflection coefficient (sigma d) was estimated under all conditions assuming sigma d = 1 - L/P at high capillary filtration rates. NT infusion significantly (P less than 0.001) reduced sigma d to 0.73 +/- 0.02 (SE) from a control level of 0.91 +/- 0.01. NT infusion also significantly increased intestinal blood flow [47.0 +/- 4.3 (SE) ml X min-1 X 100 g-1] versus control (36.6 +/- 3.2 ml X min-1 X 100 g-1), a 28.4% increase. Intestinal vascular resistance was decreased from 3.21 +/- 0.31 to 2.42 +/- 0.28 mmHg X min X ml-1 X 100 g in the absence of a change in local mean arterial blood pressure. Pore-stripping analysis of lymph and plasma solute fractions during NT infusion at high lymph flows predicted two populations of pores, 330-A and 46-A radius, accounting for 31 and 67%, respectively, of the total transcapillary hydraulic flow. NT infusion preferentially increased large-pore radius as a means of increasing intestinal capillary permeability. The rates of small- to large-pore areas and numbers were 106:1 and 5,225:1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
To examine direct influences of capillary blood flow on its permeability of water-soluble substances, we measured the local capillary permeability in the rabbit tenuissimus muscle at various capillary blood flow levels by the use of microscopic tissue clearance method. After staining the muscle with Cr-EDTA (M.W.: 341) as the test tracer by suffusing its solution around the tissue, subsequent concentration change in the tissue due to the tracer washout by capillary blood flow was measured from the intensity change on the TV monitor through the vital-microscope. The decay constant of obtained tissue clearance curve has been theoretically predicted to be equal to the local capillary permeability surface area product (PS) per unit tissue volume (Vt). The local capillary permeability (P) could be quantified by calculating the capillary surface area (S) from the perfused capillary density in the visualized microscopic field. The calculated values of P and PS/Vt in the high flow state were 6.00 +/- 0.70 (X 10(-6) cm/s) and 5.85 +/- 0.77 (X 10(-4)/s), respectively, which were significantly larger than those in the low flow state (p < 0.01). It was suggested that there was a mechanism in the red cell passage through the capillary which facilitated the substance exchange across the capillary wall.
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The assumption inherent to the single injection residue function method to determine capillary permeability have been made explicit. Furthermore, it is shown that agreement between the deduced wash-out function of the transmitted molecules of the test substances and that of reference molecules does not constitute proof of the validity of the method.
Experimental intracerebral hemorrhage has been shown to cause extensive cerebral ischemia. This study was performed to ascertain the time course of these changes and also to examine the type of brain damage that may occur under such circumstances. Halothane anesthesia was induced in rats, and 25 microliter autologous blood was injected into the caudate nucleus; the effects were studied with autoradiographic measurement of local cerebral blood flow and capillary permeability, and also by light microscopy and histochemical techniques. Blood flow returned to normal or to slightly increased levels within the first 3 hours, and ischemic levels of flow were found to persist only to a marginal degree beyond 10 minutes after the lesions were made. Capillary permeability was maximum during the first 30 minutes after the hemorrhage and diminished with time. Structural evidence of ischemic damage was localized to the cortex overlying the hemorrhage, but was not seen in the caudate nucleus. Nevertheless, histochemical investigation did reveal an area of disturbed enzyme function in the striatum. This finding of biochemical disturbance without structural evidence of ischemic damage reveals that there is an area around the hematoma that, although demonstrating disturbed function, does not show structural damage, and the milieu of this partially injured brain may be implicated in the delayed development of the ischemic brain damage that follows intracerebral hemorrhage in man.
Mild acute hypertension was induced in rats pharmacologically and non-pharmacologically with metaraminol, angiotensin II or bilateral vagotomy. The extraction fraction of water (Ew) was measured in both hypertensive and normotensive animals. It was demonstrated that cerebral blood flow did not change during hypertensive states. Under constant flow conditions Ew becomes a direct index of the cerebral capillary permeability to water. Ew was significantly decreased (P less than 0.001) in all brain regions examined in the hypertensive animals as compared to normotensive controls. However, the decrease Ew induced by hypertension was not observed if the animal had previously received bilateral carotid sinus denervation. This observation indicated that the capillary permeability response induced by hypertension is mediated by a neurogenic mechanism involving information transfer from the peripheral baroreceptors in the carotid sinus along afferent connections into the central nervous system.
We have previously demonstrated that therapy with a new specific endothelin-1 receptor antagonist (ET-RA) significantly reduced mortality in acute necrotizing pancreatitis (ANP) in the rat. Improved survival was not associated with decreased intrapancreatic trypsinogen activation or parenchymal necrosis but with reduced fluid sequestation into the third space suggesting that ET-RA counteracts systemic rather than local sequelae of severe pancreatitis. The present study further tests this hypothesis by evaluating the effect of the specific ET-1 antagonist LU-135252 on capillary blood flow, capillary density, and capillary permeability not only in the pancreas but also in the colon, and monitoring fluid losses and renal and respiratory function. The experiments demonstrate that therapy with the specific ET-RA started 6 hours after disease onset stabilizes increased capillary permeability in ANP not only in the pancreas but also in the colon. This is associated with reduced ascites and improved renal and respiratory function. Furthermore, ET-RA enhances decreased capillary blood flow and capillary density in the pancreas and colon. The present results are consistent with our previous observation that ET-RA improves outcome in ANP by counteracting systemic microcirculatory disorders (particularly capillary leakage) which are believed to contribute to organ failure in early pancreatitis in this model as well as in severe human pancreatitis.
RATIONALE AND OBJECTIVES: Dynamic magnetic resonance imaging (MRI) enhanced with a macromolecular contrast medium, albumin-(Gd-DTPA)35, was used to detect changes in microvascular characteristics in R3230 mammary adenocarcinomas induced by x-irradiation. METHODS: Tumors were implanted in either flank in nine rats. One of the tumors was exposed to single-dose x-irradiation (30 Gy) 3 days before MRI. The contralateral control tumor was shielded from irradiation. RESULTS: Capillary permeability to macromolecular contrast medium in irradiated tumors was elevated significantly (P < .05) compared to the control nonirradiated tumors. The mean estimated permeability surface area product for the irradiated tumors increased more than three-fold; 0.511 +/- .046 mL hr-1 cm-3 compared with 0.121 +/- .011 mL hr-1 cm-3 for the nonirradiated tumors. This radiation-induced increase in permeability was corroborated using a macromolecular Evans blue-protein complex measured in the same tumors using an invasive spectrophotometric technique. CONCLUSIONS: Dynamic MRI-enhanced with macromolecular contrast medium permits noninvasive quantitative estimates of capillary permeability in tumors, with and without x-irradiation. Because the transendothelial permeability for macromolecular solutes likely influences tumoral accumulation of macromolecular chemotherapeutic agents, this noninvasive technique may prove to be clinically useful in tailoring tumor treatment programs which combine radiation and chemotherapy.
Terminal circulation can be studied in vivo using capillaroscopy. This paper presents the results of systematic investigations of capillary permeability (KPU) in the nailfold. In addition to the morphology of capillary loops, we investigated the transcapillary passage and interstitial distribution of sodium fluorescein (Na-flu) in healthy persons (42) and in patients suffering from functional microangiopathies (17) or organic vascular disease (58). The effects of various therapeutic measures on the microcirculation were also studied. First, dynamic processes at the capillary loops were recorded on a video system. The second step consisted of quantification of the pericapillary light intensities (FLI) at predetermined times using a computerized video-densitometer. The measured variables, i.e. maximal interstitial FLI, diameter of the juxtacapillary halo (IK-H) and distance between the intracapillary column of red cells and the interstitial peak of FLI, provided information about the permeability of the capillaries and the interstitial diffusion of Na-flu. In healthy subjects, the interstitial FLI reached its highest values 10 sec after the appearance of Na-flu in the capillary loop, the distance between the peak of FLI and the intracapillary column of erythrocytes increased continuously over a period of 2 min, whereas the diameter of the IK-H reached a constant value after 20 sec. In patients suffering from functional microangiopathy, an increased pericapillary FLI as well as an enlarged juxtacapillary zone with elevated Na-flu concentrations could be established as objective criteria in addition to the already known alterations of the morphology of the capillary loops. Similar observations, but of much greater extent, were made in patients suffering from microvessels disease associated with collagen disease. The regional variation in the pericapillary FLI supports the assumption that morphological changes are present in these patients. KPU in patients suffering from organic macroangiopathy revealed no changes in comparison to healthy persons. The effects of conventional therapy in patients with reduced peripheral arterial perfusion on the parameters measured by KPU were of variable magnitude. The increase in trans-capillary leakage and interstitial dispersion of Na-flu was significant during systemic fibrinolysis and during the intra-arterial application of PGE1. The changes in the measured parameters were considerably smaller during therapy with phenprocoumarol and heparin, whereas treatment with inhibitors of platelet aggregation left the results of KPU unchanged.(ABSTRACT TRUNCATED AT 400 WORDS)
Pulmonary dysfunction and permeability were prospectively studied in a group of severely traumatized patients. Ventilatory parameters (i.e., PaO2/FiO2, dynamic compliance, per cent shunt, and A-a DO2) and extravascular lung water (EVLW) measurements were compared with scintigraphic determinations of pulmonary albumin extravasation. Albumin extravasation data demonstrated a pulmonary capillary permeability increase occurring shortly following trauma. The median albumin extravasation value in the patients within 24 hours of trauma was 3.6 X 10(-5)/sec, compared to a control value of -0.1 +/- 0.7 X 10(-5)/sec. Intermediate levels of albumin extravasation were found in patients studied within 48 hours of total hip replacement (1.6 +/- 0.9 X 10(-5)/sec). Eighty per cent of patients studied within the first 48 hours of their trauma had albumin extravasation values exceeding the upper limit of normal as determined by the control value + 2 S.D. In contrast to albumin extravasation values, the PaO2/FiO2, dynamic compliance, per cent shunt, A-a DO2, and EVLW did not begin to deteriorate significantly until at least 48 hours after trauma. We conclude that severe multiple trauma induces an early increase in pulmonary capillary permeability as measured by albumin extravasation scintigraphy. This change is not detectable with other commonly used measures.
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We propose a new test for measuring the "capillary permeability" with labeled albumin, with simpler methods, satisfactory results and good discrimination between normal subjects and pathological patients. In normal subjects, after the removal of the tourniquet, the radioactivity returns to former values (under 10% of this figure). In pathological patients, even after the 3 min following the removal of the tourniquet, there is no return to the former value (the retention of labeled albumin is always over 10%). It is in cyclic oedema that the test provides the most interesting results.
OBJECTIVE: The aim was to evaluate the effect of 5-aminosalicylic acid on myocardial capillary permeability for small hydrophilic molecules after ischaemia and reperfusion. METHODS: Open chest anaesthetised dogs were subjected to a 20 min occlusion of the left anterior descending coronary artery followed by 1 h reperfusion. 5-Aminosalicylic acid (bolus injection 12 mg.kg-1, followed by 105 micrograms.kg-1.min-1) (n = 10) or saline (control, n = 12) was given intravenously for 1 h, starting 20 min before ischaemia. The myocardial plasma flow rate, myocardial capillary extraction fraction, and myocardial capillary permeability-surface area (PS) product for 99mTc-DTPA were determined before ischaemia, and 5 and 60 min after the start of reperfusion by employing the single injection residue detection method. Immediately after reperfusion, the reactive hyperaemic plasma flow was measured by the 133Xe washout method. RESULTS: Four dogs (two untreated and two treated with 5-aminosalicylic acid) were eliminated due to ventricular fibrillation at the time of reperfusion. In the remaining animals (10 controls and eight treated) the plasma flow rate, capillary extraction fraction and PS were similar before myocardial ischaemia. After 5 min reperfusion, the plasma flow rate and PS were significantly increased in control animals (p < 0.02 and p < 0.008, respectively), but were unchanged in dogs treated with 5-aminosalicylic acid. In addition, after 5 min reperfusion, PS was significantly higher in the control group than in treated animals (p < 0.005). Microcirculatory variables returned to preocclusive values in both groups by 60 min after reperfusion. 5-Aminosalicylic acid had no significant effect on haemodynamics or on reactive hyperaemic plasma flow. CONCLUSIONS: The results suggest that 5-aminosalicylic acid can attenuate the microvascular changes after reversible myocardial ischaemia. The effect is potentially beneficial, and may be mediated by well recognised anti-inflammatory actions of 5-aminosalicylic acid (ie, scavenging of oxygen free radicals and neutrophil inhibition).