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Malignant ascites. Clinical and experimental observations.

Malignant ascites formation is a grave prognostic sign, but palliative efforts seem justified in some patients. Lack of knowledge concerning the natural history of this process hinders the choice of therapeutic options. Over 5 years, 107 patients with untreated malignant ascites were reviewed to define their survival. Pancreas (20), ovary (18), and colon (18) were the most frequent tumors, with 52% of patients presenting with ascites at the time of the initial cancer diagnosis. Cytology evaluation of the ascitic fluid was positive for tumor cells in 57% of cases and a high protein content was noted in 65%. Mean survival of the entire series was only 20 weeks from the time of diagnosis of ascites, with tumors of ovarian and lymphatic origin having better mean survivals of 32 and 58 weeks, respectively. Patients with high ascitic protein levels fared better than those with low levels. In an effort to explain this correlation of elevated protein levels and a favorable survival rate, a hypothesis was proposed that certain tumors secrete a factor, which alters vascular permeability and causes fluid accumulation in the absence of lymphatic obstruction. In an experimental rat model of malignant ascites, the intraperitoneal infusion of cell-free malignant ascitic fluid caused an increase in edema formation and a significant increase in capillary permeability to protein in the omentum. This demonstrated change in the leak of protein explains the formation of ascites by some tumors in the absence of tumor obstruction of the draining lymphatics of the peritoneal cavity and suggests another important mechanism in the genesis of malignant ascites.

Adult↗

Neutral endopeptidase inhibition, a new approach in the exploration of diabetic vasculopathy in rats.

Diabetic complications are mostly vascular and involve alteration in blood vessel reactivity and permeability. The contribution of the latter dysfunction to the development of target organ damage has not been thoroughly examined. In this study, we verify the acute effect of three peptidase inhibitors (phosphoramidon: N-(alpha-rhamnopyranosylhydroxyphosphinyl)-Leu-Trp, thiorphan: 3-mercapto-2-benzyl-propanoylglycine, and SQ 28,603: N-(2-mercaptomethyl)-1-oxo-3-phenylpropyl]- < or = b-alanine; each at a dose of 2 mg/kg), as well as captopril ([2S]-1-[3-mercapto-2-methyl-propionyl]-L-proline; 10 mg/kg), and an aminopeptidase inhibitor (amastatin: ([(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-Val-Val-Asp; 2 mg/kg) on capillary extravasation abnormalities in the streptozotocin-induced diabetic rat using the Evans blue method. Untreated diabetic rats exhibited a significant enhancement of Evans blue extravasation in the duodenum, upper bronchus, pancreas and skin (175 +/- 19, 94 +/- 4, 95 +/- 9 and 47 +/- 10 micrograms/g dry tissue respectively compared to 67 +/- 9, 44 +/- 5, 47 +/- 4, and 6 +/- 2 micrograms/g dry tissue). The three endopeptidase inhibitors normalized capillary permeability in all tissues. Also, treatment with captopril was associated with complete correction of capillary dysfunction in the skin and partially in the duodenum, upper bronchus, and pancreas. These findings indicate for the first time that the use of neutral endopeptidase inhibitors may be beneficial in preventing capillary abnormalities in this diabetic rat model.

Alanine↗

Neutral and DEAE dextrans as tracers for assessing lung microvascular barrier permeability and integrity.

Steady-state lymph-to-plasma concentration ratios (L/Ps) of neutral dextrans, cationic DEAE dextrans, and endogenous proteins were determined under normal and increased permeability conditions in six unanesthetized yearling sheep prepared with chronic lung lymph fistulas. Fluorescent dextrans with radii ranging from 1 to 30 nm were intravenously infused, and after 24 h, perilla ketone (PK) was given to alter permeability while the dextran infusion was maintained. Plasma and lymph samples were collected before and after PK administration and analyzed for dextran and protein concentrations after high-performance liquid chromatography size separation. Under both baseline and increased permeability conditions, DEAE dextrans had higher L/Ps than neutral dextrans of similar size but lower L/Ps than proteins of similar size. Comparison of L/Ps before and after PK revealed that the percentage change in permeability for neutral and DEAE dextrans was significantly larger than that for proteins. These results suggest that 1) the pulmonary microvascular barrier behaves as a net negative barrier, 2) some transport mechanisms for proteins and dextrans are different, and 3) neutral and cationic dextrans are more sensitive markers than proteins of the same size for assessing changes in pulmonary capillary permeability.

Animals↗

Evidence for increased permeability in reexpansion pulmonary edema.

Concurrent analyses of the colloid osmotic pressure of pulmonary edema fluid and serum were performed in two patients with reexpansion pulmonary edema. In addition, pulmonary artery wedge pressure was measured during pulmonary edema in one patient. The colloid osmotic pressure of the pulmonary edema fluid was 73 and 81 percent of the serum value. The pulmonary arterial wedge pressure in one patient was within normal limits (8 mm Hg). Reexpansion pulmonary edema appears to be due to increased pulmonary capillary permeability rather than to hemodynamic mechanisms.

Adult↗

Permeability characteristics of brain adjacent to tumors in rats.

The brain immediately surrounding 9L sarcoma and Walker 256 carcinosarcoma was evaluated, using radioactive water, albumin, red blood cells, urea, and sodium to quantitate isotopic exchange and permeability in the brain adjacent to tumor (BAT), normal brain, and, to a lesser extent, tumor. Exchange between blood and BAT for 14C-urea and 22Na averaged 53% of that for comparable regions of normal brain. This reduction in exchange is not explainable by differences in capillary surface area for transcapillary exchange in the BAT. This reduction in capillary permeability in the BAT could be detrimental to the delivery of watersoluble and rapidly binding drugs.

Animals↗

Mechanisms underlying enhanced capillary filtration induced by platelet-activating factor.

Fluid filtration rate with respect to surface area (Jv/S) from rat mesenteric capillaries was measured before and after platelet-activating factor (PAF) superfusion, a model of acute inflammation. Jv/S increased from a baseline value of 0.015 +/- 0.003 to 0.033 +/- 0.003 micron/s (n = 7 rats, P < 0.01) during PAF superfusion. Measurements of arteriolar pressure with a servo-nulling pressure system suggest that the dominant factor causing the increase in Jv/S during PAF superfusion is increased capillary permeability, rather than an increase in pressure. Jv/S did not increase when PAF superfusion was preceded by administration of the radical-scavenging enzymes catalase and superoxide dismutase, implicating a role for oxygen radicals in the PAF-induced capillary filtration. In another series of studies, three experiments were performed, i.e., PAF superfusion alone or PAF superfusion plus treatment with either a soluble form of sialyl-Lewisx oligosaccharide (SLex) or a nonbinding form of SLex (SLN). These experiments revealed that the increased Jv/S normally elicited by PAF is significantly blunted by administration of soluble SLex but not by the control oligosaccharide SLN. The results of this study invoke a role for oxygen free radicals and selectins (ligands for SLex) in the enhanced capillary fluid filtration elicited by PAF.

Animals↗

Hyperventilation enhances transcapillary diffusion of sodium fluorescein.

Voluntary hyperventilation (HV) provokes hemoconcentration due to a loss of fluid from the intravascular space. In 10 healthy male volunteers the hypothesis was tested whether HV increases transcapillary fluid shift into the interstitial compartment. For this purpose, fluorescent light intensity (FLI) alterations after intravenous injection of sodium fluorescein (Na fluorescein) before and during 3 min of HV were determined. Concomitantly, temperature and microvascular skin flux (laser Doppler fluxmetry, LDF) were recorded continuously. Hematocrit and serum proteins, as markers of hemoconcentration, increased significantly from 41.2 +/- 2.3 to 42.7 +/- 2.0% (p = 0.0023) and from 69.5 +/- 3.4 to 72.9 +/- 3.0 g/l (p = 0.0005, respectively). Skin temperature and LDF showed no changes during HV compared to baseline levels. Interstitial FLI indicating transcapillary diffusion of Na fluorescein was significantly higher (p < 0.001) during HV compared to the values recorded during the baseline period. The exact mechanism of enhanced transcapillary diffusion of Na fluorescein is not known. The distinct increase in FLI without a significant change in microvascular skin flux suggests an HV-induced increase in capillary pressure or an enhancement in capillary permeability for water and small solutes.

Adult↗

Neurogenic inflammation and lowering of interstitial fluid pressure in rat trachea is inhibited by alpha-trinositol.

The effect of alpha-trinositol (D-myoinositol-1,2,6-triphosphate) on edema formation and capillary permeability in neurogenically induced inflammatory edema was investigated in rat trachea. Interstitial fluid pressure (Pif) was studied, since increased negativity of Pif contributes to edema formation in this situation. alpha-Trinositol was used because it inhibits edema formation, capillary leakage, and increased negativity of Pif in burn-injured skin. Pif was measured with sharpened glass capillaries (3 to 7 microns) connected to a servocontrolled counterpressure system after circulatory arrest (induced by intracardiac injection of saturated potassium chloride in pentobarbital anesthesia). This was done in order to avoid the edema formation associated with inflammatory reactions, which will raise interstitial fluid volume and Pif, causing the underestimation of an increased negativity of Pif. Neurogenic inflammation induced by electrical-field stimulation of the left vagal nerve (10 V, 20 Hz, 0.5 ms) lowered Pif from -1.4 +/- 0.6 mm Hg to -8.4 +/- 2.1 mm Hg (p < 0.01). Corresponding numbers after the intravenous administration of alpha-trinositol (40 mg/kg) before stimulation were -1.2 +/- 0.4 and -1.4 +/- 0.4 mm Hg, respectively (p > 0.05). Another series of animals with intact circulation was used to study the effect of vagal nerve stimulation and alpha-trinositol on edema formation (total tissue water and extravascular 51Cr-ethylenediamine tetraacetic acid-[EDTA] space) and albumin extravasation. These parameters increased significantly after vagal nerve stimulation, while intravenous alpha-trinositol (40 and 120 mg/kg), as given above, significantly attenuated this increase. Thus, alpha-trinositol prevented a lowering of Pif and the edema formation accompanying neurogenic inflammation in rat trachea.

Analysis of Variance↗

Oxygen toxicity in normal and anoxic ventilated perfused canine lungs.

Oxygen toxicity was studied in 26 canine isolated, perfused lung lobes which included nine control lobes, 13 lungs ventilated with FIO2 1.0 for 4 hours, and four lobes ventilated with FIN2 1.0 for 1 hour prior to 4 hours of FIO2 1.0 to evaluate the postulated protective effect of anoxia. A significant increase in wet weight was seen in the O2 ventilated lungs which did not alter pulmonary capillary isogravimetric pressure (PCI), alveolar-arterial oxygen gradient, or pulmonary vascular resistance. In contrast, preliminary N2 ventilation resulted in a significant increase in PCI and greater weight gain while pulmonary vascular resistance was reduced. Pulmonary compliance was reduced minimally in all groups. Anoxic ventilation not only failed to protect the isolated canine lung from presumed increased capillary permeability of oxygen toxicity, but seemed to contribute to the formation of interstitial pulmonary edema.

Animals↗

[Pulmonary ultrastructural changes in dogs following experimental hemorrhagic shock (author's transl)].

The authors have studied the ultrastructure of the lung in dogs following experimental hemorrhagic shock. They found intra-alveolar edema, red cells in the alveolar sac, disappearance of the substance of the lamellated osmiophilic bodies and cellular degeneration. Correlation among these alterations and increase of capillary permeability as well as consumption of surfactant secretion were established.

Animals↗

Effect of nitric oxide synthase inhibition on proteinuria in glomerular immune injury.

In glomerular immune injury, the inducible isoform of nitric oxide synthase (iNOS) becomes a major catalyst of NO production. Although iNOS-catalyzed NO production is sustained and can be cytotoxic, iNOS inhibition exacerbates the magnitude of proteinuria that accompanies immune injury. To investigate putative mechanisms of this effect, we assessed changes in glomerular permeability to albumin by using the following two approaches: (i) an in vivo rat model of glomerular immune injury induced by antibody against the glomerular basement membrane (GBM), in which urine albumin excretion was measured under conditions of iNOS inhibition, and (ii) an ex vivo model of isolated rat glomeruli, in which changes in glomerular capillary permeability to albumin were assessed under conditions of NOS inhibition. In rats with anti-GBM antibody-induced glomerular injury, there was an increase in urine albumin excretion. Treatment with two structurally dissimilar iNOS inhibitors at doses sufficient to decrease urine nitrate and/or nitrite exacerbated proteinuria. In these animals, urine excretion of the isoprostane 8-iso-PGF2alpha (marker of oxidative stress) was increased. In isolated glomeruli incubated with the NOS inhibitor L-NMMA, the permeability to albumin increased. This effect was reversed by the NO donor DETA NONOate and by the superoxide dismutase mimetic Tempol. We conclude that NOS-catalyzed NO production is an important mechanism in regulating glomerular permeability to protein. This mechanism involves control of the bioavailability of superoxide.

Albuminuria↗

On the vascular action of crataemon.

The vascular action of crataemon is studied. The effect of the drug on organ blood flow is examined using isotope methods. It is established that under conditions of blood loss, 10 mg/kg crataemon sharply inceases the blood supply to the myocardium and liver. Under the same conditions the blood flow in the kidneys and intestines decreases after administration of the drug. Its effect is weaker in case of normal blood pressure. In the case of perfusion of cat hind legs the flavonoid mixture studied has a biphasic effect manifested in the form of initial brief hypertension, followed by a more prolonged and stronger depressor reaction. In larger oral doses (100 and 200 mg/kg) crataemon increases the resistance of the capillaries and decreases capillary permeability in albino rats. The experiments carried out confirm the predominantly action of crataemon on some vascular regions (heart and liver). It has biphasic effect on peripheral vessels, which may be attributed to the presence of different components. The capillary-tonic action is most probably due to the presence of rutin and rutin-like flavonoids.

Animals↗

Hemodynamic and nonhemodynamic mechanisms of experimental pulmonary edema in rats and the effect of anisodamine and tetramethylpyrazine. Part 1: Survival rate, pulmonary index, pathological change and pulmonary vascular permeability.

Pulmonary edema (PE) which is similar to the neurogenic type was induced by adrenaline (AD) administration (0.1 mg/kg) in rats. Acute progressive respiratory distress, cyanosis and dyspnea occurred. All the experimental animals in the PE group died within 20 min after AD injection, with a pulmonary index (PI) of 1.70 +/- 0.47 (mean +/- S) which was much higher than that in the normal group. The mortality rate was 100%. It was found that in rats with PE, a protein-rich fluid filled the alveolar and interstitial spaces, and ecchymosis occurred. The capillary permeability as estimated by Evans blue injection showed that Evans blue from extraction fluid and bronchoalveolar lavage (BAL) in the PE rats was at a much higher level than that in the normal control (NC) rats. In anisodamine (ADM, 654-2) and tetramethylpyrazine (TMP) treated rats, almost all the damage was diminished or absent, and the mortality rates were decreased from 100% to 4.4% and 20%, respectively. 654-2 and TMP could significantly inhibit the increase of pulmonary permeability.

Animals↗

[Pharmacology of "essential" phospholipids (author's transl)].

In an extensive pharmacological screening of "essential" phospholipids (EPL) antilipemic, hepatoprotective, broncholytic, as well as slight choleretic effects were found and the substance decreased capillary permeability. There was practically no influence on other functions or systems including the vegetative system (heart, circulation, respiration).

Animals↗

[Treatment of malignant tumors by interleukin 2 and LAK cells].

Lymphokine-activated killer (LAK) cells are cells able to lyse fresh tumor cells. In vivo treatment using LAK cells and interleukin 2 is highly toxic because of increased capillary permeability. International discussion is underway on this promising or too toxic therapy. However, such treatment opens a new way for ex vivo manipulation of cells.

Capillary Permeability↗

[Mechanism of early damage to the cardiovascular system by cardiotoxic serum].

Capillaries, small heart vessels, and internal organs (lungs, liver, kidneys, spleen, skeletal muscles, etc.) were subjected to morphofunctional study in experiments on 50 dogs with acute cytotoxic injury provoked by administering 0.5-1.5 ml of anticardial serum (ACS) into the coronary vascular bed. It was shown that ACS administration is attended by an extended reaction of the microvascular bed of the entire organism, involving disturbed capillary permeability by macromolecular compounds and appreciable changes in the morphologic structure of microvessels, with the greatest intensity seen in the left ventricular myocardium.

Animals↗