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ONO-5046, a novel inhibitor of human neutrophil elastase.

ONO-5046, N-[2-[4-(2,2-Dimethylpropionyloxy)phenylsulfonylamino] aminoacetic acid, competitively inhibited human neutrophil elastase (IC50 = 0.044 microM, Ki = 0.2 microM). It also inhibited leukocyte elastase obtained from rabbit, rat, hamster and mouse. However, ONO-5046 did not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 microM. In in vivo studies, ONO-5046 suppressed lung hemorrhage in hamster (ID50 = 82 micrograms/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase.

Animals↗

In vivo effects of prostacyclin on segmental vascular resistances, on myogenic reactivity, and on capillary fluid exchange in cat skeletal muscle.

OBJECTIVE: To analyze the local circulatory effects of prostacyclin in skeletal muscle. DESIGN: A prospective experimental study. SETTING: A university laboratory. SUBJECTS: Twelve adult cats. INTERVENTIONS: The study was performed on autoperfused, sympathectomized gastrocnemius muscle. MEASUREMENTS AND MAIN RESULTS: Arterial blood flow, total and segmental vascular resistances (arterial vessels of > 25 microns, arterioles of < 25 microns, and veins), hydrostatic capillary pressure, tissue volume, myogenic reactivity, and the capillary filtration coefficient were followed. The capillary filtration coefficient reflects the functional capillary fluid exchange area. Myogenic reactivity was evaluated as the arteriolar resistance increase after a standardized decrease in extravascular pressure. Arterial infusion of prostacyclin decreased vascular resistance by approximately 50% at the highest dose given (500 ng/kg/min). This effect was more pronounced on the arterial side, especially in arterial vessels of > 25 microns. Hydrostatic capillary pressure increased by 1.9 +/- 0.3 mm Hg, causing fluid filtration. The relative fluid filtration was less than that value shown for some other vasodilator drugs (isoprenaline, calcium-channel blockers, thiopental) in this muscle preparation. Capillary filtration coefficient decreased by 25%. Myogenic reactivity was depressed but to a lesser extent than previously observed for other vasodilator mechanisms (muscle exercise, beta-adrenergic receptor stimulation, thiopental infusion, nifedipine infusion). CONCLUSIONS: Prostacyclin is a vasodilator, both on the arterial and venous side, that restricts the increase in hydrostatic capillary pressure. The decrease in capillary filtration coefficient most likely reflects a decrease in capillary permeability, explaining the smaller relative filtration rate. The relatively well-preserved myogenic reactivity may imply a better preserved microvascular flow distribution and peripheral oxygen uptake.

Animals↗

[Mesangiocapillary glomerulonephritis, type 3].

Authors describe in 2 cases of type 3 mesangiocapillary glomerulonephritis the typical histological, pathological and clinical features of the disease. It is considered to be an ultrastructural variant of mesangiocapillary glomerulonephritis accompanied by focal subepithelial deposits reminiscent of membraneous glomerulonephritis. As the background of immune-complex deposition the increase of capillary permeability observed often in diabetes mellitus is discussed. On the basis of its more benign course this pattern is thought to be a separate subtype.

Adult↗

Innervation of vasculature and microvasculature of the human vagina by NOS and neuropeptide-containing nerves.

The aims of the present study were to determine whether nerves that contain nitric oxide synthase (NOS), calcitonin gene-related peptide (CGRP) or substance P (SP) are present in the human vagina and, if so, to determine the pattern of innervation relative to that of other neurotransmitters, particularly vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY). Surgical specimens of vaginal tissue (n = 10) from pre- and postmenopausal women were fixed and processed for immunohistochemistry of peptides and NOS and for histochemistry of NADPH-diaphorase. SP-immunoreactive nerves were very sparse, being absent from 9 of the 10 tissue samples. For other peptides and NOS, the innervation of the deep arteries and veins was greater than that of blood vessels in the propria. Capillaries in the epithelial papillae also appeared to be innervated by nerves containing NOS, CGRP, NPY and VIP. Beneath the epithelium nerve fibres formed a subepithelial plexus; no nerve cell bodies were seen. The relative density of innervation by immunoreactive fibres was PGP-9.5 > NPY > VIP >> NOS > CGRP > SP. These results imply that nerves that utilise nitric oxide or NPY, VIP or CGRP as a neurotransmitter may play a role in controlling blood flow and capillary permeability in the human vagina. The origin and function of all these nerves is discussed.

Adult↗

Control of systemic capillary leak syndrome with aminophylline and terbutaline.

PURPOSE: Patients with systemic capillary leak syndrome have a characteristic triad of hypotension, hemoconcentration, and monoclonal gammopathy. They have frequent and severe attacks of hemoconcentration and hypotension accompanied by marked plasma shifts. The exact role of this monoclonal protein is unknown, but it probably leads, in some way, to an increase in capillary permeability. Despite efforts to resuscitate the patients during an acute attack, the syndrome is often fatal. Some success has been obtained in preventing the attacks with the beta-adrenergic-stimulating agent terbutaline. The purpose of this study was to determine the effectiveness of aminophylline and terbutaline in the treatment of systemic capillary leak syndrome. METHODS: Over a decade, three patients with systemic capillary leak syndrome presented at our institution. All three patients were treated with terbutaline and aminophylline. Prednisone was used during the course of treatment in each of the three patients. RESULTS: In contrast to previous reports of partial or temporary control of episodes, all three patients are alive with almost complete resolution of their recurrent attacks and have been able to return to their normal lifestyles. CONCLUSION: The regimen of terbutaline and aminophylline effectively prevents the attacks of hypotension and hemoconcentration that occur in systemic capillary leak syndrome. The role of prednisone is not clear. Until more is known about the pathophysiology of the disorder, treatment must remain empiric and supportive.

Aged↗

Cardiac lymph flow and composition in acute myocardial ischemia in dogs.

Cardiac lymph was obtained from 12 normal dogs (group 1) for two consecutive 2-h control periods and from 7 dogs (group 2) for 2 h before and 2 h after occlusion of the circumflex branch of the left coronary artery. Lymph composition was studied with reference to pH, red blood cell (RBC) concentration, total protein content, potassium and sodium ion concentrations, and creatine phosphokinase (CPK) and acid phosphatase enzyme activities. No significant difference was noted in any variable between the two groups during the firts 2-h period. In group 1, no significant changes occurred in any variable as a result of the passage of time alone. In group 2, 2 h of myocardial ischemia produced increases of 53.3 plus or minus 5.1% in lymph flow, 67 plus or minus 5% in protein content, and 418 plus or minus 27% in the RBC concentration, suggesting increased blood capillary permeability. Lactate rose 120.5 plus or minus 27%, potassium concentration increased 16.9 plus or minus 2.4%, acid phosphatase increased 30 plus or minus 3%, and CPK rose 61.6 pluse or minus 10.9%, suggesting ischemic injury of myocardial cells. These changes in lymph were statistically significant (P LESS THAN 0.05) and reflect both capillary and myocardial cell abnormalities.

Animals↗

Deterioration of oxygenation and abnormal lung microvascular permeability during resolution of leukopenia in patients with diffuse lung injury.

To determine whether circulating leukocytes contribute to gas exchange abnormalities in diffuse lung injury, we retrospectively examined oxygenation in 6 patients who met 3 criteria: leukopenia caused by marrow aplasia from remission-inducing chemotherapy for myelogenous leukemia, the eventual resolution of leukopenia, and concurrent acute respiratory failure diagnosed clinically as increased permeability pulmonary edema. Four of the 6 patients abruptly developed overt clinical evidence of pulmonary dysfunction within the 96 h preceding the resolution of the peripheral leukopenia. In all 6 patients, the alveolar to arterial oxygen tension difference increased between leukocyte counts. The mean value for the alveolar to arterial oxygen tension difference for the group doubled during this period (148 +/- 37 mmHg 3 days prior to resolution; 290 +/- 37 mmHg 1 day after resolution; p less than 0.05). As an index of lung capillary permeability, we measured the lung permeability-surface area product for urea (PSu) for an additional patient with oxygen toxicity and drug-induced leukopenia whose hypoxemia increased immediately before the resolution of leukopenia. The PSu in this patient was high, in the range previously reported as being highly specific for increased permeability pulmonary edema with a fatal outcome. We conclude that such diffuse lung injury resembling the adult respiratory distress syndrome can occur in leukopenic patients, but the resolution of leukopenia in such patients may be associated with worsening oxygenation and with abnormally high pulmonary microvascular permeability. These observations do not prove a causal relationship but provide a clinical parallel to several leukocyte-depletion studies reported in animal models of increased permeability pulmonary edema that implicate white blood cells in the pathogenesis of hypoxemia and lung edema.

Adult↗

Glomerular immune complex deposition, circulating immune complexes, and antibodies in experimental insulinopenic diabetes.

Compared with control animals with a normal metabolism, rats with insulinopenic diabetes generally show an increase in glomerular deposition of complement-fixing immune complexes after immunization with bovine albumin and bovine gamma-globulin. Compared with the control group, the serum of the diabetic animals showed a reduction in the titers of IgM-isotype antibodies, which have a lower affinity. The concentration of the circulating immune complexes is the same. The increased frequency of glomular deposits in experimental diabetes can be explained by an increase in capillary permeability and by the formation of qualitatively different immune complexes.

Animals↗

[Prospective assessment of changes in microcirculation and central hemodynamics in patients with stable angina pectoris according to the data of radionuclide study methods].

The two-year follow-up of 102 patients aged 28-67 years who had Functional Classes I-III stable angina and took no regular antianginal therapy has demonstrated that the first deleterious changes occur in the vasodilator reserve of microcirculation. Then the capillary blood flow velocity decreases, whereas capillary permeability increases. Following 1.5 year of the follow-up there is a dramatic decline in cardiac output, coupled with a significant rise of total peripheral vascular resistance.

Adult↗

Permeability of lung capillaries to macromolecules in foetal and new-born lambs and sheep.

1. The permeability of lung capillaries to macromolecules was investigated in immature and mature foetal lambs, new-born lambs and young sheep. The placental circulation of the foetal animals was maintained intact after delivery by Caesarian section. New-born lambs and sheep were mechanically ventilated. Samples of plasma and lymph that had drained from the lung via the thoracic duct were collected over a period of 1-5 hr.2. The proteins in plasma and lymph samples were separated by fractionation on columns of Sephadex G-200. Plasma yielded three peaks of protein concentration. The K(av) value of each peak was determined, and, by calibrating the columns with known proteins, the mean radius of equivalent sphere (a) of the proteins in peak I was shown to be similar to that of fibrinogen >/= 110 A, peak II to gamma-globulin approximately 54 A and peak III to albumin approximately 34 A. Lung lymph contained the same three constituent peaks as plasma but in lower concentration. In all four groups mean lymph/plasma concentration (L/P) ratio was significantly different for each of the three peaks, being lowest for the largest molecules (peak I) and highest for the smallest (peak III).3. In five mature foetal lambs polydisperse polyvinylpyrrolidone labelled with (125)I ([(125)I]PVP) was injected I.V. early in the experiment: count rates in fractionated samples showed for plasma a continuous decline with time after injection, and for lung lymph an increase to a maximum then a decline. Steady-state L/P ratios for eleven fractions of PVP of differing molecular size ranging from 110 to 17 A were derived by compartmental analysis. For a given molecular size PVP L/P ratios were similar to protein L/P values.4. The regression of PVP L/P ratio on K(av) was linear (correlation coefficient r = 0.99), and the slope of the regression of protein L/P ratio on K(av) was significantly steeper for new-born lambs than for mature foetuses (P < 0.025) and sheep (P < 0.005), and steeper for immature foetuses than sheep (P < 0.01).5. PVP and protein L/P ratios (mature foetuses) plotted against a showed a sigmoid relation with agreement between the two sets of L/P ratios. The goodness of fit between our experimental results and Landis & Pappenheimer's (1963) capillary pore theory (eqn. (1)) was examined: L/P ratios for the larger molecules (>/= 75 A) appeared to be too high. By recalculating ratios on the assumption that the largest molecules (110 A) escape unrestricted from the capillary via leaks, the discrepancy disappears.6. Values for pore radius (r), and pore area per unit path length (A/Deltax) have been calculated for each of the four groups; r ranged from 90 to 150 A, A/Deltax from 3.3 to 0.2 cm x 10(3).kg(-1). In new-born lambs the value of r was significantly smaller, and A/Deltax larger than that of any other group. The inferences to be drawn from these results are discussed.

Albumins↗

Reduced ischemia-reperfusion injury with rolipram in rat cadaver lung donors: effect of cyclic adenosine monophosphate.

BACKGROUND: The perfusion of rat lungs retrieved from cadavers with a solution containing isoproterenol has been shown to ameliorate the ischemia-reperfusion injury seen in lungs retrieved after death, and this protective effect parallels increases in tissue cyclic adenosine monophosphate levels. In this study, we investigated the effect of rolipram, a phosphodiesterase inhibitor, on capillary permeability and lung cyclic adenosine monophosphate levels in lungs retrieved from circulation-arrested rats. METHODS: Using an isolated perfused lung circuit, we retrieved lungs from circulation-arrested donor rats either ventilated with 100% oxygen or not ventilated for varying postmortem times. The lungs were reperfused with or without rolipram (2 micromol/L). The capillary filtration coefficient and wet to dry weight ratio, indicators of pulmonary vascular integrity, were determined, and tissue levels of adenine nucleotides and cyclic adenosine monophosphate were measured by high-performance liquid chromatography. RESULTS: The capillary filtration coefficient was significantly reduced in nonventilated cadaver lungs reperfused with rolipram 120 minutes after death (p<0.05). Oxygen ventilation or reperfusion with rolipram had a similar effect on the capillary filtration coefficient. Cyclic adenosine monophosphate levels were significantly higher in rolipram-reperfused lungs retrieved 120 minutes after death in both oxygen-ventilated (p<0.01) and nonventilated (p<0.01) lungs. CONCLUSIONS: In lungs from nonventilated, circulation-arrested donors, reperfusion with rolipram reduces the ischemia-reperfusion injury that may be due to intracellular cyclic adenosine monophosphate. Alteration of perfusate may have an impact on capillary leak caused by antecedent ischemia. Thus, rolipram may be a useful adjunct in the preservation of donor lungs retrieved after death.

Adenine Nucleotides↗

Studies of the mechanism of oliguria in a model of unilateral acute renal failure.

To further evaluate the mechanism of the oliguria of acute renal failure, a model was utilized in which intense and prolonged vasoconstriction produced the unilateral cessation of urine flow. The radioactive microsphere method was used to measure total and regional blood flow before and after the intrarenal infusion of norepinephrine, 0.75 mug/kg/min, for 2 h in the dog. In the control kidney, renal blood flow increased 32% 48 h after norepinephrine in association with a fall in the fractional distribution of flow to the outer cortex. In the experimental kidney, total renal blood flow fell from 190 ml/min before norepinephrine to 116 ml/min at 48 h (P < 0.025) with a uniform reduction in cortical blood flow. After the administration of 10% body wt Ringer's solution, there was a marked redistribution of flow to inner cortical nephrons in both the control and experimental kidney. In addition, there was a marked increase in total blood flow in both kidneys. On the experimental side, flow rose to 235 ml/min, a value greater than in either the control period (P < 0.05) or at 48 h after norepinephrine (P < 0.001). However, in spite of this marked increase in blood flow, there was essentially no urine flow from the experimental kidney. In separate studies, the animals were prepared for micropuncture. In all studies, the surface tubules were collapsed, and there was no evidence of tubular obstruction or leakage of filtrate. Over 99% of the 15-muM spheres were extracted in one pass through the experimental kidney. An analysis of the forces affecting filtration suggested that an alteration in the ultrafiltration coefficient may be responsible, at least in part, for the anuria in this model. In this regard, transmission and scanning electron microscopy revealed a marked abnormality in the epithelial structure of the glomerulus. It is suggested that a decrease in glomerular capillary permeability may be present in this model of acute renal failure.

Acute Kidney Injury↗

Oxygen transport across vasa recta in the renal medulla.

In this model of oxygen transport in the renal medullary microcirculation, we predicted that the net amount of oxygen reabsorbed from vasa recta into the interstitium is on the order of 10(-6) mmol/s, i.e., significantly lower than estimated medullary oxygen requirements based on active sodium reabsorption. Our simulations confirmed a number of experimental findings. Low medullary PO(2) results from the countercurrent arrangement of vessels and an elevated vasa recta permeability to oxygen, as well as high metabolic needs. Diffusional shunting of oxygen between descending vasa recta (DVR) and ascending vasa recta also explains why a 20-mmHg decrease in initial PO(2) at the corticomedullary junction only leads to a small drop in papillary tip PO(2) (<2 mmHg with baseline parameter values). Conversely, small changes in the consumption rate of DVR-supplied oxygen, in blood flow rate, in hematocrit, or in capillary permeability to oxygen, beyond certain values sharply reduce interstitial PO(2). Without erythrocytes, papillary tip PO(2) cannot be maintained above 10 mmHg, even when oxygen consumption is zero.

Animals↗

Further characterization of a factor from endotoxin-treated serum which releases histamine and heparin from mast cells.

Upon incubation of hamster serum with bacterial endotoxin, a factor is produced which releases histamine and heparin from hamster mast cells and increases capillary permeability in guinea pig skin. The major histamine-releasing activity derived from hamster serum was characterized by gel filtration, found to have a molecular weight of approximately 60,000, and shown by electrophoresis to migrate with alpha-2- or beta-1-globulins. The ability to increase vascular permeability was not reversed by antihistamine. On the basis of these properties, the histamine-liberating factor generated by endotoxin in hamster serum differed significantly from known anaphylatoxins.

Animals↗

Ultrastructural study of the effect of acute hyper- and hypotension on the stria vascularis and spiral ligament.

The effects of acute hyper- and hypotension on the stria vascularis and spiral ligament of the rat were studied electron microscopically with the horseradish peroxidase (HRP) tracer method. Acute hypertension was induced by i.v. infusion of methoxamine chloride (Mexan), and acute hypotension by i.v. infusion of a ganglion-blocker (Arfonad) and by venesection. In both acute hyper- and hypotensive experiments, a large amount of leaked HRP spread into the intercellular spaces until it was stopped by tight junctions bordering the stria vascularis. The stria capillary endothelium displayed a dense distribution of labelled vesicles, which suggests increased vesicular transport. There was no extravasation of HRP from capillaries in the spiral ligament, despite the presence of some labelled pinocytotic vesicles. The present paper deals with the discovery of enhanced capillary permeability of the stria vascularis under acute hyper- and hypotension, and makes comparison between acute hyper- and hypotension in order to define the function of the stria vascularis.

Animals↗

Klebsiella pneumoniae enterotoxin. II. Physicochemical properties of enterotoxin.

Physicochemical properties and systemic effects of the enterotoxin of Klebsiella pneumoniae has been studied. The enterotoxin had a molecular weight between 10 000 to 50 000. It was protein in nature, and heat and acid stable, inducing a dilatatory response in the gut. It haemolyzed the erythrocytes of various animals including man. It had a capillary permeability activity. In addition, when administered parenterally it increased the level of blood glucose, serum cholesterol, serum alkaline phosphatase and serum acid phosphatase.

Acid Phosphatase↗

Fetal fluid responses to long-term 5 M NaCl infusion: where does all the salt go?

The fetus must obtain Na and Cl ions in order to grow. However, the regulation of electrolyte acquisition by the fetus is not well understood. To explore fetal electrolyte balance, we intravenously infused 5 M NaCl at a rate equal to 80% of the total fetal body Na+ and Cl- content per day (240 mM/day) for 3 days into late-gestation fetal sheep. We hypothesized that the increase in fetal osmolality resulting from the infusion would cause a transplacental water movement into the fetal compartment, leading to hydrops fetalis and/or polyhydramnios. The fetal-to-maternal osmotic gradient was initially -2.8 +/- 0.9 (SE) mosmol/kgH2O and rose by 4.8 +/- 1.8 mosmol/kgH2O during the infusion. Fetal plasma [Na+] and [Cl-] increased (3.0 +/- 0.4 and 5.5 +/- 0.5 meq/l, respectively), but the normal maternal-to-fetal transplacental concentration gradients for these ions were not reversed. Most of the infused Na+ (92 +/- 14%) and Cl- (82 +/- 12%) was excreted by the fetus in large volumes of hypotonic urine. Amniotic fluid osmolality and [Na+] were unchanged, but amniotic [Cl-] increased 5.7 +/- 2.4 meq/l. The amniotic plus allantoic fluid volume, as estimated by ultrasonography, was increased (43.5 +/- 14.5%) at day 2 and returned to control by day 3 of infusion. There was no fetal edema during the study or at autopsy. In light of these results, we propose a novel and somewhat complex mechanism for transplacental fluid and electrolyte movement in which placental capillary permeability increases along the length of the capillary.(ABSTRACT TRUNCATED AT 250 WORDS)

Amniotic Fluid↗

Intra-renal interactions between angiotensin II and atrial natriuretic factor.

ANF and Ang II have opposing functions in volume homeostasis. The extent to which they interact functionally in the glomerulus, tubules and vasculature of the kidney is examined. Functional antagonism occurs in the glomerulus due to actions on different components; ANF appears to act mainly on capillary permeability and Ang II on vasculature and capillary surface area. A major cellular interaction is apparent in the proximal tubule where inhibition of sodium transport by ANF appears to be Ang II-dependent. No interaction is evident in the distal nephron, but an opposing functional action on medullary vasculature has been demonstrated.

Angiotensin II↗