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PubMed1992

Detrimental effects of temperature on the efficacy of the University of Wisconsin solution when used for cardioplegia at moderate hypothermia. Comparison with the St. Thomas Hospital solution at 4 degrees C and 20 degrees C.

BACKGROUND: We have previously reported the superior protective properties of the University of Wisconsin (UW) solution compared with the St. Thomas solution (ST) in the rat heart subjected to the deep hypothermia (4 degrees C), thus demonstrating its possible use in cardiac transplantation. We thought it was important to evaluate the potential of the UW solution as a cardioplegic solution under the moderately hypothermic (20 degrees C) conditions of routine intraoperative myocardial protection. METHODS AND RESULTS: Isolated rat hearts were subjected to 60 minutes of ischemia at 4 degrees C or 30 (or 60) minutes of ischemia at 20 degrees C with UW, ST, and ST plus 100 mM K (ST + 100) solutions. Coronary flow, mechanical function, endothelial function, and ultrastructure were observed. Mean time (seconds) to infuse 10 ml of cardioplegic solution under constant pressure, a measure of coronary vascular resistance at 4 degrees C and 20 degrees C, respectively, for each solution were ST, 69.2 +/- 6.9 and 64.7 +/- 3.8; UW, 142.2 +/- 8.8 and 187.2 +/- 10.0 (p < 0.01); and ST + 100, 78.2 +/- 8.0 and 176 +/- 8.1 (p < 0.001). Mean recovery values of cardiac output (expressed as percentage of its preischemic value) after 60 minutes of ischemia at 4 degrees C were ST, 95.5 +/- 2.1%; UW, 93.0 +/- 2.4%; and ST + 100, 96.5 +/- 1.5%. After 30 minutes of ischemia at 20 degrees C, values were ST, 88.0 +/- 1.3%; UW, 72.2 +/- 3.6% (p < 0.005 versus ST); and ST + 100, 53.3 +/- 1.8% (p < 0.001 versus ST). CONCLUSIONS: The efficacies of UW and severely hyperkalemic cardioplegic solutions are affected by the degree of hypothermia under which they are used. Under moderate hypothermia (20 degrees C), severe hyperkalemia induces a marked increase in coronary vascular resistance that is associated with impaired myocardial protection. These studies discourage the use of UW for routine intraoperative cardioplegic arrest where the degree of hypothermia cannot be readily controlled. The ST solution does not share this constraint.

Adenosine↗

PubMed1979

Photodynamically induced alteration of cornea endothelial cell function.

Corneal endothelial cells were perfused in the specular microscope with varying concentrations of rose bengal. Corneas perfused with rose bengal in concentrations of 10(-6)M to 10(-5)M and exposed to light for periods of 0.5 to 5 min swelled at rates which were more rapid with both increasing concentration of rose bengal and increasing duration of light exposure. Corneas perfused with similar concentrations of rose bengal but not exposed to light did not swell. Combining rose bengal with 100 micrograms/ml superoxide dismutase did not reduce the corneal swelling following exposure to light, indicating that the photodynamically induced endothelial bengal perfusing solution eliminated corneal swelling following exposure of corneas to light. This indicates that the photodynamic effect of endothelium is secondary to cell functional alterations from the hydrogen peroxide produced during the dismutation reaction of superoxide free radical which is catalyzed by superoxide dismutase.

Animals↗

PubMed1989

Endothelial barrier function.

The endothelial barrier in all organ beds allows the free exchange of water, but is restrictive to varying degrees to the transport of solutes such as albumin. For example, in the brain microvessels, the endothelial barrier restricts the transport of protein, whereas in fenestrated and continuous endothelial cells of the renal and lung endothelial cells, the endothelial barrier is semipermeable. The endothelial monolayer demonstrates selectivity, i.e., the permeation of molecules is inversely related to the molecular weight. Although the "pore" theory has been used to describe the transport across the endothelial barrier, the transport of solutes is also dependent on the charge of solutes and the endothelial cell, and the ability of the solute to bind to or be taken up by endothelial cells. Receptor-mediated trancytosis of albumin may contribute to albumin transport in addition to transport by paracellular pathways (i.e., through a so-called pore). Water permeability across the endothelium is determined by the interaction of albumin with glycocalyx and interstitial components of the endothelium (the "fiber matrix"). Ambient concentration of albumin serves to lower endothelial hydraulic conductivity. Increased endothelial permeability to solutes and water in inflammatory states is dependent on the shape and configuration of endothelial cells as determined by alterations in cytoskeletal elements, such as f-actin, and as regulated by intracellular second messengers such as free cytosolic calcium.

Animals↗

PubMed1992

The vascular endothelium in diabetes and hypertension.

PURPOSE: To review recent research into the function of endothelial cells in relation to diabetes and hypertension, and the implications for cardiovascular control. ENDOTHELIAL FUNCTIONS: Endothelial cells extract and inactive circulating hormones, convert inactive precursors into vasoactive products, and synthesize and secrete vasodilator and vasoconstrictor mediators, which also modify platelet function and cell growth. DIABETES: Abnormalities in endothelial cell morphology and function are recognized features of diabetes. Diminished endothelium-dependent relaxation and enhanced endothelium-dependent contraction have been described. HYPERTENSION: Similar defects in endothelial cell function have been demonstrated in animal and human hypertension. These might lead to increased vascular tone, vasospasm, platelet activation and atheroma. THERAPY: Certain drugs modify or mimic endothelium-derived mediators. Endothelial dysfunction may contribute to cardiovascular pathology, but the precise clinical and therapeutic significance of modifying endothelial function remains to be determined.

Blood Platelets↗

PubMed1992

Electrical method for detection of endothelial cell shape change in real time: assessment of endothelial barrier function.

We have developed an electrical method to study endothelial cell shape changes in real time in order to examine the mechanisms of alterations in the endothelial barrier function. Endothelial shape changes were quantified by using a monolayer of endothelial cells grown on a small (10(-3) cm2) evaporated gold electrode and measuring the changes in electrical impedance. Bovine pulmonary microvessel endothelial cells and bovine pulmonary artery endothelial cells were used to study the effects of alpha-thrombin on cell-shape dynamics by the impedance measurement. alpha-Thrombin produced a dose-dependent decrease in impedance that occurred within 0.5 min in both cell types, indicative of retraction of endothelial cells and widening of interendothelial junctions because of "rounding up" of the cells. The alpha-thrombin-induced decrease in impedance persisted for approximately 2 hr, after which the value recovered to basal levels. Pretreatment of endothelial cells with the protein kinase C inhibitor, calphostin C, or with 8-bromoadenosine 3',5'-cyclic monophosphate prevented the decreased impedance, suggesting that the endothelial cell change is modulated by activation of second-messenger pathways. The alpha-thrombin-induced decrease in impedance was in agreement with the previously observed increases in transendothelial albumin permeability and evidence of formation of intercellular gaps after alpha-thrombin challenge. The impedance measurement may be a valuable in vitro method for the assessment of mechanisms of decreased endothelial barrier function occurring with inflammatory mediators. Since the rapidly occurring changes in endothelial cell shape in response to mediators such as thrombin are mediated activation of second-messenger pathways, the ability to monitor endothelial cell dynamics in real time may provide insights into the signal-transduction events mediating the increased endothelial permeability.

Animals↗

PubMed1988

Endothelial cell function in hemostasis and thrombosis.

Endothelial cells play a pivotal role in hemostasis and thrombosis. They produce a myriad of factors either associated with the membrane or released into the blood stream and the subendothelial matrix which are involved in various steps of hemostasis. The endothelial cell function is modulated by a diversified group of biologically active molecules, notably thrombin, vasoactive amines and cytokines. Mechanism and selectivity of the effects of these molecules differ and the difference may have important physiological implications. Most of the information is gathered through experiments performed in cultured endothelial cells. Availability of the cultured cells has greatly facilitated the understanding of endothelial cell biology. In vivo models, however, are still needed to understand how the endothelial cell function is modulated. Furthermore, as the cultured endothelial cells exhibit nor only species differences but also vascular origin difference in behavior and function, these factors should be carefully considered when designing experiments involving the use of cultured endothelial cells.

Animals↗

PubMed1988

131I-metaiodobenzylguanidine uptake in the isolated rat lung: a potential marker of endothelial cell function.

The pulmonary vascular endothelial cell plays an important role in the uptake of circulating biogenic amines. In cultured adrenomedullary cells, metaiodobenzylguanidine (MIBG) and norepinephrine (NE) are taken up by the same sodium-dependent active transport system. To examine whether a similar process occurs in the lung, the mechanism of single pass 131I-MIBG accumulation was studied in rat lungs perfused with a Krebs-Ringer bicarbonate buffer containing 4.5% bovine albumin. MIBG lung accumulation was measured as the percent extraction per g of lung tissue. In control experiments the extraction was 19.7 +/- 2.3%/g (n = 38) using a perfusate containing 0.01 microM MIBG. MIBG accumulation was significantly depressed (% decrease from control) by: cold media at 4 degrees C (84%), 0.5 mM ouabain (67%), 10 microM imipramine (70%), 0.7 microM serotonin (22%) and 40 mM K+ (48%). Pulmonary uptake of MIBG was characterized by Michaelis-Menten kinetics (Km = 0.92 x 10(-6) M and Vmax = 2.09 x 10(-9) moles/g per min). The addition of NE (0.5 microM) also altered MIBG uptake such that the Km and Vmax became 0.52 x 10(-6) M and 0.93 x 10(-9) moles/g per min, respectively. The results indicate that MIBG accumulation in the lung involves sodium-dependent, energy-requiring, active transport mechanisms similar to those known to exist for norepinephrine, and suggest that MIBG may be useful as a marker of pulmonary endothelial cell function.

3-Iodobenzylguanidine↗

PubMed1992

Splanchnic vascular endothelial dysfunction in rat endotoxemia: role of superoxide radicals.

Intravenous lipopolysaccharide, 30 mg/kg, results in rapid systemic hypotension in anesthetized rats. Interaction of lipopolysaccharide with the vascular endothelium and blood borne cells results in the elaboration of cytokines and oxygen-derived free radicals, all of which can be injurious to normal endothelial function. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats just prior to death. Endotoxemia significantly blunted superior mesenteric artery ring vasorelaxations to acetylcholine and to A23187 but not to NaNO2. Contraction of superior mesenteric artery rings from endotoxemic rats induced by U46619 was not altered. Treatment with human superoxide dismutase or U74006F, an aminosteroid, significantly preserved vasorelaxation to acetylcholine and A23187. However, the hydroxyl radical scavenger N-(2-mercaptopropionyl)-glycine did not protect the endothelium. Thus, intravenous lipopolysaccharide can induce endothelial dysfunction in superior mesenteric artery rings. Furthermore, because superoxide dismutase but not N-(2-mercaptopropionyl)-glycine preserves endothelial function, it is likely that superoxide radicals mediate the endothelial dysfunction observed in endotoxemic rats.

Acetylcholine↗

PubMed1986

Contact lens-induced corneal endothelial polymegathism: functional significance and possible mechanisms.

The corneal endothelium is principally responsible for maintenance of corneal deturgescence. Therefore, compromise of corneal endothelial functional integrity can result in corneal swelling and opacification. Contact lenses constitute a potential insult to the cornea because their wear reduces the oxygen available to that tissue. It has been reported that contact lens wear induces transient as well as permanent morphologic changes in the corneal endothelium. One of the permanent changes reported is referred to as polymegathism, which is a variation in cell size within the endothelial monolayer. Several investigators have suggested that polymegathism reflects a compromised endothelial functional status. Mechanisms proposed to explain contact lens-induced polymegathism include lactate accumulation, changes in pH, and elevation in CO2 content. We discuss these possibilities as well as speculate that these polymegathous shape changes may be a result of decreased endothelial ATP (adenosine triphosphate) levels and disturbed calcium homeostasis due to corneal endothelial hypoxia.

Actin Cytoskeleton↗

PubMed1989

[Experimental studies of the correlation of morphologic endothelial cell findings and endothelial pump function].

In our experiments corneal endothelial cell morphology after Alizarin Red and Trypan Blue staining and endothelial pump function in a perfusion chamber were investigated. As a model for morphologically degenerated tissue we used corneas that had been cryopreserved with two different methods. In control groups 1) fresh, 2) one day organ cultured and 3) corneas without endothelium were evaluated. Morphologic evaluation showed degenerations (enlarged mononucleated cells, giant cells, disseminated necrotic areas) in cryopreserved corneas as compared with control groups. However, in perfusion experiments morphologically damaged tissue showed the same deswelling pattern as organ-cultured corneas. The results show that a morphologic evaluation seems to be a more precise criterion for the quality of the tissue than the investigation of the corneal pump function in a perfusion chamber.

Animals↗

PubMed1982

Endothelial cell functions in the hemodynamic responses to stress.

ACE is a function of the endothelial cell that appears vital to integrative homeostatic physiology in stress. The endothelial cell, both in the lung and in systemic tissues, is uniquely situated to detect changes in ambient oxygen tension; thereafter, as exemplified by the effects of altered oxygen tension on ACE, the cell is capable of initiating changes that modulate its functions to reflect the altered physiologic state. Based upon extensive studies of endothelial cells propagated in tissue culture, these altered functions are rapid in onset, rapidly reversible, and quite closely correlated to PO2. Integrity of the endothelial cell membrane is necessary for the modulating changes to occur, and indeed, ACE purified from the cell is insensitive to changes in oxygen tension: it is the cell, not the enzyme, that responds to changes in oxygen tension (FIGURE 5). It is important to emphasize the interdependent nature of the several vasoactive systems. The kallikrein-kinin system, in addition to its putative role in blood pressure regulation, is an intimate component of both the coagulation and fibrinolysis plasma protease cascades. The sympathetic nervous system has multiple points of interdigitation in both the kallikrein-kinin and the renin-angiotensin systems; high levels of epinephrine stimulate renin release and activate both plasma and tissue kallikrein. In turn, both of the vasoactive peptides of these systems, bradykinin and angiotensin II, stimulate epinephrine production from the adrenal medulla. Angiotensin II enhances the potency of norepinephrine released from postganglionic sympathetic nerve endings, increasing alpha-adrenergic tone. In addition, multiple interactions have been described between angiotensin II and bradykinin and the formation of prostaglandins by endothelial cells. Preliminary data indicate that the potency of these peptides in causing prostanoid release is, as might be expected, closely correlated to ACE activity, which itself is a function of ambient PO2. These multiple interactions are diagrammed in FIGURE 9. It is noteworthy that the two fundamental regulators of the circulation, pH and PO2, can be shown to interact at the most basic level with endothelial cell function.

Altitude↗

PubMed1989

Human endothelial cells produce IL-6. Lack of responses to exogenous IL-6.

The interaction between human endothelial cells and leukocytes during immunological and inflammatory responses is in part mediated through the release of soluble mediators. We report that cultured human umbilical vein endothelial cells secrete IL-6 when stimulated with lipopolysaccharide. The monokines, IL-1 and TNF-alpha, were potent inducers of IL-6, whereas lymphotoxin was only effective at much higher concentrations. IFN gamma also was a strong stimulus of IL-6 production, but TGF-beta did not have an effect at doses modulating other endothelial cell functions. Endothelial cell IL-6 was active as hybridoma-plasmacytoma growth factor and as B-cell and hepatocyte stimulating factor. Endothelial IL-6 activity was neutralized by a specific antibody to IL-6 and it was shown by immunoprecipitation to be identical in size to human fibroblast-derived IL-6. IL-6 did not have a detectable effect on several endothelial cell functions, including proliferation, adherence of leukocytes, and synthesis of PGE2, TPA, and PAI-1. As IL-6 is probably an important regulator of host defense responses, production of this cytokine by endothelial cells may contribute to the pathogenesis of various inflammatory and immunologic diseases.

Animals↗

PubMed1984

Differential effects of hydrogen peroxide on indices of endothelial cell function.

The responses of pig aortic endothelial cells to sublethal doses of potentially toxic stimuli were investigated by monitoring K+ efflux, prostaglandin production, and the release of cytoplasmic purines. Xanthine plus xanthine oxidase reversibly stimulated these three parameters of endothelial cell function at doses that were not cytotoxic, as measured by chromium release, adenine uptake, and vital dye exclusion. The effects of xanthine plus xanthine oxidase were inhibited by catalase but not by superoxide dismutase, suggesting that H2O2 was responsible. Reagent H2O2 also reversibly stimulated K+ efflux, prostaglandin production, and the release of purines. The threshold concentration of H2O2 for these effects was approximately 10 microM, which was at least 30-fold lower than that which caused cytotoxicity. In addition to the direct effect of H2O2 in stimulating prostaglandin production (PGI2 and PGE2), prior exposure of endothelial cells to lower doses of H2O2 (less than 0.1 microM) at high oxygen tension inhibited the subsequent stimulation of prostaglandin production by ATP, A23187, and H2O2 itself. We conclude that H2O2 has substantial effects on endothelial physiology at doses up to 3,000-fold lower than those which induce cytotoxicity.

Animals↗

PubMed1988

Alpha-tocopherol, a potent modulator of endothelial cell function.

The effect of alpha-tocopherol on various endothelial cell functions was evaluated in vitro using cultures of human umbilical vein endothelial cells. Prostacyclin synthesis, plasminogen activator activity and von Willebrand factor activity were evaluated in control and alpha-tocopherol supplemented cultures. Alpha-tocopherol produced stimulation of prostacyclin production which peaked at or near 0.5 mM. Plasminogen activator activity was markedly reduced by the addition of alpha-tocopherol. Von Willebrand factor activity showed a significant decrease of processed and cellular forms that was dose-dependent. The incorporation of alpha-tocopherol into endothelial cells could be demonstrated by measuring intracellular levels of the vitamin in washed endothelial cells. Our results show that alpha-tocopherol has a profound effect on multiple endothelial cell functions which are intimately involved in hemostasis.

Cells, Cultured↗

PubMed1989

Vascular endothelial cell function and ultrastructure in thrombotic microangiopathy following allogeneic bone marrow transplantation.

We report studies on vascular endothelial function and ultrastructure in 2 cases of fatal cyclosporin (CS)-associated thrombotic microangiography following allogeneic bone marrow transplantation (BMT). Spontaneous vascular release of prostacyclin (PGI2) from a vein sample ex vivo was absent, and scanning electron microscopy (SEM) showed surface changes indicative of vascular endothelial damage (case 1). PGI2 release from cultured human umbilical vein endothelial cells incubated with patients' serum in vitro was normal in both cases. Plasma von Willebrand factor (vWF) antigen and ristocetin cofactor activity levels were raised in both patients, 5.06 and 7.02 (case 1) and 3.60 and 2.01 (case 2) (normal ranges 0.59-1.57 and 0.42-1.74 U/ml), respectively, but multimer patterns were normal. The SEM appearances coupled with the absent PGI2 release and raised vWF levels suggest that vascular endothelial damage is central to the pathogenic process in thrombotic microangiopathy following allogeneic BMT but the mechanisms appear to be distinct from those in the haemolytic uraemic syndrome and de novo thrombotic thrombocytopenic purpura. The precise role of CS in this process remains to be identified.

Adult↗

PubMed1990

Sickle erythrocytes inhibit human endothelial cell DNA synthesis.

Patients with sickle cell anemia experience severe vascular occlusive phenomena including acute pain crisis and cerebral infarction. Obstruction occurs at both the microvascular and the arterial level, and the clinical presentation of vascular events is heterogeneous, suggesting a complex etiology. Interaction between sickle erythrocytes and the endothelium may contribute to vascular occlusion due to alteration of endothelial function. To investigate this hypothesis, human vascular endothelial cells were overlaid with sickle or normal erythrocytes and stimulated to synthesize DNA. The erythrocytes were sedimented onto replicate monolayers by centrifugation for 10 minutes at 17 g to insure contact with the endothelial cells. Incorporation of 3H-thymidine into endothelial cell DNA was markedly inhibited during contact with sickle erythrocytes. This inhibitory effect was enhanced more than twofold when autologous sickle plasma was present during endothelial cell labeling. Normal erythrocytes, with or without autologous plasma, had a modest effect on endothelial cell DNA synthesis. When sickle erythrocytes in autologous sickle plasma were applied to endothelial monolayers for 1 minute, 10 minutes, or 1 hour and then removed, subsequent DNA synthesis by the endothelial cells was inhibited by 30% to 40%. Although adherence of sickle erythrocytes to the endothelial monolayers was observed under these experimental conditions, the effect of sickle erythrocytes on endothelial DNA synthesis occurred in the absence of significant adherence. Hence, human endothelial cell DNA synthesis is partially inhibited by contact with sickle erythrocytes. The inhibitory effect of sickle erythrocytes occurs during a brief (1 minute) contact with the endothelial monolayers, and persists for at least 6 hours of 3H-thymidine labeling. These results indicate that interaction between sickle erythrocytes and the endothelium may result in altered endothelial function. This altered endothelial function may contribute to the development of vascular occlusive phenomena in patients with sickle cell anemia.

Anemia, Sickle Cell↗

PubMed1986

[Disorders of thrombocyte function and/or endothelial cell damage as a cause of primary pulmonary hypertension?].

The pathophysiology of pulmonary hypertension is, in many cases, unclear and this is true especially for patients with dietary pulmonary hypertension. This paper discusses the hypothesis that platelets, directly or through their interaction with the pulmonary endothelial cell, are involved in the development of pulmonary hypertension. Platelets release vasoactive substances during aggregation or activation and these substances lead to pulmonary vasoconstriction and pulmonary hypertension. The primary target of the activated platelets could be the endothelial cell which has also been demonstrated in animal experiments with crotalaria-induced pulmonary hypertension. Changes in thromboxane--platelets and prostacyclin--endothelial cell interactions could be the basic mechanism responsible for endothelial proliferation and pulmonary vasoconstriction. It has not been ascertained, however, whether the activation of platelets or endothelial dysfunction is the primary lesion. In various animal experiments, changes in platelet function and endothelial damage, as well, have been shown to be initiated by exogenous influences. The investigation of platelets or endothelial cell function in patients with pulmonary hypertension showed evidence of platelet activation but not platelet hyperreactivity. An impaired fibrinolytic activity, which was found in the majority of these patients, was regarded as indicative of endothelial dysfunction. An interference in the physiological interaction of circulating platelets and endothelial cells in the lung with resulting endothelial proliferation and vessel occlusion could well be the initial factor. This process would be self-perpetuating in the development of pulmonary hypertension. An additional example of dietary-induced pulmonary hypertension was observed in patients in Spain after the ingestion of toxic oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effects of Escherichia coli hemolysin on endothelial cell function.

Escherichia coli hemolysin is considered an important virulence factor in extraintestinal E. coli infections. The present study demonstrates that cultured pulmonary artery endothelial cells are susceptible to attack by low concentrations of E. coli hemolysin (greater than or equal to 0.05 hemolytic units/ml; greater than or equal to 5 ng/ml). Sublytic amounts of hemolysin increased the permeability of endothelial cell monolayers in a time- and dose-dependent manner. The hydraulic conductivity increased approximately 30-fold and the reflection coefficient for large molecules dropped from 0.71 to less than 0.05, indicating a toxin-induced loss of endothelial barrier function. The alterations of endothelial monolayer permeability were accompanied by cell retraction and interendothelial gap formation. In addition, E. coli hemolysin stimulated prostacyclin synthesis in endothelial cells. This effect was strictly dependent on the presence of extracellular Ca2+ but not of Mg2+. An enhanced passive influx of 45Ca2+ and 3H-sucrose but not of tritiated inulin and dextran was noted in toxin-treated cells, indicating that small transmembrane pores comparable to those detected in rabbit erythrocytes had been generated in endothelial cell membranes. These pores may act as nonphysiologic Ca2+ gates, thereby initiating different Ca2+-dependent cellular processes. We conclude that endothelial cells are highly susceptible to E. coli hemolysin and that two major endothelial cell functions are altered by very low concentrations of hemolysin.

Animals↗