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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because diabetic vascular disease is accompanied by a state of hypercoagulability, manifested by increased thrombin activity and foci of intravascular coagulation, we investigated whether a specific procoagulant property of the endothelium--production and surface expression of tissue factor--is modified by elevated glucose concentrations. In unperturbed human vascular endothelial cells, tissue factor mRNA and expression of the functional protein were undetectable and were not induced by 10-12 days of exposure to 30 mM glucose. In thrombin-stimulated cultures, tissue-factor expression was related inversely to cellular density, with confluent cultures producing (per 10(5) cells) half the amount of tissue factor measured in sparse cultures. Cells exposed to high glucose and studied when cell number and thymidine incorporation were identical to control cells manifested increased tissue-factor mRNA level and functional protein production in response to thrombin (P = .002). This effect was not attributable to hypertonicity and was not observed after short exposure to high glucose. In contrast, the tissue-factor response to interleukin 1, a modulator of endothelial function in the context of host defense, was decreased in cells cultured in high glucose (P = .04). These findings indicate that exposure to high glucose can alter tissue-factor gene expression in perturbed vascular endothelium. The reciprocal effects of high glucose on the tissue-factor response to thrombin and interleukin 1 points to different pathways of tissue-factor stimulation by the two agents and suggests functional consequences pertinent to the increased thrombin activity and compromised host-defense mechanisms observed in diabetes.
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PMID:Modification of tissue-factor mRNA and protein response to thrombin and interleukin 1 by high glucose in cultured human endothelial cells. 278 75

Following our observations that non-esterified fatty acids (NEFAs) inhibit prostacyclin (PGI2) synthesis and accelerate PGI2 degradation, we have examined the possibility that NEFAs may also affect the activity of vascular ADPase, which converts the platelet pro-aggregatory adenosine diphosphate (ADP) to adenosine, an inhibitor of aggregation and a vasodilator. Incubation, in buffer solutions, of NEFAs with intact rat aortic rings significantly inhibited vascular ADPase activity. This inhibition was more marked at higher NEFA concentrations and with unsaturated fatty acids (linoleic, oleic) than with a saturated fatty acid (stearic). This NEFA-mediated inhibition of vascular ADPase activity could be prevented by the prior addition of fatty acid-free human albumin to the incubate. Similarly, the vascular rings recovered from NEFA-mediated inhibition by washing and further incubation in NEFA-free buffer. Therefore, elevated NEFA concentrations inhibit, reversibly, an enzyme system which is thought to protect the vascular endothelium. The NEFA-mediated inhibition of ADPase activity was also confirmed following incubation of rat aortic rings in human serum enriched with exogenous NEFA. These findings provide further evidence that NEFAs may contribute to the pathogenesis of vascular disease associated with diabetes mellitus and of other conditions where an elevation of serum NEFA concentrations occurs.
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PMID:The effect of non-esterified fatty acids on vascular ADP-degrading enzyme activity. 302 42

In this chapter, current concepts of eicosanoid biochemistry and function have been summarized. Emphasis has been placed on the importance of ascertaining a complete profile of eicosanoids synthesized by a given tissue under varying conditions of stimulation. The concept of transient intermediates, which are involved in each of the known pathways, was reviewed. Such intermediates can also represent substrate for cell-cell interactions, which have been classified and discussed. Knowledge of the synthetic mechanisms, metabolism, and catabolism of eicosanoids has surpassed our comprehension of their biologic actions. It can be speculated that eicosanoids reinforce or synergize normal homeostatic mechanisms that might proceed less effectively in their absence but occur more efficiently when they are produced. Incomplete comprehension of the functional role of eicosanoids has retarded the development of definitive pharmaceutical approaches toward inhibition or stimulation of eicosanoid production in pathophysiologic situations. With regard to thrombosis, the inflammatory response and host-defense mechanisms, leukotrienes, which have been shown to act on vascular endothelium and smooth muscle, may play an important role in occlusive vascular disease. Since leukotrienes and other hydroxy acids such as 12-HETE are not inhibited by aspirin or nonsteroidal anti-inflammatory agents, development of a unifying concept is difficult. It appears that we are approaching a point in time for reevaluation and reassessment of the role of the eicosanoid pathway in hemostasis and thrombosis. Most importantly, recent eicosanoid research has provided answers to biologic phenomena that were not explicable in the past and also explains why therapeutic trials in occlusive vascular disease were not as successful as predicted on theoretical grounds.
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PMID:Transcellular metabolism of eicosanoids. 303 35

Accumulating experimental and clinical evidence indicates that a time for reappraisal of therapeutic modalities designed to inhibit the eicosanoid pathway as it may affect vascular disease may be approaching. Pharmacologic agents originally used were chosen because they were capable of suppressing platelet functions such as aggregation, release, and adhesion. The goals of clinical trials were to evaluate medications that would prevent or reduce platelet accumulation in critically located blood vessels of the heart, brain, and extremities and on vascular prostheses. Evaluation of results of therapeutic trials has been difficult and this is superimposed on less-than-complete knowledge of the basic pharmacology of the drugs that have been used. Participation of neutrophils and possibly macrophages in the thrombotic process is now well recognized on morphologic grounds. Because different cell types such as platelets, neutrophils, and endothelial cells have been shown to interact biochemically by sharing precursors and intermediates of the eicosanoid pathway, the pharmacologic approach to inhibition of vascular disease may require reevaluation. Neutrophils appear to lack a cyclooxygenase pathway but serve as a source of the lipoxygenase product leukotriene B4 (LTB4). Actions of LTB4 include neutrophil aggregation, adhesion of neutrophils to endothelial cells, chemotaxis, chemokinesis, and plasma exudation. We have demonstrated in vitro that released free arachidonic acid from aspirin-treated platelets can serve as a source of neutrophil LTB4. Leukotrienes C4, D4, and E4 are agonists for various functions of vascular endothelium and smooth muscle. Most pharmacologic agents used in the treatment of vascular diseases inhibit the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of platelet function in thrombosis. 389 60

Acetylsalicylic acid (aspirin) inhibits prostanoid synthesis by irreversible acetylation of fatty acid cyclooxygenase (EC 1.14.99.1). It thereby inhibits synthesis of pro-aggregatory thromboxane A2 (TXA2) by platelets and is widely used in the treatment and prophylaxis of vascular disease. Its efficacy, however, may be reduced since it also inhibits formation of prostacyclin (PGI2) which is a vasodilator and anti-aggregatory agent. There is uncertainty over the optimum dose regimen for aspirin since although it inhibits platelet thromboxane production for many days, the magnitude and duration of its effect on PGI2 production by vascular endothelium in vivo is unknown. Resting plasma concentrations of PGI2 (measured as the stable hydrolysis product 6-oxo-PGF1 alpha) are at or below the limit of sensitivity of the most sensitive assays and cannot therefore be used to demonstrate a reduction in production. Bradykinin stimulates PGI2 synthesis by cultured human vascular endothelial cells and we have shown that it stimulates PGI2 production by man in vivo. We report here that an oral dose of aspirin (600 mg) causes rapid and substantial inhibition of bradykinin-stimulated PGI2 production, but recovery occurs within 6 hours; this implies that endothelial PGI2 synthesis would be spared most of the time during dosing once daily with even this relatively large dose of aspirin.
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PMID:Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man. 390 19

We have studied 25 cases of hemolytic and uremic syndrome (H.U.S.) induced by mitomycin C, collected from 1976 to 1982 in 12 Nephrology Centers. Mitomycin C was administered in successive cures at a cumulative dose higher than 50 mg/m2. This H.U.S. is characterized by its slow and late occurrence, by extra-renal, mainly respiratory, manifestations that may reveal the disease, and finally by its pathological aspects. Mesangiolysis and endothelial or mesangial enlarged and atypical nuclei are observed in addition to the usual lesions of thrombotic micro-angiopathy. The prognosis was very poor in the first cases reported. It was better, however, in the patients studied more recently, because the cumulative dose was lower. In severe cases, plasma exchange might improve long-term prognosis. The disease might be due to a direct toxic effect of mitomycin C on the vascular endothelium.
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PMID:[Nephrotoxicity of mitomycin C (apropos of 25 case reports). Results of a multicenter survey organized by the Society of Nephrology]. 392 81

In a retrospective histopathological study of 75 eyes with occlusive retinal vascular disease, intraretinal, preretinal and prepapillary neovascularisation was observed in 76%, 48% and 48%, respectively. The central retinal vein, artery and branch arteries were shown to be occluded in 48, 46 and 6 cases, respectively. Generalised obliterative arteriolovenular sclerosis was observed on 24 occasions; combined stem occlusions of the central retinal vein and artery was found in 33 specimens. A most significant finding was the presence of intramural capillaries within hyalinised retinal vessels in 51 cases (68%). These newly formed capillaries originated from proliferating vascular endothelium; their lumina communicated with the vascular lumen and continued in many instances into congeries of newly formed intra- and preretinal capillaries. The diseased parent vessels showed evidence of plasmatic insudation and transudation (100%) and endothelial proliferation (97%). These phenomena constitute the first stage of a type of retinal neovascularisation which has not hitherto been adequately described.
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PMID:Retinal neovascularisation arising from hyalinised blood vessels. 608 98

Prostacyclin, the labile prostanoid product of arachidonic acid metabolism in vascular endothelium, is the most potent known inhibitor of platelet aggregation and is highly effective in relaxing vascular smooth muscle. Its production is probably critically important in the maintenance of an intact vasculature. Although there is some evidence that prostacyclin circulates as a hormone, it is probably most important as a locally active agent in preventing thrombosis and maintaining patent vessels. Several factors can influence prostacyclin production, the most important of which probably act locally at sites of vessel wall injury. The most promising therapeutic approaches toward using prostacyclin's beneficial effects in vascular disease may lie in the use of drugs aimed at increasing prostacyclin production. Among these are thromboxane synthesis inhibitors, which act by diverting prostaglandin endoperoxides through the prostacyclin synthetase pathway, and lipoxygenase inhibitors, which might act chiefly by preventing formation of metabolites capable of inhibiting prostacyclin synthetase.
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PMID:Prostanoids in platelet-vascular interactions. 634 50

In diabetes mellitus the vascular endothelium often produces and releases abnormally low amounts of plasminogen activator, leading to an impaired fibrinolytic system, which might be of importance for the development of angiopathy. In this study tests of autonomic neuropathy (AN) were performed on diabetics without autonomic symptoms. It was discovered that diabetics without AN had a significantly lower mean fibrinolytic response to stimulation than nondiabetic controls, whereas this reduction was not found in those with AN. The suggestion that asymptomatic AN might induce a normalization of the impaired fibrinolytic system in diabetes, and thus have a modifying effect on the rate of development of angiopathy, requires further study to be properly evaluated.
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PMID:Fibrinolytic activity, autonomic neuropathy, and circulation in diabetes mellitus. 660 36

Nitric oxide (NO), derived from the vascular endothelium and other cells of the cardiovascular system, has important roles in physiological regulation of blood flow and may have pathophysiological functions in cardiovascular disease. The mechanisms involved in NO-induced vasodilatation and cytotoxicity are briefly reviewed in the context of inflammatory reactions and cardiovascular function. Although NO can hyperpolarize vascular smooth muscle, activation of the endothelium can induce hyperpolarization and vasodilatation by other means. Endogenous inhibitors of NO generated by leucocytes may compromise blood flow distribution after ischaemia and reperfusion injury. Chronic heart failure is associated simultaneously with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter ameliorates or exacerbates ventricular dysfunction. Excess NO production is also one of the earliest signs of transplant rejection, and suppression of iNOS expression by immunosuppressant drugs such as cyclosporin A might be one means by which these drugs protect allografts. Disturbances in the activity of NOS isoforms in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis. Reversing the NO defects with therapeutic agents, including angiotensin converting enzyme (ACE) inhibitors, offers promise in protecting against some manifestations of vascular disease.
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PMID:Endogenous nitric oxide in cardiovascular disease and transplantation. 754 30


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