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

This report describes, at least in part, the role of prostaglandin and cyclic nucleotide metabolism in the etiology of the vascular disease associated with diabetes mellitus. Alterations in this metabolism seem associated with induction of platelet aggregation leads to microthromboses leads to microangiopathy sequences that are subtle but inexorable over a long period of time. Prostaglandins are generally elevated in blood from patients having frank signs of diabetic retinopathy when compared with nondiabetic subjects. Prostaglandin concentration remained elevated in diabetic retinopathy patients receiving indomethacin. We formed, therefore, the working hypothesis--yet to be fully tested either in patients or animal models with and without indomethacin treatment--that the increased prostacyclin (synthesized by endothelial microsomes) and cyclic-AMP production, both of which favor prevention of platelet aggregation, accompany the increased concentration of one or more of the prostaglandin E and F compounds. Concurrently, there may be an accompanying reduction of thromboxane A2 (synthesized by platelet microsomes) and cyclic-GMP (both of which favor platelet aggregation) production in the diabetic patients. The elevated prostaglandin in the diabetic patients not receiving indomethacin could possibly be directed toward slowing but not preventing the progression of the complex disease process in diabetes.
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PMID:Proposed metabolic dysfunctions in diabetic microthromboses and microangiopathy. 23 37

Endothelial cells produce the 21-amino acid peptide endothelin, which is formed from its precursor, big endothelin, via the activity of converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and hypoxia. In vascular smooth muscle, endothelin binds to a specific receptor (ETA-subtype), which activates phospholipase C, leads to the formation of inositol trisphosphate, diacylglycerol (which activates protein kinase C), and increased intracellular Ca2+. In certain blood vessels, the endothelin receptor on vascular smooth muscle is linked to a voltage-operated Ca2+ channel via a G-protein. This explains why Ca2+ antagonists inhibit endothelin-induced contractions in certain, but not all, blood vessels. In the human forearm circulation, Ca2+ antagonists do prevent endothelin-induced contractions and unmask endothelin-induced vasodilation mediated by endothelial prostacyclin production (via the ETB-receptor). The pulmonary circulation plays an important role in the metabolism of endothelin, as the lungs take up large quantities of the peptide during passage. Endothelin has profound vasoconstrictor effects in the pulmonary circulation (and also in bronchial tissue), and its production is augmented in pulmonary hypertension. In systemic hypertension, the circulating endothelin levels appear to be normal. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are increased. Thus, endothelin is a potent mediator in the systemic and pulmonary circulation and, in particular, in diseases of the vasculature.
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PMID:Endothelin: systemic arterial and pulmonary effects of a new peptide with potent biologic properties. 133 60

A range of thromboxane A2 receptor blocking (TxRB) drugs, prostacyclin and aspirin have been assessed as inhibitors of human platelet deposition onto rabbit and human de-endothelialized arteries in vitro. Platelet deposition was quantified by measuring the radioactivity associated with de-endothelialized arteries following superfusion with 111indium-labelled human platelets reconstituted in blood. Using rabbit aorta, all of the compounds tested produced a similar maximum inhibition (approximately 70%) of platelet deposition; from scanning EM studies the residual deposition appeared to represent a monolayer of adhered platelets. The potency of the TxRB's for inhibiting deposition was GR32191 greater than or equal to GR36246 greater than SQ29,548 greater than ICI185282 greater than or equal to AH23848 much greater than BM13.177 consistent with their TxRB potency on human platelets. Using human umbilical arteries, the TxRB's achieved a smaller maximum inhibition of deposition (approximately 50%) than did prostacyclin or the fibrinogen receptor blocking peptide Gly-Arg-Gly-Asp-Ser (GRGDS) (60-75%). In addition, using human umbilical arteries, the structurally-related TxRB's GR32191 and GR36246 exhibited a greater than 1000-fold enhancement in potency as inhibitors of platelet deposition over that seen in the rabbit aorta. In preliminary experiments, GR32191 also displayed a similar high potency on human cerebral arteries. In contrast, the structurally unrelated compounds SQ29,548, ICI185282 and BM13.177 exhibited similar potencies on human umbilical arteries to those observed on the rabbit aorta; aspirin and prostacyclin also displayed similar potencies on the two preparations. The enhanced effect of GR32191 and GR36246 on human umbilical arteries therefore appears unrelated to their action as TxRB's on human platelets although the mechanism of this unique action is at present unknown. However, if these drugs exhibited a similar high potency for preventing mural thrombus formation in vivo in man, they may represent a major advance in the treatment of occlusive vascular disease.
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PMID:Effect of GR32191 and other thromboxane receptor blocking drugs on human platelet deposition onto de-endothelialized arteries. 138 66

Increased thromboxane A2 (TXA2) generation by platelets has been reported both in diabetic patients and streptozocin-induced diabetic rats. This increase is in contrast to the decreased prostacyclin (PGI2) synthesis by endothelial cells in diabetes. An imbalance in the ratio of TXA2/PGI2 has been implicated in increased platelet aggregation and a high incidence of vascular disease in human diabetes. The mechanism for this imbalance, however, remains elusive. In a previous study from our laboratory, we reported unchanged arachidonic acid levels in platelet membrane phospholipids of 3-week diabetic rats, but a decreased arachidonic acid level in platelet membrane phospholipids of 6-week diabetic rats. In the present communication, we report the role of enzymes that are involved in remodeling arachidonic acid levels of platelet membrane phospholipids in both 3- and 6-week diabetic rats. No alterations were observed in the activities of arachidonoyl-CoA synthetase, acyl-CoA: lysophosphatidylcholine acyltransferase, or phospholipase A2 in platelets from both 3- and 6-week diabetic rats. However, both increased uptake and incorporation of [14C]arachidonic acid into platelets were observed in the diabetic platelet-rich plasma. In conclusion, increased TXA2 formation in diabetic platelets is not due to alterations in the activities of enzymes involved in the incorporation into or release of arachidonate from the diabetic platelet membrane phospholipid, but may be due to increased efficiency of uptake, incorporation or possibly redistribution of this fatty acid among phospholipid classes in diabetic platelets.
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PMID:Modifications of platelet phospholipid fatty acid composition in streptozocin-induced diabetic rats. 143 63

As survival improves following heart-lung transplantation (HLT) the importance of obliterative bronchiolitis (OB) as a cause of late death increases. Whilst coronary occlusive disease (COD) may be less common in heart-lung transplant recipients than in patients receiving heart transplants, COD associated with OB can be lethal. We have studied 22 long-term survivors of heart-lung transplantation at an average of 25 months following transplantation during rest and at 50 W supine exercise and with prostacyclin induced vasodilation. Cardiac index increased less with exercise as the physiological measurement of OB using forced expiratory volume in one second (FEV1) fell (P = 0.018). Although resting pulmonary vascular resistance increased with falling FEV1, this increase was still within the normal range. We conclude that a fall in cardiac reserve on exercise accompanies the fall in FEV1 which characterizes OB and may reflect cardiac vascular disease.
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PMID:Late pulmonary haemodynamic changes in heart-lung transplantation. 160 Sep 89

Atherosclerosis can be defined in broad terms as a vascular disease accompanied by dysregulation of cholesterol metabolism and the accumulation of smooth muscle cells and macrophages within the vessel wall. At the interface of the blood and the vessel wall is the endothelium, which actively participates in a plethora of critical homeostatic functions in addition to affecting cholesterol trafficking in the underlying smooth muscle cell and macrophage. These events include: 1) inflammation resulting in release of cytokines, 2) changes in vascular reactivity causing release of endothelial cell derived relaxing factor (EDRF) and PGI2, and 3) control of vascular smooth cell proliferation via release of growth factors and growth suppressor molecules. Each process has been linked to the regulation of cholesterol accretion in the arterial cell. Furthermore, each homeostatic process is regulated by transmembrane signaling mechanisms at the lipid-protein interface of the membrane. Data have emerged recently indicating that biological response modifiers that trigger transmembrane signaling work in a sequential manner to control cell function. We review studies of the regulatory mechanisms of transmembrane signal transduction that advance the concept that phosphorylation of the specific protein components of the receptor machinery may result in a cooperative cellular response to ligands that will ultimately affect cholesterol delivery and trafficking within cells. We review recent data demonstrating that eicosanoids and cytokines released from one cell activate their receptors on neighboring cells, and interact with each other during this "cross-talk phenomenon." Cross-talking among phosphorylation reactions involving, for example, protein kinases A and C and tyrosine protein kinase, coupled with the highly regulated eicosanoid pathways and the diacylglycerol-phosphatidyl inositol (DG-PI) system, are discussed in terms of their metabolic impact on cholesterol delivery, intracellular processing, and efflux.
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PMID:Signal transduction in atherosclerosis: integration of cytokines and the eicosanoid network. 164 57

The endothelium not only mediates relaxation but is a source of contracting factors. Endothelium-dependent contractions are elicited by physical and chemical stimuli (i.e., hypoxia, pressure, and stretch) and autacoids, local and circulating hormones. The mechanism of endothelium-dependent contractions to hypoxia involves withdrawal of nitric oxide. The endothelial cyclooxygenase pathway can produce thromboxane A2, prostaglandin H2, and superoxide anions. The peptide endothelin is a potent contracting factor; its production is stimulated by vasopressor hormones, platelet-derived factors, coagulation products, and cytokines, whereas endothelium-derived nitric oxide, prostacyclin, and a smooth muscle cell-derived inhibitory factor reduce endothelin production. In hypertension, the release of cyclooxygenase-dependent endothelium-derived contracting factors to stretch, acetylcholine, and platelet-derived products is augmented. Vascular endothelin production in hypertension remains controversial but appears mostly normal; it is augmented in the presence of vascular disease or renal insufficiency. The endothelium-dependent inhibition of endothelin-induced contractions is reduced in hypertension while the reactivity of vascular smooth muscle may be normal, increased, or reduced. The potentiating effects of low concentrations of endothelin on contractions to norepinephrine are augmented with aging and hypertension. In atherosclerosis, the production of the cyclooxygenase-dependent endothelium-derived contracting factors and endothelin is enhanced. Thus, endothelium-derived contracting factors can profoundly affect vascular tone and counteract relaxing factors produced within the endothelium. In hypertension and atherosclerosis, the role of contracting factors appears to become more dominant, leading to an imbalance of endothelium-dependent vascular regulation.
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PMID:Endothelium-derived contracting factors. 173 45

Cigarette smoking is associated with an increased risk and extent of advanced atherosclerotic vascular disease in peripheral as well as coronary arteries. The likelihood of claudication, amputation, stroke, abdominal aortic aneurysm, and failure of vascular reconstruction is higher in smokers than nonsmokers. Smoking exerts its deleterious effects through many interactive mechanisms. Nicotine and carbon monoxide produce acute cardiovascular consequences, including altered myocardial performance, tachycardia, hypertension, and vasoconstriction. Smoking injures blood vessel walls by damaging endothelial cells, thus increasing permeability to lipids and other blood components. Among metabolic and biochemical changes induced by smoking are elevated plasma, free fatty acids, elevated vasopressin, and a thrombogenic balance of prostacyclin and thromboxane A2. Chronic smoking is associated with a tendency for increased serum cholesterol, reduced high density lipoprotein, and other lipid effects that contribute to atherosclerosis. In addition to rheologic and hematologic changes from increased erythrocytes, leukocytes, and fibrinogen, smokers have alterations in platelet aggregation and survival that produce thrombosis. Considering the ubiquitous repercussions of this menace, vascular surgeons should play an active role in motivating their patients to quit smoking.
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PMID:The peripheral vascular consequences of smoking. 206 25

Prostacyclin and endothelium-derived relaxing factor (or nitric oxide) are unstable mediators produced by the vascular endothelium, that are important for local regulation of platelet behavior and blood flow. This review focuses on the basic biochemistry and pharmacology of prostacyclin, its interactions with nitric oxide and nitrovasodilator drugs, and the implications of disturbances in this system for vascular disease, particularly hypertension and atherosclerosis. Prostacyclin and its stable analogs are also finding limited therapeutic applications in preservation of platelet function, pulmonary hypertension, and investigation into the cytoprotective and antiatherosclerotic properties is continuing.
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PMID:Prostacyclin and vascular function: implications for hypertension and atherosclerosis. 208 4

The effects of estradiol and progesterone added to the growth medium of human umbilical vein endothelial cells for 72 h on the formation and release of prostacyclin were investigated. The influence on collagen-induced platelet aggregation and on the platelet formation of thromboxane A2 following aggregation, of the growth medium collected before and after thrombin stimulation of the endothelial cells, was studied simultaneously. Under basal conditions, endothelial cells grown with progesterone released significantly less prostacyclin into the growth medium than did controls (p less than 0.05). Following thrombin stimulation, endothelial cells grown with estradiol (p less than 0.05) or a combination of estradiol and progesterone (p less than 0.01) contained significantly less prostacyclin than controls. No significant effects on the platelet aggregation or platelet thromboxane formation could be found. This study indicates a lowering effect of both female sex hormones on the endothelial cell prostacyclin formation and release. This may be of significance for the increased risk of vascular disease in pregnant women and oral contraceptive users, but can hardly explain the consequences of the hormonal loss occurring at the menopause.
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PMID:Female sex hormones and platelet/endothelial cell interactions. 209 21


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