Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present studies were performed to determine if abnormal endothelium-dependent vascular relaxation in atherosclerosis is due to decreased production or release of endothelium-derived relaxing factor (EDRF) by atherosclerotic rabbit vessels or if atherosclerotic vessels are less sensitive to the relaxing effects of EDRF. EDRF release was quantified using two approaches, by the response of bioassay detector vessels and also by the activation of guanylate cyclase within cultured endothelial cells. Using these assays, atherosclerotic vessels were found to release significantly less EDRF than normal vessels in response to both receptor- and nonreceptor-mediated stimuli. Relaxations of normal and atherosclerotic vessels to luminally applied EDRF (derived from normal rabbit aortas stimulated by the calcium ionophore, A23187) and nitric oxide, a putative EDRF, were also studied. Atherosclerotic vessels were more sensitive to EDRF than normal vessels, and equally sensitive to nitric oxide. Additional studies performed in organ chambers failed to demonstrate augmented constriction of atherosclerotic vessels in response to acetylcholine in the presence or absence of methylene blue or LY83583, compounds which inhibit the effect of EDRF. We conclude that decreased EDRF release is the principal underlying mechanism responsible for abnormal endothelium-dependent vascular relaxation in atherosclerosis.
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PMID:Mechanisms of abnormal endothelium-dependent vascular relaxation in atherosclerosis: implications for altered autocrine and paracrine functions of EDRF. 257 20

The recent discovery of endothelium-derived relaxation factor (EDRF) has altered the traditional classification of vasodilators used in angina pectoris and heart failure. If a vasodilator induces release of EDRF from the epithelium it is classified as endothelium-dependent, if not it is independent. Sodium nitroprusside and SIN-1 (active metabolite of molsidomine) are the main independent vasodilators since the endothelium relaxation factor appears to be principally a nitric oxide radical in these synthetic vasodilators. In contrast, calcium-channel blockers and a good number of endogenous chemical mediators (acetylcholine, bradykinin, serotonin, etc.) are endothelium-dependent. Furthermore, simple increase in blood flow through the large vessels can result in endothelium-dependent vasodilation (flow rate-dependence) the extent of which depends on the drug examined. The fact that the pharmacologic response of a vasodilator can be altered under certain pathologic conditions (atherosclerosis, hypertension, diabetes, etc.) further increases the importance of the role of the vascular endothelium in the action of vasodilators since endothelial modulation may then be completely diverted to secretion of endothelium-derived contracting factors (EDCFS).
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PMID:[Vasodilator agents and the vascular endothelium]. 262 13

This review discusses the role of three mediators synthesized by the vascular endothelium, which are involved in maintaining the surface of the endothelial cells in a non-thrombogenic state. Prostacyclin, discovered in 1976, is a product of arachidonic acid metabolism. This labile prostanoid, with a chemical half life of approximately three minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Endothelium-derived relaxing factor (EDRF), discovered in 1980, is even more labile than prostacyclin with a half life counted in seconds. It also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Recently, it has been identified as nitric oxide. Prostacyclin and EDRF are released together following stimulation of receptors on endothelial cells and cooperate to inhibit platelet aggregation and adhesion. 13-HODE, acts from inside the cell to make the endothelial surface less adhesive and is not released. These mediators act together to form the endothelial defence mechanism against adhering blood cells. Underproduction can lead to diseases such as hypertension or atherosclerosis. A mainly fish diet, rich in eicosapentaenoic acid alters the prostacyclin/thromboxane balance in favour of prostacyclin-like activity. This type of diet may provide protection against atherosclerosis and myocardial infarction.
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PMID:Mediators and the anti-thrombotic properties of the vascular endothelium. 264 8

In recent years it has become apparent that endothelial cells have important implications in the regulation of vascular smooth muscle tone, vascular permeability and platelet reactivity. One important physiological feature of these cells is the formation of the endothelium-derived relaxing factor (EDRF). This short-lived compound is a potent vascular smooth muscle relaxant and it also inhibits platelet aggregation and adhesion to the vessel wall. Its active principle seems to be nitric oxide (NO), and consequently it can be regarded as the "endogenous nitrovasodilator". In addition to EDRF, endothelial cells synthesize prostacyclin which also has platelet antiaggregatory and vasodilator properties. A reduced effectiveness of the EDRF mechanism is implicated, especially in those events of the vascular pathophysiology associated with an increased vascular tone or vasospasm. For example, a reduced production and/or action of EDRF has been found in animal models of atherosclerosis as well as in atherosclerotic human coronary arteries. In addition, prostacyclin production is reduced under these conditions. In different animal models of hypertension and diabetes mellitus, endothelium-mediated relaxation is also found to be reduced. In addition, under certain pathophysiological conditions, the endothelium seems to produce vasoconstrictor material.
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PMID:[Endothelial functions in cardiovascular diseases]. 265 5

Endothelial cells can release substances which profoundly affect vascular tone and platelet function. The inhibitory substances include endothelium-derived relaxing factor (EDRF or nitric oxide), prostacyclin and probably an endothelium-derived hyperpolarizing factor. Endothelin is a potent vasoconstrictor peptide released from endothelial cells. Under certain conditions, the endothelium can also produce angiotensin II, thromboxane A2 and a cyclooxygenase-dependent endothelium-derived contracting factor. In normal arteries, the effects of EDRF appear to dominate. In diseased arteries, the release and action of EDRF is impaired and that of endothelium-derived contracting factors is increased. Hyperlipidaemia, atherosclerosis and hypertension reduce endothelium-dependent relaxations. Hypoxia inhibits the release of EDRF and prolonged ischaemia severely impairs the response. Regenerated endothelium at sites of mechanical injury exhibits selective defects in response to aggregating platelets. The more effective release of EDRF in arterial compared with venous bypass grafts further suggests an involvement of the factor in preventing vascular occlusion. Therapeutic interventions with specific drugs and diets can augment the impaired endothelium-dependent relaxation of diseased arteries. Thus, functional changes of the endothelium in coronary artery disease may be an important factor in the development of vasospasm, ischaemia and thrombosis.
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PMID:Endothelium-derived relaxing and contracting factors: potential role in coronary artery disease. 268 Apr 93

Polyunsaturated fatty acid (PUFA) components of the diet, especially of the omega-3 variety, protect against atherosclerosis and its related thrombotic complications. Mechanisms involved probably involve the eicosanoids. Classic PGE1 has now found a role in the treatment of peripheral vascular disease. Prostacyclin (PGI2) discovered over ten years ago has also been introduced into clinical medicine; orally active analogs are being introduced with clinical potential in a variety of atherosclerotic and thrombotic disorders. "Endothelium-derived relaxing factor (EDRF)" has been identified with nitric oxide, an active metabolite of the classic nitrodilator compounds, which (like NO itself) is synergistic with prostacyclins in inhibition of platelet activation, but without similar synergistic effects on vasodilation. This finding is of considerable importance both from physiological and therapeutic standpoints. The therapeutic efficacy of acetylsalicylic acid (ASA, aspirin) in the secondary prevention of myocardial infarction is now established. For primary prevention, it is probably inferior to diet (e.g. fish oil) and lifestyle changes due to increased incidence of cerebrovascular bleeding. The unfulfilled therapeutic promise of thromboxane synthesis inhibitors may be overcome by introduction of dual TX receptor/synthesis inhibitors. Recent advances suggest that PGE1, prostacyclin analogs and high dose fish oil could act beneficially against background nitrodilator therapy in preventing thrombosis and mitogen-stimulated restenosis following thrombolytic or surgical treatment of coronary artery occlusion.
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PMID:Therapeutic impact of eicosanoids in atherosclerotic disease. 269 16

This article reviews what is known of endothelium-derived relaxing factor and its possible physiologic and pathophysiologic roles. This relaxing factor is now thought to be nitric oxide or a ready source of it. It acts as an endogenous nitrovasodilator, stimulating soluble guanylate cyclase to increase cyclic guanosine monophosphate (GMP) levels in vascular smooth muscle and platelets, with consequent relaxant and anti-aggregatory effects (predominantly when stimulated through receptor-operated channels). Its actions are thus synergistic with those of cyclic adenosine monophosphate (AMP)-mediated stimulation (for example, adenosine, prostacyclin). Endothelium-derived relaxing factor is unstable and is thought to act only very locally in vivo. Its release is continuous in the basal state and is stimulated by a number of neuropeptides and by agents released during platelet activation and thrombosis--with large differences in activity among different vessels. Endothelium-derived relaxing factor activity is also flow related, thereby coordinating vasomotor behavior in an intact vascular tree in response to changes in flow. Endothelium-derived relaxing factor activity is reduced in several pathologic states, including atherosclerosis.
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PMID:Endothelium-derived relaxing factor. 304 36

This review discusses the role of three mediators, synthesized by vascular endothelial cells, that help to keep the surface of the normal endothelium nonthrombogenic. The first is prostacyclin, a product of arachidonic acid metabolism discovered in 1976. This labile prostanoid, with a half-life of approximately 3 minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Prostacyclin and its analogues are currently being tested clinically for use in cardiovascular diseases such as primary pulmonary hypertension. The second mediator discussed is endothelium-derived relaxing factor (EDRF), discovered in 1980, which also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Substances that stimulate the release of EDRF include acetylcholine, bradykinin, and adenosine 5'-diphosphate. EDRF is even more labile than prostacyclin, with a half-life of about 6 seconds, and it has recently been identified as nitric oxide. Prostacyclin and EDRF are released together following stimulation of endothelial receptors and synergize to inhibit platelet aggregation. 13-Hydroxy-9,11-octadecadienoic acid, a third suggested mediator, is not released but acts from inside the cell to make the endothelial surface nonadhesive for circulating blood cells. It is proposed that these three mediators form the endothelial defense mechanism against blood-borne cells and chemicals and that breakdown of this barrier results in diseases such as hypertension and atherosclerosis.
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PMID:Mediators produced by the endothelial cell. 306 Apr 28

Endothelial cells release a potent vasodilator which activates guanylate cyclase and thereby induces relaxation of vascular smooth muscle cells. The so-called endothelium-derived relaxing factor (EDRF) is released by acetylcholine, local and circulating hormones, and substances released from aggregating platelets or formed during activation of the coagulation cascade. Nitric oxide (NO) probably accounts for the factor's activity. Thus, endothelial cells produce endogenous nitrates causing vasodilatation and inhibition of platelet adhesion and aggregation. Under physiological conditions, EDRF may play a role in the prevention of vasospasm and thrombosis. On the other hand, the impairment of endothelial regulatory mechanisms in atherosclerosis and hypertension may be involved in the pathogenesis of vascular occlusion and thereby of myocardial infarction, stroke and peripheral vascular disease.
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PMID:[Endothelium-derived relaxing factor(s): endogenous nitrates in the circulation?]. 306 71

Recent pharmacologic evidence supports the importance of the integrity of the endothelium in modulating vascular reactivity. The endothelial cells produce one or more endothelium derived relaxing factor(s) or EDRF that cause relaxation of vascular smooth muscle cells through production of cyclic guanosine monophosphate (GMP) and subsequent activation of protein kinase. While the molecular pharmacology of vascular relaxation is now well defined and numerous factors have been identified that inhibit or stabilize EDRF, the chemical identity of EDRF still is uncertain. Nitric oxide appears to be one such EDRF. Alterations in vasoreactivity observed during surgical manipulation, trauma, inhalational anesthesia, atherosclerosis, and other disease states can now be explained by their influence on the endothelial cells and EDRF. Further, it is now clear that nitrovasodilators act directly on the vascular smooth muscle cell to produce biological intermediates that mimic the endogenous factors. While anesthesiologists and critical care physicians have traditionally focused on hormonal and nervous system control of vascular reactivity, the effects of various drugs and manipulations on EDRF appear to be of clinical importance. In this manuscript we review the pharmacology of EDRF and of exogenous nitrovasodilators with particular reference to factors that can modulate vasoreactivity.
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PMID:Endothelium-dependent vascular smooth muscle control. 307 30


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