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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past 10 years, it has become obvious that endothelium regulates vasomotion, modulates hemostasis, influences vascular permeability, and controls blood vessel growth. The role of endothelium in modulating vasomotor tone is mediated by the releasing of a number of potent vasoactive compounds, including endothelium-derived relaxing factors (one of which is either nitric oxide or a compound that releases nitric oxide), vasoactive prostaglandins, endothelium-derived hyperpolarizing factor, and a number of constricting factors (such as thromboxane A2, endothelin, superoxide anion, L-arginine-dependent products etc.). This role of the endothelium is dramatically changed by several disease processes, including diabetes mellitus, cerebrovascular disease, and so on. Abnormalities of endothelial regulation of vascular tone may contribute to a number of clinical syndromes, including atherosclerosis, hypertension, septic shock syndrome, and many others. Endothelium dysfunction, characterized by altered synthesis or release of these relaxing factors along with maintained or facilitated synthesis or release of contracting factors, can lead to various pathological conditions such as thrombosis, vasospasm, and hypertension. Better understanding of the exact nature of endothelial dysfunction, including the role played by endothelium-derived vasoactive factors, may provide a basis for novel therapies in these vasculopathies.
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PMID:Endothelium dysfunction in cardiovascular diseases. 795 98

The aim of this study was to use periarterial manipulation to produce an atheroma-like neo-intima in rabbits and study resting blood flow and vascular responsiveness in vivo. One common carotid artery was enclosed in a silastic collar to induce a neo-intima similar to that of human early atherosclerosis, and carotid blood flow was measured periodically over 8 days in 8 conscious rabbits. The vasodilator responses to intravenous infusions of the endothelium-dependent vasodilator, acetylcholine, and glyceryl trinitrate were measured in each artery at 2 and 7 days after surgical placement of the collar, and again following infusion of the nitric oxide synthase inhibitor, N-nitro-L-arginine (NOLA, 15 mg/kg). Histological examination of the arterial segments at completion of the study revealed significant intimal thickening of the regions of artery enclosed in the collar. Resting blood flow was lower in the collared vascular bed as compared with the control, from as early as 2 days after surgery. Acetylcholine- and glyceryl trinitrate-induced decreases in carotid resistance, however, were no different between the arteries after 2 days. At 7 days after surgery, the vasodilator response to acetylcholine was significantly impaired in the collared vascular bed when compared with the control, while the glyceryl trinitrate-induced vasodilatation was similar in the two beds. Following NOLA infusion, mean arterial pressure was significantly increased and blood flow through both arteries was reduced. After NOLA, acetylcholine-induced vasodilatation in the collared vascular bed was no longer different from the vasodilatation in the control bed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired vasodilator function of nitric oxide associated with developing neo-intima in conscious rabbits. 802 80

This review concerns our understanding of the molecular basis of platelet function in haemostasis. In particular, we indicate how research into platelet membrane glycoprotein (GP) receptors is yielding vital information on the mechanisms of platelet adhesion and aggregation. These receptors, nearly always complexes of two or more subunits, are now known to belong to distinct gene families, some of which are unique to platelets while others are widely distributed in mammalian tissues. GP Ib-IX complexes are responsible for the high-shear-rate-dependent adhesion of platelets to von Willebrand factor (vWF) exposed within the subendothelium of damaged vessels. Other adhesion receptors include members of the VLA subclass of the integrin family: VLA-2, VLA-5 and VLA-6, which mediate platelet adhesion to collagen, fibronectin and laminin, respectively. Platelet aggregation is initiated by distinct populations of receptors specific for each physiological agonist. Many of these receptors, including the highly important and recently cloned thrombin receptor, have seven transmembrane domains and possess highly selective agonist-binding determinants. Finally, we highlight platelet aggregation and the role of GP IIb-IIIa complexes which, following platelet activation, bind fibrinogen and other adhesive proteins. The latter, through being polyvalent for GP IIb-IIIa, then form the bridges linking adjoining platelets. The 'ligand-binding pocket' of GP IIb-IIIa contains at least three sequences essential for ligand binding; fibrinogen also binds to the activated complex through identified domains, one of which, the Arg-Gly-Asp (RGD) sequence, is also found in vWF and the other adhesive proteins able to support platelet aggregation. Finally, we further describe how these, and other glycoproteins in both surface and internal membrane systems, constitute a complex receptor network capable of translocation and reorganization after platelet activation. In cardiovascular disease, platelets accumulate within arteries whose luminal surface has been modified through atherosclerosis. Recent molecular advances are yielding exciting opportunities for the development of new, and more powerful, drugs acting as specific inhibitors of thrombotic processes.
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PMID:A review of the role of platelet membrane glycoproteins in the platelet-vessel wall interaction. 802 47

Hypercholesterolemic and atherosclerotic coronary endothelial dysfunction consist of a progressive, not irreversible, impairment in reactions to various endothelium dependent relaxing substances in both the epicardial coronary artery and in the resistance vessel. Paradoxical vasoconstriction, dynamic stenoses and dysregulation of the coronary blood flow make this endothelial dysfunction contribute to the pathogenesis of myocardial ischemia. The selectivity of the impairment makes the concept of specific receptor operated signal transductions in hypercholesterolemia and low doses of oxidized LDL likely. In progressive atherosclerosis and high levels of oxidized LDL the dysfunction may spread to other receptors, the availability of L-arginine may decrease and the metabolism of EDRF change. Cholesterol-lowering therapy may restore this endothelial dysfunction. This paper will discuss the recent pathophysiological insights in dyslipidemic endothelial dysfunction and exposes the mode of action of various therapeutic drugs.
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PMID:Endothelial dysfunction and dyslipidemia: possible effects of lipid lowering and lipid modifying therapy. 805 97

T lymphocytes and macrophages (M phi) have been seen to accumulate at sites of lesions in blood vessel walls, suggesting that these cells may contribute to the pathogenesis of inflammatory reactions. Tumour necrosis factor-alpha (TNF-alpha), a cytokine produced by both M phi and T lymphocytes, plays a major role in inflammatory reactions, blood vessel formation, thrombosis and atherosclerosis. We now report that secretion of TNF-alpha by cloned CD4+ rat T cells, and to a lesser degree by peripheral T cells, and M phi can be induced in vitro in the absence of antigen, in a major histocompatibility complex (MHC) class II-independent manner by integrin-mediated recognition of immobilized components of extracellular matrix such as fibronectin and laminin; the secretion of TNF-alpha by the interacting resting cells on fibronectin was partially abrogated by the presence of the Arg-Gly-Asp (RGD)-containing amino acid sequence. This T cell-M phi interaction involves CD2 and CD4 molecules and requires a signal transduced in the T cells by a protein tyrosine kinase. Thus, a multicellular interaction with extracellular matrix protein exposed as a consequence of vascular wall injury can serve to signal the secretion of TNF-alpha which induces the recruitment of additional immune cells to the developing lesion.
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PMID:Extracellular matrix induces tumour necrosis factor-alpha secretion by an interaction between resting rat CD4+ T cells and macrophages. 809 10

Nitric oxide is widely distributed in the body. It has an important role in the regulation of the circulation and as yet, ill-defined roles in nervous and immune systems. It is derived from L-arginine from a reaction catalysed by a constitutive intracellular enzyme, nitric oxide synthase. It is recognised as the endogenous nitrovasodilator whose action is mimicked by all exogenous nitrovasodilators. After production in the vascular endothelial cell, it diffuses to the smooth muscle cell where it activates the enzyme guanylate cyclase which leads to an increase in cyclic GMP and thence to muscle relaxation. The duration of its action is brief, a few seconds. Disorders of NO metabolism underlie many disease states including endotoxic shock in which prolonged production of nitric oxide may be induced by cytokines. Deficiencies in endogenous production may account for hypertension in various disease states including atherosclerosis and chronic renal failure. NO therapy been used experimentally to successfully treat idiopathic pulmonary hypertension and pulmonary hypertension associated with cardiac and respiratory diseases. However, the long-term benefits have yet to be studied. Administration of NO requires the use of a device to monitor the concentrations of both NO and of NO2. The latter is a noxious agent and a time-related product of the reaction between NO and O2 and is a possible contaminant of preparations of NO. Precautions must be taken to prevent contamination of the work-place atmosphere with NO and NO2. These include gas scavenging and the use of a leak-free system for spontaneous and mechanical ventilation. Using NO in its gaseous form, clinicians have at long last been provided with the means to treat pulmonary hypertension without adversely causing systemic hypotension. The therapy is most suited to short-term use in mechanically ventilated patients. Safe practical long-term NO therapy must await the development of agents which release NO from aerosol preparations.
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PMID:The role of nitric oxide (formerly endothelium-derived relaxing factor-EDRF) in vasodilatation and vasodilator therapy. 812 32

Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited disorder caused by the substitution of glutamine for arginine at position 3500 in apo B-100. The presence of mutant apo B-100 in low-density lipoproteins (LDL) markedly reduces their affinity for the LDL receptor, leading to hypercholesterolaemia and increased proneness to coronary artery disease. In some FDB heterozygotes the clinical picture is indistinguishable from that in heterozygous familial hypercholesterolaemia (FH). In European and N. American populations the frequency of FDB is at least as high as that of FH. In most lipid clinics, 2-5% of patients given a clinical diagnosis of FH have FDB, not FH. Most FDB heterozygotes respond well to drugs that lower plasma LDL levels by inducing receptor activity. This may be due partly to increased receptor-mediated hepatic removal of mutant and normal precursors of LDL, using apo E as recognition element. Several important lessons can be learnt from the study of FDB.
Atherosclerosis 1993 Dec
PMID:Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. 814 33

The vascular endothelium is the site of formation of several powerful mediators. One of these is NO, a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen. NO elicits relaxation of VSMC by activating cytosolic guanylate cyclase. NO also counteracts platelet adhesion and aggregation. The biological actions of NO make it a key substance in the endogenous defense against vascular occlusion and thrombosis. The basal formation of NO maintains a moderate but significant vasodilation in the systemic resistance vessels and counteracts platelet activity. When blood flow in conduit arteries is increased there is an augmented endothelial formation of NO, eliciting flow-dependent vasodilation. Beside this, several vasodilators (acetylcholine, bradykinin, histamine, substance P) operate by stimulating endothelial NO formation. On the other hand, drugs like nitroglycerin and papaverine operate independently of the vascular endothelium. Vasodilator mechanisms, physiological as well as pharmacological, may therefore be characterized as endothelium-dependent (i.e. NO-mediated), or endothelium-independent (i.e. not mediated by NO). Physiologically, mixed mechanisms occur. Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation, increased degradation, decreased sensitivity to the NO formed, or a mixture of these factors. Irrespective of the mechanism behind, this is referred to as endothelial dysfunction. Endothelial dysfunction occurs in several cardiovascular settings, like atherosclerosis, hypercholesterolaemia, diabetes, and essential hypertension. Endothelial dysfunction leads to an impaired tissue perfusion, increased local vascular resistance, decreased defense against thrombus formation, and possibly also decreased defense against hypertrophy of the VSMC in the vessel wall media. In patients with CHD, endothelial dysfunction leads to an impaired coronary flow response to physical and mental stress, and to promotion of platelet adherence and aggregability. Endothelial dysfunction is thereby a probable aggravating factor in the atherosclerotic process, adding a functional component on top of the structural lesions characterizing this disease. A particular form of endothelial dysfunction, limited to the arterial resistance vessels, may explain the symptoms and clinical characteristics of microvascular angina. In patients with essential hypertension, endothelial dysfunction prevails, adding a functional component to the structural factors also in this disease. Hitherto, the only therapeutic tools available to restore endothelial dysfunction appear to be restriction of the dietary intake of lipids, possibly reinforced with intake of antioxidants like fish oil and vitamin E. However, large clinical trials to confirm the efficacy of such therapy in reversing endothelial dysfunction have not been conducted. In the future, more directly acting therapeutic regimens, aimed at supporting or substituting the endogenous formation of NO, are likely to appear as well.
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PMID:Endothelial nitric oxide and cardiovascular disease. 815 Dec 63

We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.
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PMID:Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. 817 41

Nitric oxide reacts with superoxide to form peroxynitrite, a potential mediator of oxidant-induced cellular injury. The endothelium is a primary target of injury in many pathological states, including acute lung injury, sepsis, multiple organ failure syndrome, and atherosclerosis, where enhanced production of nitric oxide and superoxide occurs simultaneously. It was hypothesized that stimulation of endothelial cell nitric oxide production would result in formation of peroxynitrite. Immediate oxidant production was detected by luminol- and lucigenin-enhanced chemiluminescence from cultured bovine aortic endothelial cells exposed to bradykinin or to the calcium ionophore A23187. Luminol-enhanced chemiluminescence was efficiently inhibited by the nitric oxide synthase inhibitor nitro-L-arginine methyl ester and by superoxide dismutase, implying dependence on the presence of both nitric oxide and superoxide for oxidant production. Inhibition of luminol-enhanced chemiluminescence by nitro-L-arginine methyl ester was partially reversed by L-arginine, but not by D-arginine. Cysteine, methionine, and urate, known inhibitors of peroxynitrite-mediated oxidation, inhibited luminol-enhanced chemiluminescence, while the hydroxyl radical scavengers, mannitol and dimethylsulfoxide, and catalase did not. Bicarbonate increased luminol-enhanced chemiluminescence in a concentration-dependent manner. Superoxide production, detected by lucigenin-enhanced chemiluminescence, was slightly increased in the presence of nitro-L-arginine methyl ester, suggesting that endothelial cell-produced superoxide was partially metabolized by reaction with nitric oxide. These results are consistent with agonist-induced peroxynitrite production by endothelial cells and suggests that peroxynitrite may have an important role in oxidant-induced endothelial injury.
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PMID:Agonist-induced peroxynitrite production from endothelial cells. 817 19


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