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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was conducted to examine whether nitric oxide regulates lipid metabolism. In Experiment 1, rats were fed for 5 wk diets with or without 0.2 g/kg L-N-nitroarginine (L-NNA), a specific inhibitor of nitric oxide synthase, that were or were not supplemented with 40 g/kg L-arginine. Rats fed L-NNA had significantly higher concentrations of serum triglyceride and total cholesterol, lower concentrations of serum nitrate, and a lower ratio of HDL-cholesterol to total cholesterol than rats fed the basal diet. These alterations were suppressed by supplementing L-arginine to the L-NNA-containing diet. In Experiment 2, rats were fed diets with or without 0.2 g/kg L-NNA. Dietary L-NNA elevated serum concentrations of free fatty acids without affecting those of ketone bodies. L-NNA lowered the activity of hepatic carnitine palmitoyltransferase, the rate-limiting enzyme of fatty acid oxidation, but did not affect activities of hepatic glucose-6-phosphate dehydrogenase and fatty acid synthase which are lipogenic enzymes. These results suggest that the lower nitric oxide level in rats fed L-NNA leads to hyperlipidemia and that the elevation in serum triglyceride might be due to reduced fatty acid oxidation.
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PMID:Feeding rats the nitric oxide synthase inhibitor, L-N(omega)nitroarginine, elevates serum triglyceride and cholesterol and lowers hepatic fatty acid oxidation. 885 18

In this review, the role of the macrophage in the pathophysiology of coronary artery disease (CAD) is examined. The central interaction of macrophage, endothelial cell and smooth muscle cell in the context of hyperlipidemia is considered. The macrophage appears to be at the beginning of a chain of events that starts with elevated low density lipoprotein (LDL). Stress, particularly in those with a core hostility, may be associated not only with higher catecholamine levels but also with higher serum lipid levels. These lipids will in turn be processed to oxidized LDL by macrophage and endothelial cells. Oxidized LDL molecules will contribute to atherosclerotic plaquing. A side effect of such plaque formation may be a diminished vasodilatory response to the nitric oxide (NO) produced by macrophages and endothelium. Indeed, paradoxical vasoconstriction occurs in atherosclerosis in response to neurotransmitters such as serotonin and acetylcholine, which under normal circumstances cause vasodilation. There also is evidence that both macrophages and endothelial cells can regulate NO production through a specific mu 3 morphine receptor, an effect that can be blocked by naloxone. The clinical effectiveness of morphine and nitroglycerin in CAD patients may relate to these mechanisms. More research will be needed to elucidate the neuroimmunologic basis for atherosclerosis with prospects for better treatment and management in future.
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PMID:Neuroimmunologic implications in coronary artery disease. 887 69

Coronary arteries are regulated by neuronal mechanisms, hormones and paracrine mediators. The importance of endothelium-dependent mechanisms has recently been recognized. The endothelium responds to mechanical and chemical signals from the blood by releasing mediators that modulate vascular tone and structure, platelet function, coagulation and monocyte adhesion. Important relaxing factors are nitric oxide, prostacyclin and a putative hyperpolarizing factor. Nitric oxide also inhibits smooth muscle proliferation and, together with prostacyclin, platelet function. Bradykinin-induced nitric oxide production is reduced by angiotensin-converting enzyme. Endothelin-1, thromboxane A2 and prostaglandin H2 are contracting factors. Thromboxane A2 and prostaglandin H2 activate platelets, while endothelin has no direct platelet effects, but causes smooth muscle proliferation. In hypercholestermia, endothelium-dependent relaxation is impaired and contraction as well as adhesion of monocytes and platelets enhanced. Pharmacological correction of hyperlipidemia by statins also improves or normalizes endothelial dysfunction in patients. Angiotensin-converting enzyme inhibitors have similar effects.
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PMID:Lipids and endothelial function: effects of lipid-lowering and other therapeutic interventions. 888 99

The endothelium lines all vessels of the body and is the most important structure for communication between the flowing blood and the vessel wall. Healthy endothelium has antiadhesive and antithrombotic properties and is crucial for maintaining blood flow. It serves as a permeability barrier and prevents noxious agents from entering the vessel wall. Endothelial cells have secretory functions and secrete vasorelaxant substances. Therefore, functioning endothelium sustains the homoeostasis of the vessel wall. Endothelial functions are impaired by risk factors for cardiovascular disease such as hypertension, hyperlipidemia and hyperglycemia. Hypertension leads to decreased generation of nitric oxide in endothelial cells, thereby diminishing their vasorelaxant properties. Hypertension also contributes to an increase in endothelial cell permeability leading to intimal edema. Thirdly, hypertension increases the expression of adhesion molecules and increases the adherence of leukocytes to the vessel wall. Hence, hypertension directly contributes to the pathological alterations of the endothelium and it seems that these effects initiate and accelerate the pathogenesis of chronic vascular disease.
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PMID:Hypertension, the endothelium and the pathogenesis of chronic vascular disease. 888 53

The endothelium is involved in both the physiological regulation of vascular tone and the structural transformation of the vessel under pathological conditions. Under physiological conditions, endothelial cells continuously secrete nitric oxide (NO), which relaxes smooth muscle cells and ensures vessel patency. Damaged or excessively activated endothelial cells can also secrete vasoconstrictor factors, the best known of which is endothelin-1 (ET-1), as well as factors that affect the differentiation and growth of vascular smooth muscle cells. How endothelial cell damage contributes, under pathological conditions, to vascular disease can best be illustrated in patients with diabetes mellitus, in whom there are pronounced changes in endothelial cell structure and function. Endothelial cells also interact with cells in the bloodstream, ET-1 and other factors are released from endothelial cells into the bloodstream, where their chemotactic action can induce leucocytes and platelets to migrate to the endothelial wall. Endothelial cells induce adhesion by expression of specific surface adhesion molecules (selectins, integrins and a supergene family of immunoglobulins) that can interact with ligands on the leucocytes and platelets. The expression of adhesion molecules is increased in endothelial cells chronically damaged by risk factors for atherosclerosis. The disturbed permeability of the endothelial layer in patients with diabetes mellitus and/or hyperlipidaemia leads to an increased influx of substances from the circulation into the vessel wall. In addition, endothelial cell dysfunction can lead to accelerated intravessel blood coagulation. It is evident that the endothelium plays a central role in many of the early pathophysiological processes involved in atherosclerosis. It is therefore important to investigate the effects of antiatherosclerotic therapy on endothelial cell function and cell-to-cell interactions. Until recently, little was known about the direct effects of calcium antagonists on endothelial cell function. Recent studies, including two clinical studies, indicate that calcium antagonists primarily affect interactions of endothelial cells, smooth muscle cells, monocytes and platelets, which play a central role in the early phases of the development of atherosclerosis, whereas the protective effect of these agents on the vascular system appears to be low at later stages.
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PMID:Endothelial function. General considerations. 903 50

Our object was to evaluate the effects of regular mild exercise on blood pressure and on circulating level of ouabainlike factors (OLF) and of nitrate anion, an endproduct of nitric oxide (NO) in humans. We measured plasma ouabainlike immunoreactivity (OLI) and nitrate ions (NO3.) before and after mild exercise for 3 months' duration in 16 patients with essential hypertension, diabetes mellitus, obesity, or hyperlipidemia. Plasma OLI was measured using an amplified ELISA system with anti-ouabain antibody and biotinyl-tyramide. Serum NO3. was measured with high-performance liquid chromatography (HPLC) with an anion-exchange column. With the reverse phase HPLC system with an octa decylsilyl silicagel column, the elution volume of plasma OLI of a healthy volunteer matched that of authentic ouabain in a gradient elution system of acetonitrile/H2O. Plasma OLI levels decreased significantly by about 34% after mild exercise, and NO3. levels tended to be within the reference interval in normal volunteers. Body weight, diastolic and systolic blood pressure, serum triglyceride and acetylcholine esterase (a marker of the fatty liver) were significantly decreased (p < 0.01) after 3 months of regular mild exercise. The plasma OLI level was significantly correlated with plasma NO3., there was a trend toward a correlation with diastolic blood pressure (p = 0.06) before and after regular exercise. Regular mild exercise led to a decrease in plasma levels of OLI, and acetylcholine esterase activity and blood pressure in adult patients. Results suggest that changes in OLF production contribute to the blood pressure regulation seen in patients who exercise regularly.
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PMID:Vasodepressor effects of exercise are accompanied by reduced circulating ouabainlike immunoreactivity and normalization of nitric oxide synthesis. 910 42

New evidence suggests an interaction between hyperlipidemia, activation of the renin-angiotensin system, and atherosclerotic disease. In patients with atherosclerosis and hyperlipidemia, coronary endothelial dysfunction is usually diffuse and affects vasomotor tone, platelet activity, thrombosis, fibrinolysis, and regulation of inflammatory cells. Angiotensin II, an important oxidant, alters the binding of low-density-lipoprotein (LDL) cholesterol to its receptors and increases endothelial uptake of LDL. Endothelial dysfunction is worsened by the suppression of nitric oxide production and/or release via angiotensin II-associated degradation of bradykinin and oxygen free radical production, resulting in inadequate vasorelaxation. Therapy with angiotensin-converting enzyme (ACE) inhibitors appears to eliminate these untoward effects and may ameliorate the tendency for myocardial infarction associated with elevated plasma levels of angiotensin II. Although the role of ACE inhibitors in the prevention and/or treatment of coronary artery disease in patients without left ventricular dysfunction remains to be established, the capacity of ACE inhibition to correct endothelial dysfunction offers promise. The ability of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to improve endothelial function, prevent the progression of coronary atherosclerosis, reduce the incidence of ischemic events, and improve survival is well known. Potentially, ACE inhibitors may have an additive or synergistic effect on the development of atherosclerosis and the clinical consequences of this disease when used in combination therapy with lipid-lowering strategies.
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PMID:The potential use of angiotensin-converting enzyme inhibitors in patients with hyperlipidemia. 912 18

Low density lipoprotein (LDL) plays an important role in atherogenesis. Focal accumulation within the arterial intima of excess amounts of cholesterol-rich LDL leads to the migration and recruitment of monocytes, which then differentiate into macrophages after taking up large amounts of oxidatively modified LDL via their scavenger receptors and become lipid-laden 'foam cells' within the subendothelial space. It is generally accepted that oxidized LDL and hyperlipidaemia impair endothelial-dependent vascular relaxation, yet the existing literature on the effects of oxidatively modified LDL on endothelium-derived nitric oxide (NO) and prostacyclin (PGI2) release is inconclusive, since oxidized LDL has been reported to enhance or reduce NO and PGI2 production. Our studies using cultured human endothelial and smooth muscle cells have established that basal rates of L-arginine (NO precursor) transport, NO and PGI2 production and soluble guanylyl cyclase activity are unaffected by pretreatment (for 1 or 24 h) with native LDL, or with mildly or highly oxidized LDL. In contrast, highly oxidized LDL inhibited histamine-stimulated release of NO and PGI2 from human endothelial cells and induced an adaptive increase in the level of intracellular glutathione in human smooth muscle cells, a response which was prevented by the chain-breaking antioxidant alpha-tocopherol. Although initial rates of L-arginine transport and basal NO and PGI2 release from human endothelium are unaffected by oxidized LDL, agonist-stimulated release of these vasodilators is markedly attenuated. Elucidation of the mechanisms regulating these responses and their sensitivity to dietary antioxidants could lead to alternative strategies for reducing atherogenesis.
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PMID:Modulation of vascular tone by low density lipoproteins: effects on L-arginine transport and nitric oxide synthesis. 912 49

The JCR:LA-cp rat exhibits the obesity/insulin resistance/hypertriglyceridemia syndrome in an extreme form. These normotensive rats spontaneously develop advanced atherosclerosis and ischemic myocardial lesions. The calcium channel antagonist, nisoldipine, was administered to obese rats of the JCR:LA-cp strain in drinking water at a dose of 1 mg/kg from age 6 weeks. Nisoldipine-treated rats showed no change in food consumption or body weight compared with control animals. Plasma glucose and insulin levels also were unchanged in the nisoldipine-treated rats. Insulin-mediated total glucose turnover, an index of insulin sensitivity as measured by euglycemic insulin clamp, was similarly not improved. Serum triglyceride levels in obese male rats were markedly reduced (57%; p < 0.001, at age 12 weeks), whereas obese female rats showed no significant change in triglyceride levels and an increase in esterified cholesterol in response to nisoldipine treatment. The impaired endothelium-dependent (nitric oxide-mediated) vascular relaxation of the male cp/cp rats was not improved by nisoldipine treatment. The severity of atherosclerotic raised lesions in the aortic arch of male cp/cp rats was significantly reduced (p < 0.01) by nisoldipine treatment, and this was accompanied by a major reduction in the incidence of ischemic myocardial lesions (85%; p < 0.01). Thus nisoldipine treatment ameliorates atherosclerotic damage and myocardial injury even in the presence of gross obesity, hyperinsulinemia, and significant hyperlipidemia. This effect appears to involve protection of the vascular wall from atherogenesis and probably antivasocontractile effects at the smooth muscle level as well.
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PMID:Cardioprotective and hypolipidemic effects of nisoldipine in the JCR:LA-cp rat. 921 99

The JCR:LA-corpulent rat is an animal model that, if homozygous for the cp gene (cp/cp), spontaneously exhibits obesity and a severe insulin resistance, with a resultant hyperinsulinemia and hypertriglyceridemia. The obese male rats show defective nitric oxide-mediated vascular relaxation, advanced atherosclerosis, and ischemic myocardial lesions. Benfluorex has both anorectic and metabolic effects that lower body weight and improve insulin sensitivity in obesity and type 2 diabetes. Male cp/cp rats that were treated with benfluorex (or pair-fed to the treated animals) from the time of weaning, at 3 weeks of age, showed a marked delay in the development of postprandial hyperinsulinemia. At 12 weeks of age benfluorex-treated cp/cp rats did not show the extreme insulin response to a test meal that was observed in untreated or pair-fed rats. Both benfluorex-treated and pair-fed rats had a significant increase in sensitivity to acetylcholine-induced (nitric oxide-mediated) vascular relaxation. Corpulent male rats were also treated from 6 to 39 weeks of age with benfluorex in the feed at a dose of approximately 36 mg/kg/day at 12 weeks of age and decreasing to 23 mg/kg/day at 39 weeks to determine the effects on cardiovascular outcomes. The rats showed a sustained decrease in food consumption and body weight, although they exhibited 50% of the excess body weight of the controls and were grossly obese. Both fasting insulin concentrations and the hyperplasia of the islets of Langerhans were decreased by approximately 50%. Serum triglyceride concentrations were decreased by 44%, and free cholesterol and cholesteryl esters by 30%. The severity of the atherosclerotic lesions on the aortic arch was decreased (P < 0.05). There was also a decrease in the size of early ischemic myocardial lesions that are characterized by cell lysis and chronic inflammatory cell infiltration. Mature, scarred myocardial lesions were essentially absent in the hearts of 39-week-old benfluorex-treated rats. Long-term major food restriction (18 g/day) decreased the body weights of obese rats to essentially those of lean control animals, with similar beneficial effects on the insulin resistance and hyperlipidemia. While myocardial lesion frequency was reduced in these much thinner animals, lesions remained and the apparent effect was not statistically significant. This evidence shows that the beneficial metabolic effects of benfluorex are associated with long-term effects on the vessel wall and delay the onset of insulin resistance and cardiovascular disease in an animal model.
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PMID:Antiatherogenic effects of long-term benfluorex treatment in male insulin resistant JCR:LA-cp rats. 924 64


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