UMLS:C0020473 - FACTA Search

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

Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver in the fed state. HISS action accounts for 50-60% of the glucose disposal produced by a wide range of insulin doses (5-100 mU/kg). Although the chemical nature of HISS is unknown, precluding pharmacokinetic studies, the pharmacodynamics of HISS has advanced because of the use of the rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used following a bolus of insulin. HISS action can be blocked by hepatic denervation and restored by intraportal but not intravenous infusion of acetylcholine or a nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24-hr fasting in rats. Cats and dogs appear to require a longer period of fasting to prevent HISS action. Lack of HISS action is suggested to be the cause of post-meal hyperglycemia and hyperlipidemia in type 2 diabetes and other disease states with similar metabolic dysfunction. The RIST can be carried out up to six times in the same animal, is not affected by pentobarbital anesthesia, and can readily differentiate HISS-dependent and HISS-independent insulin action.
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PMID:Practice and principles of pharmacodynamic determination of HISS-dependent and HISS-independent insulin action: methods to quantitate mechanisms of insulin resistance. 1242 50

We tested the hypothesis that exercise training (Ex) attenuates the effects of hyperlipidemia on endothelial function by enhancing NO-mediated vasorelaxation in porcine brachial (Br) arteries. Adult female pigs were fed a normal-fat (NF) or high-fat (HF) diet for 20 wk. Four weeks after initiation of the diet, pigs underwent Ex or remained sedentary (Sed) for 16 wk. Relaxation to ACh was impaired by HF (P = 0.03). The combination of HF and Sed impaired ACh-induced relaxation more than HF or Sed alone (P = 0.0002). Relaxation to high doses of bradykinin (BK) was impaired by HF (P = 0.0002). Ex significantly improved ACh-induced relaxation (P = 0.01) and tended to improve relaxation to BK (P = 0.38). To determine the mechanism(s) by which HF and Ex affected relaxation to ACh and BK, relaxation was assessed in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME; to inhibit NO synthase), indomethacin (Indo; to inhibit cyclooxygenase), or l-NAME + Indo. In the presence of l-NAME, Indo, or l-NAME + Indo, ACh-induced relaxation was no longer different between HF and NF arteries; however, relaxation remained greater in Ex than in Sed arteries. In the presence of l-NAME or Indo, BK-induced relaxation was no longer altered by HF but was enhanced by Ex. In the presence of l-NAME + Indo, BK-induced relaxation was enhanced by HF and Ex. These data indicate that hyperlipidemia impairs ACh- and BK-induced relaxation by impairing NO- and PGI(2)-mediated relaxation. Ex attenuates the effects of HF by enhancing a vasodilator mechanism independent of NO and PGI(2).
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PMID:Exercise training preserves endothelium-dependent relaxation in brachial arteries from hyperlipidemic pigs. 1267 52

The endothelial cell layer displays the features of a distributed organ and has a variety of biological functions such as keeping the balance between coagulation and fibrinolysis, expression of adhesion molecules for cells in the immune system, metabolism of noradrenaline and 5-hydroxytryptamine, and conversion of angiotensin I and bradykinin. The endothelium also regulates the underlying smooth muscle layer and vascular tone by release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) as well as vasoconstricting factors such as endothelin, superoxide (O(2)(-)), and thromboxane. We have reviewed the nature, mechanisms of action, and role of these factors in regulation of vascular tone, with special emphasis on NO. By a process catalyzed by NO synthase, NO and citrulline is formed from the substrates molecular O(2) and L-arginine. The main receptor for NO is guanylyl cyclase leading to formation of smooth muscle cyclic guanosinmonophosphate and relaxation. EDHF is an endothelium-derived factor causing vasorelaxation of the underlying smooth muscle layer by hyperpolarization. The nature of EDHF is still unknown, but several candidates for EDHF have been proposed such as potassium ions, hydrogen peroxide, and epoxyeicosatrienoic acids. Prostaglandins such as prostacyclin and prostaglandin E2 binds to specific receptors followed by increases in cyclic adenosinmonophosphate and vasorelaxation, while contractile prostaglandins constrict vessels by activation of thromboxane and endoperoxidase receptors. Superoxide anions induce contraction of vascular smooth muscles cells by scavenging NO. Endothelin is a potent endothelium-derived contractile factor. The synthesis of endothelin-1 is induced by hypoxia, thrombin, interleukin-1, transforming growth factor-beta1, vasopressin, and catecholamines. Cardiovascular risk factors like age, hypertension, and hyperlipidemia are associated with impaired endothelium-dependent vasodilation either as a consequence of increased inactivation of endothelium-derived vasodilators or increased formation of endothelium-derived contracting factors. This imbalance of endothelium-derived factors plays a role for development of atheroslerosis and ischemic vascular diseases.
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PMID:[Role of nitric oxide and other endothelium-derived factors]. 1273 1

The endothelial generation of reactive oxygen species (ROS) is important both physiologically and in the pathogenesis of many cardiovascular disorders. ROS generated by endothelial cells include superoxide (O2-*), hydrogen peroxide (H2O2), peroxynitrite (ONOO-*), nitric oxide (NO), and hydroxyl (*OH) radicals. The O2-* radical, the focus of the current review, may have several effects either directly or through the generation of other radicals, e.g., H2O2 and ONOO-*. These effects include 1) rapid inactivation of the potent signaling molecule and endothelium-derived relaxing factor NO, leading to endothelial dysfunction; 2) the mediation of signal transduction leading to altered gene transcription and protein and enzyme activities ("redox signaling"); and 3) oxidative damage. Multiple enzymes can generate O2-*, notably xanthine oxidase, uncoupled NO synthase, and mitochondria. Recent studies indicate that a major source of endothelial O2-* involved in redox signaling is a multicomponent phagocyte-type NADPH oxidase that is subject to specific regulation by stimuli such as oscillatory shear stress, hypoxia, angiotensin II, growth factors, cytokines, and hyperlipidemia. Depending on the level of oxidants generated and the relative balance between pro- and antioxidant pathways, ROS may be involved in cell growth, hypertrophy, apoptosis, endothelial activation, and adhesivity, for example, in diabetes, hypertension, atherosclerosis, heart failure, and ischemia-reperfusion. This article reviews our current knowledge regarding the sources of endothelial ROS generation, their regulation, their involvement in redox signaling, and the relevance of enhanced ROS generation and redox signaling to the pathophysiology of cardiovascular disorders where endothelial activation and dysfunction are implicated.
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PMID:Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. 1547 99

Hyperhomocyst(e)inemia is associated with an increased risk for atherosclerotic disease and venous thromboembolism. The impact of elevated plasma homocysteine levels seems to be clinically relevant, since the total cardiovascular risk of hyperhomocyst(e)inemia is comparable to the risk associated with hyperlipidemia or smoking. There is substantial evidence for impairment of endothelial function in human and animal models of atherosclerosis, occurring even before development of overt plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of atherosclerotic lesion development and predicts future vascular events. NO is the most potent endogenous vasodilator known. It is released by the endothelium, and reduced NO bioavailability is responsible for impaired endothelium-dependent vasorelaxation in hyperhomocyst(e)inemia and other metabolic disorders associated with vascular disease. Substances leading to impaired endothelial function as a consequence of reduced NO generation are endogenous NO synthase inhibitors such as ADMA. Indeed there is accumulating evidence from animal and human studies that ADMA, endothelial function and homocyst(e)ine might be closely interrelated. Specifically elevations of ADMA associated with impaired endothelium-dependent relaxation were found in chronic hyperhomocyst(e)inemia, as well as after acute elevation of plasma homocyst(e)ine following oral methionine intake. The postulated mechanisms for ADMA accumulation are increased methylation of arginine residues within proteins, as well as reduced metabolism of ADMA by the enzyme DDAH, but they still need to be confirmed to be operative in vivo. Hyperhomocyst(e)inemia, as well as subsequent endothelial dysfunction can be successfully treated by application of folate and B vitamins. Since ADMA seems to play a central role in homocyst(e)ine-induced endothelial dysfunction, another way of preventing vascular disease in patients with elevated homocyst(e)ine concentrations could be supplementation with L-arginine to reverse the detrimental effects of ADMA.
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PMID:Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction. 1572 Feb 2

Cardiovascular diseases have been increasing in association with life style changes and increasing trends of hyperlipidemia and diabetes in Japan. On the other hand, cerebrovascular diseases, which largely comprise of small-vessel diseases such as hypertensive brain hemorrhage and lacunar brain infarction, have been considered to be dependent on aging and hypertension. Recently, however, atherothrombotic brain infarction (ATBI) has been rapidly increasing in Japan, and this increase occurs precedently in urban area such as Kanto and Kansai Districts. The present paper, therefore, summarizes the classification of diverse subtypes of cerebrovascular diseases and their underlying vascular lesions. Furthermore, it also focuses the risk factors for cerebrovascular diseases and the vascular lesions, and aims to clarify the factors and background which may have contributed to the increase of ATBI in Japan. Arteriosclerotic changes of small arteries in the brain parenchyma are considered to play an important role in development of cerebral white matter lesions (leucoaraiosis) and lacunar infarction. Oxidative stresses such as smoking, lipid peroxidation, and others are suggested to give impacts on the lesion formation through the effects on various functions of arterial trees and nitric oxide (NO) production from the arterial endothelial cells. Therefore, This paper presents the data indicating the significant correlation of these oxidative stress markers and polymorphism of endothelial NO synthase gene which may be relating to the pathogenesis of cerebral white matter lesions, and discusses about the usefulness of these new risk factors for cerebrovascular diseases.
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PMID:[Risk factors for cerebrovascular diseases]. 1596 6

Metabolic syndrome is a cluster of metabolic abnormalities, including hypertension, hyperlipidemia, hyperinsulinemia, glucose intolerance and obesity. In such lifestyle-related diseases, impairment of nitric oxide (NO) production or bioactivity has been reported to lead to the development of atherogenic vascular diseases. Therefore, in the present study we investigated changes in the NO/cyclic guanosine monophosphate (cGMP) system in aortas of SHR/NDmcr-cp (cp/cp) rats (SHR-cp), a model of the metabolic syndrome. In aortas of SHR-cp, endothelium-dependent relaxations induced by acetylcholine and endothelium-independent relaxations induced by sodium nitroprusside were significantly impaired in comparison with Wistar-Kyoto rats. Furthermore, protein levels of soluble guanylyl cyclase and cGMP levels induced by sodium nitroprusside were significantly decreased. In contrast, protein levels of endothelium NO synthase and cGMP levels induced by acetylcholine were significantly increased, and plasma NO2 plus NO3 levels were also increased. The levels of lipid peroxide in plasma and the contents of 3-nitrotyrosine, a biomarker of peroxynitrite, in aortas were markedly increased. These findings indicate that in the aortas of SHR-cp, NO production from the endothelium is augmented, although the NO-induced relaxation response is impaired. Enhanced NO production may be a compensatory response to a variety of factors, including increases in oxidative stress.
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PMID:Disturbances in nitric oxide/cyclic guanosine monophosphate system in SHR/NDmcr-cp rats, a model of metabolic syndrome. 1618 78

Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.
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PMID:Metabolic effects of melatonin on oxidative stress and diabetes mellitus. 1621 26

Diabetic vascular disease is accompanied by decreased formation of the vasodilators, nitric oxide (NO), and prostacyclin and increased formation of vasoconstrictor eicosanoids, which exacerbate the progression of vascular disease. Similarities between the dysfunction introduced by short-term effects of elevated glucose and long-term effects of diabetes suggest that the alteration in endothelial factors in diabetes primarily results from exposure of endothelial cells to elevated glucose, although undoubtedly hyperlipidemia contributes as well. A key alteration in endothelial cell phenotype is increased formation of reactive oxygen species. This is in part due to uncoupling of endothelial NO synthase such that it generates superoxide anion in addition to NO. This is responsible for NO synthase to produce peroxynitrite, a damaging molecule. Peroxynitrite inactivates prostacyclin synthase leading to the accumulation of inflammatory and prothrombotic eicosanoids. This not only helps to explain the impairment of endothelial vasodilator mechanisms, but also increased progression of vascular disease. Many of these cellular abnormalities can be prevented by adequate scavenging of oxygen-derived free radicals or by blocking the actions of the eicosanoids at thromboxane (TP) receptors. Exposure to elevated glucose also gives rise to oxidants in smooth muscle, and recent studies indicate that oxidation of cysteine thiols under these conditions may prevent physiological NO signaling. As a result, the responsiveness to NO is impaired and accounts in part for abnormal endothelium-dependent vasodilation.
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PMID:Role of nitric oxide in diabetic complications. 1628 Jun 43

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

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