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

We have presented our experience with the use of inhaled nitric oxide in children with congenital heart disease and pulmonary hypertension, which indicates that nitric oxide is a selective pulmonary vasodilator that may improve patient management, particularly after surgical procedures requiring cardiopulmonary bypass. Indeed, we have now seen several patients in whom all resuscitative maneuvers for the treatment of pulmonary hypertensive crises were unsuccessful until inhaled nitric oxide was added to the therapeutic regimen. In addition, our studies using inhaled nitric oxide as an investigational probe point toward endothelial injury as a contributor to post-cardiopulmonary bypass pulmonary vasoconstriction. Inhaled nitric oxide relieves pulmonary vasoconstriction associated both with left atrial or pulmonary venous hypertension and following the relief of mitral valve or pulmonary venous obstruction. Absence of a response on the usually reactive pulmonary vascular bed of the neonate should prompt a careful search for anatomic, and possibly surgically remediable, pulmonary vascular obstruction. In the short term nitric oxide is less effective in the older patient with obliterative pulmonary vascular disease. It is possible that recent experimental work with long-term nitric oxide inhalation might be applicable to this group of patients. Nitric oxide may have a unique role in the management of the patient after lung transplantation, as it both reduces right ventricular afterload and improves intrapulmonary shunting. Is nitric oxide the ideal agent for testing pulmonary vascular reactivity? Nitric oxide is simple to deliver by either mask or ventilator and, as a trial of vasoreactivity over 15 min, remains free of side effects that might be encountered during long-term administration, such as methemoglobinemia or nitrogen dioxide toxicity. Indeed, no patient developed significant methemoglobinemia after a trial of nitric oxide and neither was a level of nitrogen dioxide above 1 ppm registered during the administration. Thus, nitric oxide gas fulfills many of the ideal characteristics, as suggested by Rubin,92 required of a drug to test the acute responsiveness of the pulmonary circulation. It has better pulmonary dilating effects than systemic, a short half-life, and minimal adverse effects and it can be both easily and quickly administered. Whether it is able to reliably predict the effect of long-term administration of orally active agents awaits confirmation. Certainly, inhaled nitric oxide is rapidly becoming the standard agent to test pulmonary vascular reactivity during diagnostic cardiac catheterization at our institution.
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PMID:Clinical applications of inhaled nitric oxide in children with pulmonary hypertension. 856 53

Oxidized low density lipoprotein (LDL) may be of central importance in triggering atherosclerosis. One potential pathway involves the production of nitric oxide (NO) by vascular wall endothelial cells and macrophages. NO reacts with superoxide to form peroxynitrite (ONOO-), a potent agent of LDL oxidation in vitro. ONOO- nitrates the aromatic ring of free tyrosine to produce 3-nitrotyrosine, a stable product. To explore the role of reactive nitrogen species such as ONOO- in the pathogenesis of vascular disease, we developed a highly sensitive and specific method involving gas chromatography and mass spectrometry to quantify 3-nitrotyrosine levels in proteins. In vitro studies demonstrated that 3-nitrotyrosine was a highly specific marker for LDL oxidized by ONOO-. LDL isolated from the plasma of healthy subjects had very low levels of 3-nitrotyrosine (9 +/- 7 micromol/mol of tyrosine). In striking contrast, LDL isolated from aortic atherosclerotic intima had 90-fold higher levels (840 +/- 140 micromol/mol of tyrosine). These observations strongly support the hypothesis that reactive nitrogen species such as ONOO- form in the human artery wall and provide direct evidence for a specific reaction pathway that promotes LDL oxidation in vivo. The detection of 3-nitrotyrosine in LDL isolated from vascular lesions raises the possibility that NO, by virtue of its ability to form reactive nitrogen intermediates, may promote atherogenesis, counteracting the well-established anti-atherogenic effects of NO.
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PMID:Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima. 899 8

Most patients with diabetes die from macrovascular complications. Little is known about the pathogenesis of diabetic vascular disease, but recent advances in molecular genetics and oxidation chemistry provide clues to the mystery of diabetes and atherosclerosis. Genetic variants of well-known proteins such as lipoprotein lipase and apolipoprotein E are common. These proteins are suitable candidates for mediating diabetic vascular risk because their variants can produce hypertriglyceridemia, a risk factor for atherosclerosis in diabetes. However, mutations could have different effects on lipoprotein flux across arteries depending on whether expression is dominant in the vascular space or the vascular wall. Lipoproteins retained in the arterial wall are subject to oxidative modification, which could be dependent on glycoxidation, the enzyme myeloperoxidase, or reactive nitrogen species derived from nitric oxide. Accelerated vascular disease in diabetes is likely the result of complex interactions between metabolic derangements such as hyperglycemia, mutations in genes controlling lipid metabolism, and antioxidant defense mechanisms.
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PMID:The mystery of diabetes and atherosclerosis: time for a new plot. 903 85

Oxidatively damaged LDL may play a critical role in the pathogenesis of atherosclerotic vascular disease. Several pathways promote LDL oxidation in vitro but the physiologically relevant mechanisms have proven difficult to identify. Detection of stable compounds that result from specific reaction pathways has provided the first insights into the mechanism of oxidative damage in the human artery wall. Mass spectrometric analysis of protein oxidation products isolated from atherosclerotic tissue implicate tyrosyl radical, reactive nitrogen intermediates and hypochlorous acid in LDL oxidation and lesion formation in vivo. Hypochlorous acid is only generated by the phagocytic enzyme myeloperoxidase, which can also generate tyrosyl radical and reactive nitrogen intermediates. Chiral phase high-pressure liquid chromatography analysis of lipid oxidation products suggests that cellular lipoxygenases may also play a role at certain stages. In contrast, LDL isolated from atherosclerotic tissue is not enriched in protein oxidation products characteristic of free metal ions, which are the most widely studied in vitro model of LDL oxidation. These observations provide the first direct chemical evidence for reaction pathways that promote LDL oxidation in human atherosclerosis.
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PMID:Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis. 933 50

Diabetic patients typically have not only hyperglycemia but also dyslipidemia. Study of the pathogenic components of the diabetic milieu and mechanisms of accelerated atherosclerosis is hindered by inadequate animal models. A potentially suitable animal model for human diabetic dyslipidemia is the pig, because it carries a large fraction of total cholesterol in low-density lipoprotein (LDL), similar to humans. In this study, male Sinclair miniature pigs were made diabetic by destroying the insulin-producing cells of the pancreas with alloxan and then were fed a high fat and high cholesterol diet for comparison with pigs fed a nondiabetic high fat and high cholesterol diet and control pigs. Diabetic pigs exhibited hyperglycemia, but plasma urea nitrogen, creatinine, and transaminase levels were in the normal range, indicating no adverse effects on kidney and liver function. The lipoprotein profile in diabetic pigs was similar to that found in human diabetic patients and was characterized by hypertriglyceridemia (2.8-fold increase versus control and high fat-fed pigs) and a profound shift of cholesterol distribution into the LDL fraction (81%) versus the distribution in high fat-fed (64%) and control (57%) pigs. LDL particles were lipid-enriched and more heterogeneous in diabetic pigs. Apolipoprotein B was distributed among a much broader spectrum of LDL particles, and apolipoprotein E was partially redistributed from high-density lipoprotein to apolipoprotein B-containing lipoproteins in diabetic pigs. There was little change in apolipoprotein A-I distribution. Diabetic pigs showed several early signs of excess vascular disease. In diabetic pigs, 75% of the coronary artery segments showed contractile oscillations in response to prostaglandin F(2alpha) compared with 25% in high fat-fed pigs and 10% in control pigs. Endothelium-dependent relaxation of brachial arteries was nearly abolished in diabetic pigs but unchanged in high fat-fed versus control pigs. Carotid artery Sudan IV staining for fatty streaks was significantly increased only in diabetic pigs. This porcine model should provide insights into the etiology of human diabetic dyslipidemia and facilitate study of peripheral vascular and coronary artery disease in diabetic patients.
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PMID:Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet. 1059 79

Ascorbic acid enhances NO bioactivity in patients with vascular disease through unclear mechanism(s). We investigated the role of intracellular ascorbic acid in endothelium-derived NO bioactivity. Incubation of porcine aortic endothelial cells (PAECs) with ascorbic acid produced time- and dose-dependent intracellular ascorbic acid accumulation that enhanced NO bioactivity by 70% measured as A23187-induced cGMP accumulation. This effect was due to enhanced NO production because ascorbate stimulated both PAEC nitrogen oxide (NO(2)(-) + NO(3)(-)) production and l-arginine to l-citrulline conversion by 59 and 72%, respectively, without altering the cGMP response to authentic NO. Ascorbic acid also stimulated the catalytic activity of eNOS derived from either PAEC membrane fractions or baculovirus-infected Sf9 cells. Ascorbic acid enhanced bovine eNOS V(max) by approximately 50% without altering the K(m) for l-arginine. The effect of ascorbate was tetrahydrobiopterin (BH(4))-dependent, because ascorbate was ineffective with BH(4) concentrations >10 microm or in PAECs treated with sepiapterin to increase intracellular BH(4). The effect of ascorbic acid was also specific because A23187-stimulated cGMP accumulation in PAECs was insensitive to intracellular glutathione manipulation and only ascorbic acid, not glutathione, increased the intracellular concentration of BH(4). These data suggest that ascorbic acid enhances NO bioactivity in a BH(4)-dependent manner by increasing intracellular BH(4) content.
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PMID:Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. 1074 76

Nitric oxide ((.)NO) signaling pathways and lipid oxidation reactions are of central importance in both the maintenance of vascular homeostasis and the progression of vascular disease. Because both of these pathways involve free radical species that can also react together at extremely fast rates, convergent interactions between these pathways are expected. Biochemical and cell biology studies have defined multiple interactions of (.)NO with oxidizing lipids that could lead to either vascular protection or potentiation of inflammatory vascular injury. For example, low levels of (.)NO generated by endothelial nitric oxide synthase can terminate propagating lipid radicals and inhibit lipoxygenases, reactions that would be protective. Alternatively, if generated at elevated levels, for example, after inducible nitric oxide synthase expression in inflammation, (.)NO can be converted to prooxidant species, such as peroxynitrite (ONOO(-)) and nitrogen dioxide ((.)NO(2)), that can potentiate inflammatory injury to vascular cells. Finally, both enzymatic and nonenzymatic lipid oxidation reactions can influence (.)NO bioactivity by directly scavenging (.)NO or altering the induction and catalytic activity of nitric oxide synthase enzymes. In this review, we summarize the biochemical interactions between (.)NO and lipid oxidation reactions and discuss the recognized and potential roles of these reactions in the vasculature.
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PMID:Interactions between nitric oxide and lipid oxidation pathways: implications for vascular disease. 1113 68

Recent evidence argues strongly that the marked increase in risk for atherosclerotic heart disease seen in diabetics cannot be explained by a generalized increase in oxidative stress. Here, we used streptozotocin to induce hyperglycemia in cynomolgus monkeys for 6 months and tested whether high glucose levels promote localized oxidative damage to artery wall proteins. We focused on three potential agents of oxidative damage: hydroxyl radical, tyrosyl radical, and reactive nitrogen species. To determine which pathways operate in vivo, we quantified four stable end products of these reactants -- ortho-tyrosine, meta-tyrosine, o,o'-dityrosine, and 3-nitrotyrosine -- in aortic proteins. Levels of ortho-tyrosine, meta-tyrosine, and o,o'-dityrosine, but not of 3-nitrotyrosine, were significantly higher in aortic tissue of hyperglycemic animals. Of the oxidative agents we tested, only hydroxyl radical mimicked this pattern of oxidized amino acids. Moreover, tissue levels of ortho-tyrosine and meta-tyrosine correlated strongly with serum levels of glycated hemoglobin, a measure of glycemic control. We conclude that short-term hyperglycemia in primates promotes oxidation of artery wall proteins by a species that resembles hydroxyl radical. Our observations suggest that glycoxidation reactions in the arterial microenvironment contribute to early diabetic vascular disease, raising the possibility that antioxidant therapies might interrupt this process.
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PMID:A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. 1151 39

Nitric oxide (NO) is a major free radical modulator of smooth muscle tone, which under basal conditions acts to preserve vascular homeostasis through its anti-inflammatory properties. The biochemistry of NO, in particular, its rapid conversion in vivo into secondary reactive nitrogen species (RNS), its chemical nature as a free radical and its high diffusibility and hydrophobicity dictate that this species will interact with numerous biomolecules and enzymes. In this review, we consider the interactions of a number of enzymes found in the vasculature with NO and NO-derived RNS. All these enzymes are either homeostatic or promote the development of atherosclerosis and hypertension. Therefore their interactions with NO and NO-derived RNS will be of central importance in the initiation and progression of vascular disease. In some examples, (e.g. lipoxygenase, LOX), such interactions provide catalytic 'sinks' for NO, but for others, in particular peroxidases and prostaglandin H synthase (PGHS), reactions with NO may be detrimental. Nitric oxide and NO-derived RNS directly modulate the activity of vascular peroxidases and LOXs through a combination of effects, including transcriptional regulation, altering substrate availability, and direct reaction with enzyme turnover intermediates. Therefore, these interactions will have two major consequences: (i) depletion of NO levels available to cause vasorelaxation and prevent leukocyte/platelet adhesion and (ii) modulation of activity of the target enzymes, thereby altering the generation of bioactive signaling molecules involved in maintenance of vascular homeostasis, including prostaglandins and leukotrienes.
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PMID:Interactions of nitric oxide-derived reactive nitrogen species with peroxidases and lipoxygenases. 1176 4

Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.
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PMID:Vasoprotection by nitric oxide: mechanisms and therapeutic potential. 1212 64


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