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)

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13

The endothelium mediates a number of responses (relaxation or contraction) of arteries and veins from animals and humans. The endothelium-dependent relaxations are due to the release, by endothelial cells, of potent non-prostanoid vasodilator substances. Among these, the best characterized is endothelium-derived relaxing factor (EDRF), which is believed to be nitric oxide (NO). Nitric oxide is formed by the metabolism of L-arginine by the constitutive NO synthase of endothelial cells. In arterial smooth muscle, the relaxation evoked by EDRF is explained by the stimulation by NO of soluble guanylate cyclase that leads to the accumulation of cGMP. In a number of animal blood vessels and in human coronary arteries, the endothelial cells release a substance that causes hyperpolarization of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive (alpha 2-adrenoceptor activation, serotonin, aggregating platelets, leukotrienes) and insensitive (adenosine diphosphate (ADP), bradykinin) G proteins. In blood vessels from animals with regenerated and reperfused endothelium, and/or atherosclerosis, there is a selective loss of the pertussin toxin-sensitive mechanism of EDRF release, which favours the occurrence of vasospasm, thrombosis and cellular growth. The available information from isolated human blood vessels or obtained in situ concurs with the conclusions reached from studies with isolated animal tissues. In addition to relaxing factors, the endothelial cells can produce contracting factors (endothelium-derived contracting factors; EDCFs) which include superoxide anions, endoperoxides, thromboxane A2 and endothelin. From animal studies it can be concluded that the propensity to release EDCFs is maintained, or even augmented, in diseased blood vessels. The switch from a normally predominant release of EDRFs to that of EDCFs may play a crucial role in atherosclerosis.
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PMID:Endothelial dysfunction and atherosclerosis. 940 68

The endothelial cells of the vascular system are responsible for many biological activities that maintain vascular homeostasis. Responding to a variety of chemical and physical stimuli, the endothelium elaborates a host of vasoactive agents. One of these agents, endothelium-derived relaxing factor, now accepted as nitric oxide, influences both cellular constituents of the blood and vascular smooth muscle. A principal intracellular target for nitric oxide is guanylate cyclase, which, when activated, increases the intracellular concentration of cyclic guanosine monophosphate, which in turn activates protein kinase G. Acting by this pathway, nitric oxide induces relaxation of vascular smooth muscle and inhibits platelet activation and aggregation. Derangements in endothelial production of nitric oxide are implicated as both cause and consequence of vascular diseases, including hypertension, atherosclerosis, and coronary artery disease.
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PMID:Nitric oxide and regulation of vascular tone: pharmacological and physiological considerations. 950 27

Mammalian endothelium acts as a mediator in arterial and venous relaxation and contraction. Endothelium-dependent relaxation is due to endothelial release of powerful, non-prostanoid vasodilatory substances. The best known of these is the endothelial factor EDRF identified as nitrous oxide (NO). It is the end result of the metabolism of L-arginine by the NO synthetase of endothelial cells. In arterial smooth muscle, the relaxation induced by EDRF is explained by NO stimulation of soluble guanylate cyclase, leading to accumulation of GMPc (cyclic guanosine monophosphate). In some animal vessels and in human coronary arteries, endothelial cells release a substance which induces hyperpolarisation of the cell membrane (endothelial derived hyperpolarising factor, EDHF). Release of EDRF by the cell membrane may be mediated by G proteins sensitive to pertussis toxin (activation of the alpha 2 adrenoreceptor, serotonin, platelet aggregation, leukotrienes) or non-sensitive G proteins (adenosine-diphosphate (ADP), bradykinin). In animal blood vessels where the endothelium is regenerated and reperfused, and/or atherosclerotic, a selective loss of the mechanism of EDRF release is observed, sensitive to pertussis toxin, which favors vasospasm, thrombosis and cellular proliferation. The available data on isolated or in situ human blood vessels concord with studies on isolated animal tissues. In addition to the relaxation factors, endothelial cells can also secrete contracting factors (endothelium derived contracting factors: EDCF); these include superoxide anions, endoperoxides, thromboxane A2 and endothelin. Animal studies indicate that the tendency to release EDCF is maintained or even increased in damaged vessels. The change from normally dominant EDRF release to EDCF release could play an important role in atherosclerosis.
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PMID:[Endothelial dysfunction and atherosclerosis]. 951 9

Pentaerythritol tetranitrate is an organic nitrate ester that undergoes metabolization to pentaerythritol, pentaerythritol trinitrate, pentaerythritol dinitrate and pentaerythritol mononitrate. Recent data suggested that pentaerythritol tetranitrate is endowed with vasoprotective activities in experimental atherosclerosis. This study was undertaken to gain insight into the underlying mechanism. The basic mechanism of action of all pentaerythritol nitrates was evaluated by measuring liberation of nitric oxide (NO), stimulation of human soluble guanylate cyclase and vasorelaxation in rabbit aorta. A subsequent in vivo study in New Zealand White rabbits was performed to investigate the effects of a 4 months lasting nonintermittent oral treatment with 6 mg pentaerythritol tetranitrate kg(-1) day(-1) on vascular superoxide production, endothelium dependent vasorelaxation and vasorelaxation to pentaerythritol tetranitrate itself. The formation rates of NO from the pentaerythritol nitrates (100 microM, n = 5) in presence of 5 mM cystein were (in nM min(-1)): 62.1 +/- 3.2 (pentaerythritol tetranitrate), 21.3 +/- 0.9 (pentaerythritol trinitrate), 6.4 +/- 0.6 (pentaerythritol dinitrate) and 3.2 +/- 0.4 (pentaerythritol mononitrate). Similarly, the pD2 values (-log M) for half-maximal activation of soluble guanylate cyclase decreased from pentaerythritol tetranitrate (3.391 +/- 0.09, n = 4) to pentaerythritol mononitrate (2.655 +/- 0.04, n = 3) as did the pD2 values (in -log M) for half-maximal relaxation of rabbit aortic rings (n = 7) from pentaerythritol tetranitrate (8.3 +/- 0.17) to pentaerythritol mononitrate (5.0 +/- 0.11). Significant correlations were found between the NO formation rates and the pD2 values for enzyme stimulation (r = 0.98, P = 0.002) and vasorelaxation (r = 0.90, P = 0.049) suggesting that these effects of the pentaerythritol nitrates were mediated by NO. The results of the in vivo study showed that aging induces a significant increase of aortic superoxide production (median values, n = 10) from 2.45 nM mg(-1) min(-1) (age 7 months) to 3.39 nM mg(-1) min(-1) (age 11 months, P < 0.01) that was prevented by concurrent treatment with pentaerythritol tetranitrate (2.76 nM mg(-1) min(-1)). In vitro vasorelaxation to pentaerythritol tetranitrate was identical in all groups indicating absence of nitrate tolerance. Endothelium-dependent vasorelaxation was also identical in all groups. These data suggest that oral treatment with pentaerythritol tetranitrate reduces vascular oxidant stress by an NO-dependent pathway, which may contribute to the vasoprotective activity of pentaerythritol tetranitrate in experimental atherosclerosis.
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PMID:Effects of nonintermittent treatment of rabbits with pentaerythritol tetranitrate on vascular reactivity and superoxide production. 975 35

The endothelium plays an obligatory role in a number of relaxations of isolated arteries. These endothelium-dependent relaxations are due to the release by the endothelial cells of potent vasodilator substances [endothelium-derived relaxing factors (EDRF)]. The best characterized EDRF is nitric oxide (NO). Nitric oxide is formed by the metabolism of L-arginine by the constitutive NO synthase of endothelial cells. In arterial smooth muscle, the relaxations evoked by EDRF are explained best by the stimulation by NO of soluble guanylate cyclase that leads to the accumulation of cyclic GMP. The endothelial cells also release an unidentified substance that causes hyperpolarization of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive (alpha2-adrenergic activation, serotonin, thrombin, aggregating platelets) and insensitive (adenosine diphosphate, bradykinin) G-proteins. In blood vessels from animals with regenerated endothelium, and/or atherosclerosis, there is a selective loss of the pertussis-toxin sensitive mechanism of EDRF-release which favors the occurrence of vasospasm, thrombosis and cellular growth.
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PMID:Endothelial dysfunction and vascular disease. 980 82

Endothelial cell-derived nitric oxide (NO) has been suggested to inhibit smooth muscle cell proliferation, resulting in the reduction of intimal hyperplasia during atherogenesis. The present study investigates the role of NO from exogenous and endogenous sources on the proliferation of human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (CAEC). Three different NO-generating compounds [sodium nitroprusside (SNP), S-nitroso-glutathione (GSNO) and S-nitroso-acetylpenicillamine (SNAP)] were found to inhibit endothelial cell proliferation measured with three independent methods (cell counting, [3H]thymidine incorporation, DNA histograms) with significant inhibition occurring at concentrations > or = 100 microM. Growth-inhibiting effects were observed after long-term treatment (18-96 h) as well as after short stimulation with NO donors (10 min with a subsequent NO donor-free culture period of 18 h) and were comparable in culture medium (20% serum, growth factor supplementation) and serum-deficient medium (1% serum). The NO donor effects were mediated by the release of NO as they were prevented by NO scavenging. Superoxide dismutase (SOD) was found not to interfere with these effects suggesting that peroxynitrite formation was unlikely to be involved. 1H-[l,2,4]Oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ), a specific inhibitor of the soluble guanylate cyclase, was observed not to alter the antiproliferative effects of NO donors although it completely prevented NO-mediated increase of cyclic guanosine 3',5'-monophosphate (cGMP), suggesting that the NO-induced growth inhibition was not mediated by cGMP. Furthermore, inhibition of endogenous NO production by N-nitro-L-arginine methylester (L-NAME) did not affect endothelial cell growth regardless of using serum plus growth factor supplement, growth factor supplement alone, or thrombin to stimulate proliferation. We suggest that constitutively synthesized NO may not regulate endothelial cell proliferation whereas the growth-inhibiting NO effects may occur when an inducible NO synthase associated with a persistently high NO production is expressed in the atherosclerotic vessel wall.
Atherosclerosis 1999 May
PMID:Nitric oxide inhibits proliferation of human endothelial cells via a mechanism independent of cGMP. 1038 Dec 77

Endothelium injury plays an important role in atherosclerosis. Damage to the endothelium results in vascular smooth muscle cell proliferation. Natriuretic peptides present a potent antimitogenic action, mediating their biological effects via the binding of guanylate cyclase-linked atrial natriuretic peptide (ANP) receptor and the production of cyclic GMP. In a previous study, we demonstrated that L-citrulline, the by-product of nitric oxide synthesis, could relax rabbit aortic rings by stimulating the guanylate cyclase-linked ANP receptor. In this work, we investigated the effect of L-citrulline on vascular smooth muscle cell proliferation. L-Citrulline (10(-8) M) significantly decreased rat aortic (A10 cell line) vascular smooth muscle proliferation. The percentage of inhibition exerted by L-citrulline on days 3, 5, and 7 of the proliferation curve was 20.0 +/- 0.5%, 37.5 +/- 8.3%, and 28. 5 +/- 7.2%, respectively. In addition, L-citrulline also inhibited serum-induced DNA synthesis, measured as 5-bromo-2'-deoxyuridine incorporation. 5-Bromo-2'-deoxyuridine incorporation into nuclei of vehicle-treated cells was 40.5 +/- 2.4%, whereas in L-citrulline-treated cells the percentage decreased to 36.0 +/- 4.1%, 29.1 +/- 2.0% (P <.01, n = 4), 30.5 +/- 2.4% (P <.05, n = 4), and 23.1 +/- 0.5% (P <.001, n = 4) for 10(-10), 10(-9), 10(-8), and 10(-7) M, respectively. Zaprinast, a phosphodiesterase type V inhibitor, enhanced 5-bromo-2'-deoxyuridine incorporation in serum-stimulated cells. Moreover, L-citrulline inhibition of serum-stimulated DNA synthesis was abolished by HS-142-1 (10(-5) M), an ANP receptor antagonist. In another group of experiments, L-citrulline was shown to increase intracellular cyclic GMP levels from 2.1 +/- 0.2 pmol of cGMP/mg protein to 4.1 +/- 0.1 for L-citrulline (10(-8) M) (P <.001, n = 3). These findings suggest that L-citrulline decreases vascular smooth muscle cell proliferation in the A10 cell line by acting on DNA synthesis by mechanisms that involve the ANP receptor.
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PMID:L-Citrulline, the by-product of nitric oxide synthesis, decreases vascular smooth muscle cell proliferation. 1038 92

1. Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E degrees xLDLR degrees ) develop atherosclerosis. The aim of this study was to investigate changes in endothelium-dependent vasodilation and vasomotion in thoracic aortic rings of E degrees xLDLR degrees mice. 2. K+-induced contractions of the aorta from E degrees xLDLR degrees mice were stronger than those from control mice. The sensitivity of E degrees xLDLR degrees aorta to phenylephrine (PE) was decreased but the maximal contractions were increased. Acetylcholine-induced, but not sodium nitroprusside-induced, relaxations of E degrees xLDLR degrees aorta was decreased. 3. PE induced rhythmic activity in both E degrees xLDLR degrees and control aorta but the amplitude was larger in E degrees xLDLR degrees than in control mice. PE-induced rhythmic activity in both E degrees xLDLR degrees and control aorta was augmented by increase in extracellular Ca2+-concentration, but was abolished by removal of the endothelium, the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor LY-83583, high K+ solution and ryanodine. 4. 4-Aminopyridine, a voltage-dependent potassium (KV) channel blocker, increased basal tension and induced rhythmic activity in E degrees xLDLR degrees aorta but not in control aorta. 5. The Ca2+-activated potassium (KCa) channel blockers tetraethylammonium and charybdotoxin abolished PE-induced rhythmic activity in E degrees xLDLR degrees aorta. 6. In conclusion, opening of Kv channels in E degrees xLDLR degrees mice aorta is reduced and it is susceptible to be depolarized resulting in Ca2+ entry. The vascular smooth muscle is then dependent on compensatory mechanisms to limit Ca2+-entry. Such mechanisms may be decreased sensitivity to vasoconstrictors, or increased opening of KCa channels by NO via a cyclic GMP-dependent mechanism.
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PMID:Enhanced phenylephrine-induced rhythmic activity in the atherosclerotic mouse aorta via an increase in opening of KCa channels: relation to Kv channels and nitric oxide. 1051 43

Vascular smooth muscle cell (VSMC) migration participates in atherosclerosis and arterial restenosis after balloon angioplasty. Because these processes are enhanced in insulin-resistant states, our goal was to determine whether insulin affects VSMC migration and, if so, how. The migration of primary cultured VSMCs from canine femoral artery was measured with the use of a wound migration assay and related to cGMP levels. Insulin (1 nmol/L) did not affect migration or cGMP production in control cells. When inducible nitric oxide synthase (iNOS) was induced by 24-hour preincubation with lipopolysaccharide and interleuken-1beta, basal migration decreased, cGMP production increased, and insulin inhibited migration by >90% and stimulated cGMP production by 3-fold. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine blocked the affect of insulin on the migration of VSMCs with iNOS. 8-Bromo-cGMP inhibited VSMC migration in control cells, and 1-H-1[1,2,4]oxadiazolo-[4, 3a]quinoxolin-1-one, a selective inhibitor of guanylate cyclase, blocked the inhibition by insulin of migration of cells with iNOS. We conclude that insulin does not normally affect cGMP production or the migration of these VSMCs. However, after the induction of iNOS, insulin stimulates cGMP production and inhibits migration via an NOS-and a cGMP-dependent mechanism.
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PMID:Insulin inhibits migration of vascular smooth muscle cells with inducible nitric oxide synthase. 1064 15


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