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)

The effects of hypercholesterolaemia on the endothelium-dependent and -independent vascular reactivity of the superior mesenteric artery has been examined in anaesthetized rabbits in-vivo. Rabbits were fed with either standard or cholesterol-enriched diet for 24 weeks. Plasma lipids and changes in the endothelin content of plasma and vascular tissue were measured in the superior mesenteric artery and in the thoracic aorta. The functional severity of atherosclerosis was determined by examining vascular responses in the isolated thoracic aorta. The blood flow in the superior mesenteric artery was measured by transit-time flowmetry and drugs were injected through an intra-abdominal aortic catheter. Acetylcholine (5, 10, 20 microg kg(-1)) elicited dose-dependent, mesenteric vasodilation in normocholesterolaemic rabbits. In hypercholesterolaemic animals the response to acetylcholine was completely abolished and even became a vasoconstriction. Endothelin levels in plasma and in the vascular tissue were significantly elevated in hypercholesterolaemic animals compared with controls. Cromakalim at a dose of 3 microg kg(-1), elicited similar mesenteric vasodilation in hypercholesterolaemic and normocholesterolaemic animals. These experiments show that the endothelium-dependent responses of the superior mesenteric artery to acetylcholine are functionally impaired by prolonged hypercholesterolaemia, that this altered vascular reactivity is associated with the elevation of endothelin levels in the circulation and in vascular tissues, and that in hypercholesterolaemia the mesenteric vasodilator effect of the K+-channel opener cromakalim is entirely preserved, suggesting that severe hypercholesterolaemia does not depress the function of ATP-sensitive potassium channels in mesenteric vascular smooth muscle.
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PMID:Differential efficacy of vasodilators in hypercholesterolaemic rabbits. 981 Nov 65

Cholesterol feeding results in impaired endothelium dependent vasorelaxation. The role of nitric oxide in this process is unclear. The aim of this study was to evaluate the role of nitric oxide in cholesterol-induced vasomotor dysfunction by examining the effect of overexpression of eNOS in the hypercholesterolemic rabbit aorta on vascular reactivity. Vascular rings from the thoracic aorta of hypercholesterolemic rabbits were exposed ex vivo either to an adenoviral vector encoding endothelial nitric oxide synthase (AdeNOS) or Escherichia coli beta Galactosidase (AdbetaGal). Transgene expression was examined by histochemistry for beta galactosidase, immunohistochemistry for eNOS and cyclic GMP measurements and vasomotor studies were performed. Transgene expression was found to localize to the endothelium and adventitia. cGMP levels were significantly greater in AdeNOS compared to AdbetaGal transduced rings. Acetylcholine mediated relaxation was significantly impaired in cholesterol fed rabbits and was markedly improved by overexpression of eNOS. These results suggest that reduced NO bioavailability observed in cholesterol-induced vascular dysfunction can be partially overcome by eNOS gene transfer.
Atherosclerosis 1998 Dec
PMID:Ex vivo gene transfer of endothelial nitric oxide synthase to atherosclerotic rabbit aortic rings improves relaxations to acetylcholine. 986 75

1. Elevated plasma levels of homocysteine (HC) and copper have both been associated with the development of inflammatory vascular diseases, such as atherosclerosis. In this study, the effects of a combination of HC and copper on nitric oxide (NO)-mediated relaxation of isolated rat aortic rings were investigated. 2. Exposure to HC (10-100 microM; 30 min) had no effect on relaxation to acetylcholine (ACh; 0.01-10 microM, n=4). Pre-incubation of aortic rings with a higher concentration of HC for an extended period (1 mM; 180 min) significantly inhibited endothelium-dependent relaxation (n=4), but this inhibition was prevented by the presence of the copper chelator bathocuprione (10 microM, 180 min, n=6). 3. Exposure to HC (100 microM) and copper (10-100 microM; 30 min) caused a copper concentration-dependent inhibition of endothelium-dependent relaxation (n=4). This inhibitory effect was reduced in the presence of either superoxide dismutase (SOD; 100 u ml(-1); n=4) or catalase (100 u ml(-1); n=4), and further reduced by the presence of both enzymes (n=5). 4. HC and copper (100 microM; 30 min) significantly inhibited endothelium-independent relaxation to glyceryl trinitrate (0.01-10 microM; n=8). In contrast, HC (1 mM), alone or in combination with copper (100 microM), did not inhibit relaxation to the endothelium-independent relaxant sodium nitroprusside (0.01-10 microM; n=4). 5. These data indicate that the presence of copper greatly enhances the inhibitory actions of HC on NO-mediated relaxation of isolated aortic rings. The reduction of inhibition by catalase and SOD indicates a possible role for copper-catalyzed generation of superoxide and hydrogen peroxide leading to an increased inactivation or decreased production of endothelium-derived NO.
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PMID:Investigation of the inhibitory effects of homocysteine and copper on nitric oxide-mediated relaxation of rat isolated aorta. 1019 85

Human internal mammary arteries (IMA) are relatively protected from atherosclerosis. Estrogen plays a protective role in cardiovascular disease. It causes in vitro and in vivo vasodilatation, but the mechanisms are contradictory. To investigate the in vitro vasomotor effect of estrogen on IMA and the role of endothelium, we studied 30 IMA segments harvested from 10 men during coronary artery bypass grafting surgery. Patients with diabetes mellitus, hypercholesterolemia, hypertension, and smoking were excluded. Twenty IMA rings had intact endothelium ((+)Endo) and 10 rings were denuded of endothelium ((-)Endo). Vasomotor response of each ring was expressed as the percentage of maximal response to norepinephrine (NE). Acetylcholine (10(-8)-10(-5) M) given to (+)Endo and (-)Endo rings induced vasorelaxation of 72 +/- 30.4% and vasoconstriction of 48.5 +/- 20.1%, respectively. 17-Beta-estradiol (10(-8)-10(-5) M) given after maximal precontraction with NE induced marked relaxation in (+)Endo (80.9 +/- 39.2%), but no significant vasomotor effect in (-)Endo rings (P < 0.0001). Vasorelaxation to 17-beta-estradiol (10(-6) M) in (+)Endo rings was 64.5 +/- 18.4 and 8.6 +/- 8.4%, before and after 15-min treatment with nitric oxide synthase inhibitor, L-nitroarginine methyl ester, respectively (n = 14, P < 0.0001). Tamoxifen (10(-6) M) decreased 17-beta-estradiol (10(-7) M)-induced relaxation by 71%. In conclusion, 17-beta-estradiol induces endothelium-dependent NO-mediated vasodilation of human mammary arteries in vitro. This response is mediated through estrogen receptors.
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PMID:Estrogen induces nitric oxide-mediated vasodilation of human mammary arteries in vitro. 1034 89

Abnormalities in vascular endothelial function, which occur early in atherosclerosis, may play an etiologic role in the development of the disease or represent a marker for the extent of atherosclerosis. Endothelial dysfunction, usually characterized by demonstration of decreased endothelium-dependent vasorelaxation, may be a sensitive and specific method to detect vascular disease in its earliest stages. In this context, separation of abnormalities in receptor-mediated and flow-mediated endothelium-dependent vasodilatory responses may allow for the most accurate characterization of endothelial dysfunction. In 35 patients undergoing routine annual cardiac catheterization after heart transplantation, changes in epicardial lumen area and coronary blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously using an intravascular ultrasound (IVUS) catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed for distinction between receptor-mediated and flow-mediated endothelium-dependent vascular responses. Peak flow with the endothelium-independent resistance vessel dilator adenosine occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/-11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large-vessel vasodilator, caused an immediate increase in both flow and lumen area, but a second peak of dilation was observed, and maximal area occurred 46 sec after maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler flow measurements after infusion of vasoactive agents allows for distinction between and evaluation of the relative contribution of agonist-mediated and flow-mediated responses, which may offer important and unique insights into coronary endothelial function.
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PMID:Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow-mediated from receptor-mediated endothelial responses. 1034 24

Atherosclerosis is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) activity. Enhancement of NO activity may have an antiatherogenic action. This study was performed to determine whether angiotensin-converting enzyme (ACE) inhibition improves peripheral vascular NO activity in patients with atherosclerosis. In the femoral circulation of 43 patients with atherosclerosis and 10 controls, we studied endothelium-dependent vasodilation with bradykinin and acetylcholine, and endothelium-independent vasodilation with sodium nitroprusside before and after enalaprilat. In 22 patients, we repeated these infusions in the presence of L-N(G) monomethyl arginine (L-NMMA). Doppler-femoral artery flow velocity was measured. Before ACE inhibition, acetylcholine responses were depressed in patients with atherosclerosis compared with controls (p = 0.03). Enalaprilat did not alter femoral vascular tone at rest or vasodilation with sodium nitroprusside, but potentiated bradykinin-mediated vasodilation in patients (p<0.001) and controls (p = 0.02). Acetylcholine-mediated vasodilation was augmented only in patients (p<0.001), but not in control subjects. L-NMMA inhibited the potentiation by enalaprilat of acetylcholine and bradykinin responses. This study demonstrates that ACE inhibition selectively improves endothelial dysfunction in human atherosclerosis by enhancing NO activity. The antithrombotic and antiproliferative effects of NO may reduce adverse manifestations related to atherosclerosis during long-term therapy.
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PMID:Effect of enalaprilat on nitric oxide activity in coronary artery disease. 1040 42

In humans, increased plasma homocysteine (Hcy) has been shown to be correlated with occlusive arterial diseases and atherosclerosis. Studies of isolated conductance vessels of experimental animals suggest that Hcy may interfere with local vasoregulatory mechanisms, yet the effect of hyperhomocysteinemia (HHcy) on the function of microvessels, such as skeletal muscle arterioles, has not been investigated. Male Wistar rats were divided into 2 groups: control rats (C; plasma Hcy, 7.1+/-0.3 micromol/L; n=25), and rats made HHcy by 1 g/kg body weight daily intake of methionine in the drinking water for 4 weeks (plasma Hcy, 23.6+/-2.9 micromol/L; P<0.01 versus C; n=25). First-order arterioles ( approximately 130 micrometer in diameter) were isolated from gracilis muscle, cannulated, and pressurized (80 mm Hg, no-flow conditions). Changes in diameter were observed by videomicroscopy. Arteriolar constrictions to norepinephrine (NE; 3x10(-7) mol/L) were significantly (P<0.01) greater in HHcy compared with C rats (C, 37.7+/-4.9%; HHcy, 59.5+/-5. 2%). Removal of the endothelium (-E) augmented NE-induced constrictions only in arterioles from C rats, whereas it had no effect on responses of arterioles from HHcy rats (C-E, 55.9+/-6.9%; HHcy-E, 56.5+/-7.0%). Dilations to cumulative doses of acetylcholine (ACh; 10(-8) mol/L) were significantly reduced in arterioles from HHcy rats (C, 64.0+/-5.2%; HHcy, 24.1+/-6.8%). Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine (L-NNA; 10(-4) mol/L) significantly decreased ACh-induced dilations of C arterioles, whereas it did not affect HHcy arterioles. Similar alterations were found in arteriolar dilations to histamine, another known NO-dependent agonist. Endothelium-independent dilations to the NO donor sodium nitroprusside were not different in arterioles from C and HHcy rats, either in the presence or absence of L-NNA. Presence of superoxide dismutase and catalase (scavenger of reactive oxygen metabolites) did not affect HHcy-induced alterations in the ACh response. We conclude that hyperhomocysteinemia reduces rat skeletal muscle arteriolar dilations in response to ACh and histamine, and enhances constrictions to NE, alterations that are likely to be caused by the reduced mediation of these responses by NO. The reduced activity of NO in arterioles may contribute to the microvascular impairment described in HHcy.
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PMID:Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia. 1044 68

Physical training increases free radical production and consumes antioxidants. It has previously been shown that acute exercise markedly increases the susceptibility of LDL to oxidation but whether such changes are observed during physical training is unknown. We measured circulating antioxidants, lipids and lipoproteins, and blood flow responses to intrabrachial infusions of endothelium-dependent (acetylcholine, ACh, L-N-monomethyl-arginine, L-NMMA) and -independent (sodium nitroprusside, SNP) vasoactive agents, before and after 3 months of running in 9 fit male subjects. Maximal aerobic power increased from 53 +/- 1 to 58 +/- 2 ml/kg min (P < 0.02). All circulating antioxidants (uric acid, SH-groups, alpha-tocopherol, beta-carotene, retinol) except ascorbate decreased significantly during training. Endothelium-dependent vasodilatation in forearm vessels decreased by 32-35% (P < 0.05), as determined from blood flow responses to both a low (10.8 +/- 2.1 vs. 7.3 +/- 1.5 ml/dl min, 0 vs. 3 months) and a high (14.8 +/- 2.6 vs. 9.6 +/- 1.8) ACh dose. The % endothelium-dependent blood flow (% decrease in basal flow by L-NMMA), decreased through training from 37 +/- 3 to 22 +/- 7% (P < 0.05). Blood flow responses to SNP remained unchanged. The decrease in uric acid was significantly correlated with the change in the % decrease in blood flow by L-NMMA (r = 0.74, P < 0.05). The lag time for the susceptibility of plasma LDL to oxidation in vitro, LDL size and the concentration of LDL cholestetol remained unchanged. We conclude that relatively intense aerobic training decreases circulating antioxidant concentrations and impairs endothelial function in forearm vessels.
Atherosclerosis 1999 Aug
PMID:Intense physical training decreases circulating antioxidants and endothelium-dependent vasodilatation in vivo. 1048 62

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

Atherosclerosis develops and progresses spontaneously in apolipoprotein E-knockout (apoE-KO) mice. A direct consequence of atherosclerosis is an increase in vascular stiffness. Pulse wave velocity (PWV) has been used to assess the stiffness of large vessels and was found to be increased in patients with atherosclerosis. In the present study, aortic stiffness was assessed by PWV in 4- and 13-mo-old apoE-KO mice and age-matched controls (C57BL/6J). In 13-mo-old apoE-KO mice with extensive atherosclerotic lesions in the aorta (61 +/- 4%), PWV increased significantly (3.8 +/- 0.2 m/s) compared with controls (2.9 +/- 0.2 m/s). Endothelial nitric oxide (EDNO)-mediated vasorelaxation in response to ACh was markedly diminished in the aortic rings isolated from 13-mo-old apoE-KO mice compared with age-matched controls. In contrast, in 4-mo-old apoE-KO mice with only moderate atherosclerotic lesions in the aorta (23 +/- 5%), there were no significant changes in PWV and EDNO-mediated relaxation compared with controls. Blood pressure was not different among the four groups of mice. There were no significant differences in endothelium-independent vascular responses to sodium nitroprusside among different groups investigated. Histological evaluation revealed focal fragmentation of the elastic laminae in the aortic walls of 13-mo-old apoE-KO mice. These results demonstrate for the first time that aortic stiffness determined by PWV increases in 13-mo-old apoE-KO mice. Endothelial dysfunction and elastic destruction in vascular wall caused by atherosclerosis may have contributed.
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PMID:Increased aortic stiffness assessed by pulse wave velocity in apolipoprotein E-deficient mice. 1066 72


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