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)

Endothelial dysfunction based on lack of nitric oxide (NO) may contribute to several settings of cardiovascular disorder. Chronic oral supplementation with the NO precursor L-arginine counteracts the development of aortic atherosclerosis in cholesterol-fed rabbits, and i.v. infusion of L-arginine may acutely improve endothelium-dependent coronary epicardial vasodilation in patients with hypercholesterolemia (HC). To clarify whether excess NO precursor may also improve general cardiovascular performance in HC, we measured working capacity indices of myocardial ischemia, and basal and post-occlusive forearm and skin blood flow in nine patients with elevated plasma cholesterol (9.1 +/- 0.2 mumol/l) following random double-blinded administration of L-arginine (16 g i.v.) or placebo. Infusion of L-arginine raised the plasma concentration of this amino acid from 85 +/- 12 to 2460 +/- 230 mumol/l but did not change the plasma level of the major NO metabolite nitrate. Maximal working capacity, indices of myocardial ischemia, and basal and post-occlusive blood flow in the skin or forearm did not differ between the treatments. The lack of positive effect of L-arginine compared to placebo indicates that excess NO precursor did not improve microvascular endothelial function in the patients, or alternatively, that the indices measured in the present study were not dependent on endothelial microvessel function. Thus, in patients with HC, deficiency of precursor for NO formation does not seem to impair either maximal exercise capacity myocardial perfusion during maximal exercise, or maximal vasodilator capacity in skeletal muscle or skin.
Atherosclerosis 1995 Dec
PMID:Acute supplementation with the nitric oxide precursor L-arginine does not improve cardiovascular performance in patients with hypercholesterolemia. 877 Mar 16

L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce intimal plaque area in cholesterol (Chol)-fed rabbits. We have studied endogenous NO production in such animals in vitro (endothelium-dependent relaxations) and in vivo (assessed by urinary NO3- excretion) before and during chronic oral administration of L-arginine and inhibitor of NO synthesis, L-NAME. Vascular superoxide anion (O2-) production of aortic rings was measured under basal conditions and following exposure to phorbol-myristate-acetate (PMA). Cholesterol feeding reduced endothelium-dependent relaxations and decreased urinary NO3- excretion. These effects were potentiated by administration of L-NAME. L-arginine partly restored endothelium-dependent relaxations and increased NO3- excretion. PMA-stimulated O2- production was increased in aortic rings from rabbits given cholesterol ( +159 +/- 28%; mean +/- S.E.M.) or cholesterol + L-NAME ( +149 +/- 37%) as compared with controls ( -22 +/- 7%). In rabbits given cholesterol + L-arginine, O2- production was decreased to control levels ( +14 +/- 17%; P < 0.05). We conclude that the systemic synthesis of NO is impaired in cholesterol-fed rabbits, as indicated by the decreased urinary excretion of NO3-. Enhanced O2- production may further contribute to the decreased biological activity of NO in hypercholesterolaemia. L-arginine restores endothelial function in hypercholesterolaemia by enhancing NO production and by protecting NO from early breakdown by O2-.
Atherosclerosis 1995 Oct
PMID:Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. 880 73

In this study, plasma NO2- and NO3- (NOx-) levels were studied after lowering cholesterol with simvastatin in 26 outpatients with hypercholesterolemia (male, 9; female, 17; mean age, 59 +/- 12 years; cholesterol level > 220 mg/dl). Simvastatin (5 mg) was orally administered once daily, and blood samples were collected before, and after 4 and 12 weeks of treatment. Total, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol were lowered (total, 254 +/- 44 mg/dl to 209 +/- 34 mg/dl; VLDL, 48 mg/dl [5-126 mg/dl] to 34 mg/dl [10-67 mg/dl]; LDL, 171 +/- 41 mg/dl to 133 +/- 37 mg/dl), but high-density lipoprotein (HDL) cholesterol was elevated (33 +/- 9.5 mg/dl to 39 +/- 11 mg/dl) at 12 weeks after starting simvastatin. Although the effects of simvastatin on the lipid levels nearly reached their maximum levels at 4 weeks, NOx- was elevated in a linear fashion with simvastatin (before; 8 +/- 17 mumol/l, at 12 weeks; 57 +/- 32 mumol/l). The % changes in the NOx- correlated directly with those in HDL-cholesterol at 12 weeks (P < 0.002) but not with other lipoprotein cholesterol fractions. These results suggest that simvastatin lowers cholesterol levels and elevates HDL while increasing the plasma NOx- levels.
Atherosclerosis 1996 Nov 15
PMID:Simvastatin increases plasma NO2- and NO3- levels in patients with hypercholesterolemia. 900 3

Increased incidence of cardiovascular disease in postmenopausal women (PMW) is accompanied by ovarian dysfunction; hormone replacement therapy (HRT) can have cardioprotective effects. Because hypertension and atherosclerosis are associated with impaired release of endothelium-derived nitric oxide (NO) and increased levels of low-density lipoproteins (LDL), we investigated whether HRT augments NO release, and whether these increases are accompanied by a decrease in LDL levels in PMW. We determined serum nitrite/ nitrate (NO2-/NO3-) and LDL levels at baseline (before initiation of HRT) and during the 6th and 12th months of the study. The PMW (n = 26) received continuous oral administration of estradiol valerate (Progynova, 2 mg daily) for 21 days supplemented with either oral cyproterone acetate (CPA; 1 mg; n = 11) or medroxyprogesterone acetate (MPA; 5 mg; n = 15) on days 12-21 of each treatment cycle. Blood samples in the PMW receiving HRT were collected at times while the subjects were taking estradiol valerate alone and estradiol valerate plus CPA or MPA. Compared with the samples collected at baseline, serum NO2-/NO3- levels increased significantly from 20.1 +/- 1.58 mumol/L at baseline to 30 +/- 3.7 mumol/L (P < 0.01) in samples collected after 12 months of HRT while the PMW were not taking progestins (CPA or MPA), and to 25.4 +/- 2 mumol/L (P < 0.05) when all the samples, regardless of the treatment with CPA or MPA, were included in the analysis. Moreover, > 30% increase in serum NO2-/NO3- levels were observed only in 13 (responders) out of 26 PMW substituted with estradiol valerate, suggesting that estradiol may improve endogenous NO synthesis in a differential fashion. Compared with baseline, no significant increases in serum NO2-/NO3- were observed in samples collected while the estradiol-treated responders were taking either CPA or MPA. In contrast to NO2-/NO3- serum LDL levels were significantly reduced in samples collected after 12 months of HRT (P < 0.05 vs. baseline). Furthermore, levels of NO2-/NO3 showed a significant negative correlation with the levels of LDL (r2 = 0.17; P < 0.05) in the responders but not in nonresponders. These results indicate that oral administration of estradiol valerate in PMW for HRT increases circulating NO levels, an effect that may contribute to the cardioprotective effects of HRT in PMW. In addition, our data suggests but does not prove that concomitant administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release. Finally, our data provides evidence for the existence of responders and nonresponders to postmenopausal estrogen treatment with respect to improvement of endogenous NO levels, suggesting that a significant number, but not all, of the hormonally substituted PMW profit fully from the beneficial properties of a HRT.
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PMID:Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate. 902 24

We investigated the effect of lead nitrate (0.5-5.0 microM) on the repair of wounded monolayer of cultured bovine aortic endothelial cells. It was morphologically found that lead decreases the appearance of the cells in the wounded area in a concentration-dependent manner without degenerative changes after a 48-h incubation. Although mercury weakly inhibited the repair with nonspecific cell damage, the other cations including bismuth, cobalt, manganese and nickel failed to affect the repair. The inhibition of endothelial repair caused by lead was observed even when stimulated by exogenous either basic or fibroblast growth factor. These results indicated that inhibition of the repair process of damaged endothelial cell layer is a component of lead-induced vascular lesions such as atherosclerosis.
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PMID:Inhibitory effect of lead on the repair of wounded monolayers of cultured vascular endothelial cells. 905 98

Aortic ring studies have demonstrated a decrease in endothelium-dependent relaxation or an enhanced response to vasoconstrictors in rabbits fed a high-cholesterol diet. Whether such abnormalities exist in the renal circulation is unclear. The purpose of this study was to determine functional renal responses to acetylcholine (ACh) or angiotensin II (ANG II) infusion in anesthetized rabbits after 8-10 wk of either a control diet (ACh, n = 6; ANG II, n = 6) or a 1% cholesterol diet (ACh, n = 7; ANG II, n = 7). Mean arterial pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) were measured. Renal vascular resistance (RVR) was calculated as MAP/RBF. For ANG II experiments, captopril (15 microg x kg(-1) x min(-1)) was infused to suppress endogenous ANG II production. After two control clearance periods, either ACh (1 microg x kg(-1) x min(-1)) or ANG II (0.5 ng x kg(-1) x min(-1)) was infused into the renal artery; RBF was allowed to stabilize before experimental clearances. RBF increased with ACh (control: 25 +/- 2 to 39 +/- 2 ml/min; cholesterol: 26 +/- 2 to 40 +/- 3 ml/min) and decreased with ANG II infusions (control: 40 +/- 4 to 25 +/- 3 ml/min; cholesterol: 36 +/- 3 to 24 +/- 2 ml/min). Nitrate/nitrite excretion also increased with ACh infusion (control: 2.3 +/- 1.0 to 5.2 +/- 1.8 nmol x kg(-1) x min(-1); cholesterol: 2.3 +/- 0.3 to 6.0 +/- 1.3 nmol x kg(-1) x min(-1)). However, there were no significant differences between control and cholesterol groups in either response. GFR was unaltered during ACh and ANG II infusions. MAP, RVR, and urinary sodium and potassium excretion did not differ between groups in response to either drug. These results suggest that, despite significant hypercholesterolemia and large-vessel atherosclerosis, both nitric oxideinduced vasodilation and endothelium-dependent modulation of ANG II vasoconstriction in the renal circulation are unaffected by cholesterol feeding.
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PMID:Cholesterol feeding does not alter renal hemodynamic response to acetylcholine and angiotensin II in rabbits. 908 58

This study was to examine the effects of estrogen replacement on atherosclerosis formation in ovariectomized cholesterol-fed rabbits. We also examined serum levels of nitrite/nitrate, stable metabolites of nitric oxide, to investigate the involvement of nitric oxide. Female New Zealand White rabbits were ovariectomized and divided into 3 groups; 1) fed a normal diet (ND group, n=5), 2) fed a 1% cholesterol diet (CD group, n=6), or 3) fed a 1% cholesterol diet and received estrogen replacement (CD+E group, n=7). After 3 months, the rabbits were sacrificed to examine atherosclerosis formation. Atherosclerosis was not observed in ND. The oil red 0 positive area in the aorta was significantly greater in CD than in CD+E (CD, 17.3+/-2.2; CD+E, 9.3+/-0.8%, p<0.05). Stenosis of the coronary artery was also significantly greater in CD than in CD+E (CD, 30.6+/-9.7; CD+E, 6.7+/-2.9%, p <0.05). There was no significant difference in serum lipids between CD and CD+E. Serum nitrite/nitrate levels were significantly lower in CD than in ND (ND, 37.6+/-3.6; CD, 25.3+/-3.1 microM, p<0.05). There was a non-significant trend towards higher nitrite/nitrate levels after estrogen replacement (CD+E, 34.4+/-3.8 microM, p=0.08 vs. CD). These results suggest that direct actions on vascular wall including nitric oxide production contribute to the anti-atherogenic effects of estrogen.
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PMID:Effects of estrogen on atherosclerosis formation and serum nitrite/nitrate concentrations in cholesterol-fed ovariectomized rabbits. 922 63

Estradiol retards the development of atherosclerosis. Animal models have suggested that NO may be a critical effector molecule in this cardiovascular protection. In this study, female human umbilical vein endothelial cells (HUVECs) were propagated in phenol red-free gonadal hormone-free medium and pretreated with 17 beta-estradiol (E2). Reduced NO2- and NO3- (NOx) concentration, determined by chemiluminescence, demonstrated a rapid increase in basal HUVEC NO release in response to physiological concentrations of E2. The estrogen receptor (ER) antagonist ICI 164,384 inhibited the augmented NO release, demonstrating an ER-mediated component of this response. Because endothelial NO synthase (eNOS) activity is largely regulated by cytosolic Ca2+, relative [Ca2+]i in response to E2 was determined in a fluorometric assay. E2 did not promote HUVEC Ca2+ fluxes. Furthermore, eNOS activity in E2-pretreated endothelial whole-cell lysates was not dependent on additional Ca2+. Despite involving the ER, this is a nongenomic effect E2, as demonstrated by maintained responses in transcriptionally inhibited cells and by the rapidly (10 minutes) of cGMP formation in an NO bioassay. We demonstrate, for the first time, that independent of cytosolic Ca2+ mobilization, there is augmentation of eNOS activity with a resultant increase in HUVEC basal NO release in response to short-term estradiol exposure. Implications for the cardiovascular protective role of estrogen are discussed.
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PMID:17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. 935 64

Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.
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PMID:Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. 940 4

Since the classical studies by Furchgott and Zawadski (Nature, 1980, 286, 373-376), the vascular endothelium is known to play a fundamental role in the regulation of haemostasis and vasomotor activity. This is primarily due to its strategic interface position between the circulating blood and smooth muscle cells of the media. Due to the presence of specific receptors to mediators released during platelet aggregation (thrombin, ATP, serotonin, PAF, etc.), and the presence of mechanoreceptors sensitive to shearing forces generated by blood flow along the vessel wall, the endothelium is able to release, at the two poles of the cell, vasodilator and antiaggregant substances called "endothelium derived relaxing factors" (EDRFs), the best known for which are nitric oxide (NO) ans prostacyclin (PGl2). In the absence of endothelium (angioplasty), or in the case of endothelium dysfunction related to cardiovascular diseases such as hypertension, heart failure, atherosclerosis or diabetes, EDRF synthesis is absent or defective and its oxidative catabolism in increased (particularity by superoxide anion), resulting in varying degrees of disorders of haemostasis (thrombosis) and/or arterial and venous vasomotor activity. The only known effective treatment to palliate these dysfunctions is exogenous NO, supplied in the form of nitrate (nitroglycerin, isosorbide dinitrate, 5-mononitrate) or "NO donors" (Sin1, nitroprussate). The advantage of these substances is that their vasodilator effects (and, in some cases, their antiaggregant effects) are strictly endothelium-independent and they remain effective regardless of the causes and severity of endothelial dysfunction.
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PMID:[Nitrates and coronary vascular endothelium dysfunction]. 945 72


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