***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background —Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations . Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events . This study was design ed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease . Methods and Results —Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography . The effect of the coadministration of vitamin C ( 24 mg/min ) was assessed in a subgroup of 179 patients .  Cardiovascular events , including death from cardiovascular causes , myocardial infa rct ion , ischemic stroke , coronary angioplasty , and coronary or peripheral bypass operation , were studied during a mean follow-up period of 4.5 years . Patients experiencing cardiovascular events ( n=91 ) had lower vasodilator responses to acetylcholine ( P < 0.001 ) and sodium nitroprusside ( P < 0.05 ) , but greater benefit from vitamin C ( P < 0.01 ) . The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation ( P = 0.001 ) , the effect of vitamin C ( P = 0.001 ) , and age ( P = 0.016 ) remained independent predictors of cardiovascular events . Conclusions —Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease . These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity OBJECTIVES The aim of this study was to examine the association between brachial artery flow-mediated dilation ( FMD ) and cardiovascular events in a cohort of initially asymptomatic post-menopausal women , with adjustment for the presence of the major cardiovascular risk factors . BACKGROUND Conventional major cardiovascular risk factors ( cigarette smoking , hypercholesterolemia , hypertension , and diabetes ) fail to explain nearly 50 % of cardiovascular events . Defining the magnitude of future risk for the development of clinical events is a major focus of effective primary prevention . Evaluation of endothelial function , utilizing the noninvasive measurement of the brachial artery FMD , may serve as a screening tool to individualize high-risk patients . METHODS We conducted a prospect i ve study on 2,264 post-menopausal women , age 54 + /- 6 years . The length of the follow-up was 45 + /- 13 months ( range 6 to 65 months ) . RESULTS During observation , 90 major events were recorded . Risk-adjusted relative risk values result ed 1.0 , 1.33 ( 95 % confidence interval [ CI ] 1.09 to 4.09 ) , and 4.42 ( 95 % CI 2.97 to 8.01 ) for women in the higher , intermediate , and lower tertile of FMD , respectively ( p < 0.0001 for trend ) . The event rate for women in the lower tertile ( FMD < or=4.5 % ) was greater than the combined event rate noted in the other 2 tertiles ( women in the lower tertile accounted for 51 events [ 56.6 % of total events ] ) . When added to age and other conventional cardiovascular risk factors ( smoking habits , presence of hypercholesterolemia , history of diabetes , hypertension ) , FMD contributed significantly to the model predicting cardiovascular events ( likelihood ratio chi-square change : 10.22 ; p < 0.0001 ) . CONCLUSIONS In post-menopausal women , the knowledge of FMD provided incremental prognostic information regarding the risk of developing cardiovascular events Abstract — Flow-mediated dilatation ( FMD ) of conduit arteries is dependent on an intact endothelium , although the mechanisms are not fully understood . Using high-resolution ultrasound , we examined the role of endothelial mediators in radial artery dilatation in response to transient ( short period of reactive hyperemia ) and sustained ( prolonged period of reactive hyperemia , h and warming , or an incremental infusion of acetylcholine into the distal radial artery ) hyperemia . After short episodes of reactive hyperemia , FMD was abolished by local infusion of the nitric oxide synthesis inhibitor NGmonomethyl-l-arginine ( 5.3±1.2 % versus 0.7±0.7 % , P < 0.001 ) . In contrast , basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia , h and warming , and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition . Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD .  Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia , but the response to sustained hyperemia was normal . These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus . Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide , whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition . Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide – dependent pathway and preservation of non nitric oxide – mediated dilatation to sustained flow stimuli Studies of experimental diabetes mellitus ( DM ) suggest that increased nitric oxide ( NO ) bioactivity contributes to renal hyperfiltration . However , the role of NO in mediating hyperfiltration has not been fully eluci date d in humans . Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM .  Renal function and brachial artery flow-mediated vasodilatation ( FMD ) were measured before and after an intravenous infusion of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester ( l-NMMA ) in 21 healthy control and 37 type 1 DM patients . Measurements in DM participants were made under clamped euglycemic conditions . The effect of l-NMMA on circulating and urinary NO metabolites ( NO(x ) ) and cGMP and on urinary prostanoids was also determined . Baseline characteristics were similar in the two groups . For analysis , the DM patients were divided into those with hyperfiltration ( DM-H , n = 18 ) and normal glomerular filtration rate ( GFR ) levels ( DM-N , n = 19 ) . Baseline urine NO(x ) and cGMP were highest in DM-H. l-NMMA led to a decline in GFR in DM-H ( 152 ± 16 to 140 ± 11 ml·min(-1)·1.73 m(-2 ) ) but not DM-N or healthy control participants . The decline in effective renal plasma flow in response to l-NMMA ( 806 ± 112 to 539 ± 80 ml·min(-1)·1.73 m(-2 ) ) in DM-H was also exaggerated compared with the other groups ( repeated measures ANOVA , P < 0.05 ) , along with declines in urinary NO(x ) metabolites and cGMP . Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to l-NMMA . l-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups . In patients with uncomplicated type 1 DM , renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation , suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity Background — We sought to clarify , using functional and biological approaches , the role of epoxyeicosatrienoic acids , nitric oxide (NO)/reactive oxygen species balance , and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension . Methods and Results — Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by h and skin heating . The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases ( fluconazole ) and NO synthase ( NG-monomethyl-L-arginine [ L-NMMA ] ) . Compared with controls , hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating , as shown by the lesser slope of their diameter – shear stress relationship . In controls , heating-induced flow-mediated dilatation was reduced by fluconazole , L-NMMA , and , to a larger extent , by L-NMMA+fluconazole . In patients , flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls . Furthermore , local plasma epoxyeicosatrienoic acids increased during heating in controls ( an effect diminished by fluconazole ) but not in patients . Plasma nitrite , an indicator of NO availability , increased during heating in controls ( an effect abolished by L-NMMA ) and , to a lesser extent , in patients , whereas , inversely , reactive oxygen species increased more in patients ( an effect diminished by L-NMMA ) . Plasma endothelin-1 decreased during heating in controls but not in patients . Conclusions — These results show that an impaired role of epoxyeicosatrienoic acids contributes , together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway , to conduit artery endothelial dysfunction in essential hypertension . Clinical Trial Registration — https://www.eudract.ema.europa.eu . Unique identifier : RCB2007-A001–10 - 53 BACKGROUND Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atherosclerosis . Therefore , we prospect ively investigated whether coronary endothelial dysfunction predicts disease progression and cardiovascular event rates . METHODS AND RESULTS Coronary vasoreactivity was assessed in 147 patients using the endothelium-dependent dilator acetylcholine , sympathetic activation by cold pressor testing , dilator responses to increased blood flow , and dilation in response to nitroglycerin .  Cardiovascular events ( cardiovascular death , unstable angina , myocardial infa rct ion , percutaneous transluminal coronary angioplasty , coronary bypass grafting , ischemic stroke , or peripheral artery revascularization ) served as outcome variables over a median follow-up period of 7.7 years . Patients suffering from cardiovascular events during follow-up ( n=16 ) had significantly increased vasoconstrictor responses to acetylcholine infusion ( P=0 . 009 ) and cold pressor testing ( P=0.002 ) , as well as significantly blunted vasodilator responses to increased blood flow ( P<0.001 ) and the intracoronary injection of nitroglycerin ( P=0.001 ) . Impaired endothelial and endothelium-independent coronary vasoreactivity were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis . By multivariate analysis , all tests of coronary vasoreactivity were significant , independent predictors of a poor prognosis , even after adjustment for traditional cardiovascular risk factors or the presence of atherosclerosis itself . CONCLUSIONS Coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates . Thus , the assessment of coronary endothelial vasoreactivity can provide pivotal information as both a diagnostic and prognostic tool in patients at risk for coronary heart disease Design and participants A double-blind , crossover , r and omized study was design ed to evaluate the effect of 3-month treatment with a lower versus a higher antihypertensive dosage of ramipril ( 5 or 10 mg/day ) on nitric oxide (NO)-dependent vasodilation in 46 untreated patients with essential hypertension . Radial artery flow-mediated dilation ( FMD ) , before and after the intra-arterial infusion of NG-monomethyl-L-arginine ( L-NMMA ) , to block NO synthase , and the response to sublingual glyceril trinitrate ( GTN , 25 μg ) were measured at baseline and after the two treatment periods as a change in artery diameter ( computerized system from ultrasound scans ) . Plasma angiotensin II and oxidative stress markers were also assessed . Results FMD was significantly ( P < 0.01 ) lower in hypertensive patients ( 4.6 ± 1.8 % ) than in normotensive subjects ( 7.1 ± 2.6 % ) , whereas the response to GTN was similar . L-NMMA significantly ( P < 0.001 ) inhibited FMD in normotensive but not in hypertensive 
    Output:
    
This comprehensive analysis demonstrates that FMD of conduit arteries in humans is , at least in part , mediated by NO