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PubMed2004

[Anti-hypertensive drugs associated with the improvement of endothelial function].

Vascular endothelium is not merely a barrier between circulating blood and tissue, but also regulates vascular tone through the secretion of numerous vasoactive substances in response to hemodynamic changes. Thus endothelial injuries by hypertension and atherogenic risk factors play important pathogenic roles in the vascular disease state, and the protection of endothelial function leads to amelioration of progressive vascular disease. In this review, we describe the pathophysiology of endothelial dysfunction in vascular disease, and therapeutic significance of vaso-protective agents, especially in the cotex of endothelial protection.

Animals↗
PubMed2006

Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for 'pleiotropic' functions of statin therapy.

AIMS: Statin therapy is associated with improved endothelial vasodilator function. The clinical availability of ezetimibe, a potent novel cholesterol absorption inhibitor, enables to differentiate lipid-lowering effects from potential non-lipid-lowering (pleiotropic) mechanisms of statins. METHODS AND RESULTS: Forearm blood flow (FBF) responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were measured by venous occlusion plethysmography in four prospectively defined groups of patients with stable coronary artery disease (CAD) before and after 4 weeks of lipid-lowering therapy. Group A (n=15): de novo monotherapy with 10 mg/day ezetimibe; Group B (n=15): 10 mg/day ezetimibe as an add-on to chronic simvastatin therapy with 20 mg/day; Group C (n=15): dose escalation from chronic 10 to 40 mg/day atorvastatin; and Group D (n=15): de novo monotherapy with 40 mg/day atorvastatin. After 4 weeks of therapy, LDL cholesterol levels were significantly reduced in all four groups. Neither ezetimibe monotherapy (Group A) nor ezetimibe combined with 20 mg simvastatin (Group B) was associated with an increase in ACH-mediated FBF responses after 4 weeks. In contrast, dose escalation of atorvastatin from 10 to 40 mg/day (Group C) or de novo therapy with 40 mg atorvastatin/day (Group D) was associated with a significant increase in ACH-mediated FBF responses (P<0.013). CONCLUSION: Thus, both statins and ezetimibe effectively lower LDL-levels within 4 weeks of therapy. However, only statin therapy is associated with improved endothelial vasodilator function, disclosing the relevance of pleiotropic effects of statins during short-term treatment of patients with CAD.

Acetylcholine↗
PubMed2001

[Improvement of endothelial function in patients with hypercholesterolemia and normal coronary arteries with lipid-lowering therapy].

INTRODUCTION AND AIMS: In patients with coronary risk factors the presence of endothelial dysfunction in epicardial arteries has been documented. The purpose of this study was to determine whether endothelial dysfunction, documented hypercholesterolemic patients and angiographically normal coronary arteries, improves by reduction and normalization of lipid levels. PATIENTS AND METHOD: In 10 patients with hypercholesterolemia and normal coronary angiography, the endothelium-dependent coronary vasomotion was studied by intracoronary infusion of acetylcholine into the left anterior descending coronary artery. Vasomotion changes in response to acetylcholine were analyzed by quantitative angiography. Five patients without coronary risk factors and normal coronary arteries formed the control group. Patients with hypercholesterolemia were treated with lipid-lowering therapy (diet and lovastatin) and endothelial function was reevaluated after 24 +/- 4 months. RESULTS: In the initial study, hypercholesterolemic patients compared with the control group showed a vasoconstrictor response to serial doses of acetylcholine(10(-6) M, 10(-5) M, 10(-4)M) indicative of endothelial dysfunction (study group: -0.3 +/- 10%, -6 +/- 4%, -18 +/- 10% vs control group: -0.6 +/- 6%, -2 +/- 6%, 3+/-6%; p < 0.01 to 10(-4) M acetylcholine dose. During follow-up hypercholesterolemic patients who a significant reduction in total cholesterol levels and LDL. Compared to first study, at follow-up, there was an improvement in the response to acetylcholine (-0.4 +/- 4%, -3 +/- 6%, -3 +/- 10%; p<0.001 vs basal values at 10(-4) M acetylcholine concentration). Reduction in total cholesterol during follow-up was related to the improvement in the vasoconstrictor response to acetylcholine (r=0.53; p< 0.05). CONCLUSION: In patients with hypercholesterolemia and angiographycally normal coronary arteries with documented endothelial dysfunction, the reduction and normalization of lipid levels during follow-up may improve endothelium-dependent coronary vasomotion.

Acetylcholine↗
PubMed2001

Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects.

Previous studies investigating homocysteine and vascular disease have relied on total plasma homocysteine as the sole index of homocysteine status. We examined the dynamic relationship between vascular endothelial function and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine to identify the homocysteine form associated with endothelial dysfunction in humans. We investigated 14 healthy volunteers (10 men, 4 women). Brachial artery flow-mediated dilatation was measured at baseline and at 30, 60, 120, 240, and 360 minutes after oral (1) L-methionine (50 mg/kg), (2) L-homocysteine (5 mg/kg), and (3) placebo. Plasma concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine were measured at each time point, and nitroglycerin-induced dilatation at was assessed at 0, 120, and 360 minutes. Flow-mediated dilatation fell, and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine increased after oral homocysteine and oral methionine (all P<0.05 for difference in time course compared with placebo). Flow-mediated dilatation showed a reciprocal relationship with reduced homocysteine during both homocysteine and methionine loading. In both loading studies, peak reduction in flow-mediated dilatation coincided with maximal reduced homocysteine concentrations. In contrast, there was no consistent relationship between flow-mediated dilatation and free oxidized homocysteine, protein-bound oxidized homocysteine, or related species. Nitroglycerin-induced dilatation was unchanged by oral homocysteine and oral methionine (P>0.10 compared with placebo). Reduced homocysteine is closely associated with endothelial dysfunction during oral methionine and oral homocysteine loading. Our observations support the hypothesis that reduced homocysteine is the deleterious form of homocysteine for vascular function in vivo and suggest a less important role for other homocysteine species.

Administration, Oral↗
PubMed2005

Impaired endothelial function in coronary heart disease patients with depressive symptomatology.

OBJECTIVES: The purpose of this study was to assess whether depressive symptomatology was associated with vascular endothelial dysfunction in patients with coronary heart disease (CHD). BACKGROUND: In patients with CHD, the presence of depression is associated with a two to four times increased risk of mortality, but the disease pathways involved are uncertain. Endothelial dysfunction is an established risk factor for cardiovascular events in patients with CHD. METHODS: Flow-mediated dilation (FMD) of the brachial artery, a measure of endothelial function, was assessed in 143 patients (99 men, 44 women), ages 40 to 84 years (mean age, 63 +/- 10 years), with documented CHD. RESULTS: Patients with significant depressive symptomatology, as indicated by a Beck Depression Inventory (BDI) score > or = 10 (n = 47) showed attenuated FMD (p = 0.001) compared with patients that were not depressed (BDI < 10; n = 96). The use of antidepressant medication was associated with improved FMD (p < 0.05). CONCLUSIONS: The increased risk of cardiovascular events in CHD patients with elevated symptoms of depression may be mediated, in part, by endothelial dysfunction.

Adult↗
PubMed2004

Artichoke juice improves endothelial function in hyperlipemia.

Artichoke extracts have been shown to produce various pharmacological effects, such as the inhibition of cholesterol biosynthesis and of LDL oxidation. Endothelial dysfunction represents the first stage of atherosclerotic disease; it is usually evaluated in humans by a noninvasive ultrasound method as brachial flow-mediated vasodilation (FMV) and by the determination of several humoral markers such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. Aim of the study was to investigate the effects of dietary supplementation with artichoke juice on brachial FMV of hyperlipemics. We studied 18 moderately hyperlipemic patients (LDL cholesterol > 130 <200 mg/dl and/or triglycerides >150 <250 mg/dl) of both genders and 10 hyperlipemic patients, matched for age, sex and lipid parameters. All subjects were under isocaloric hypolipidic diet. A basal determination of serum lipids, soluble VCAM-1, ICAM-1, E-selectin and brachial FMV was performed. Thereafter patients were given 20 ml/die of frozen artichoke juice. The same parameters were repeated after 6 weeks. After artichoke treatment there was an increase of triglycerides (156 +/- 54 vs 165 +/- 76 mg/dL, p <0.05) and a reduction of total cholesterol (261 +/- 37 vs 244 +/- 38 mg/dL, p <0.05) and LDL cholesterol (174 +/- 31 vs 160 +/- 34 mg/dL, p <0.05). Controls showed a significant decrease in total and LDL cholesterol (respectively: 267 +/- 22 vs 249 +/- 20 mg/dL and 180 +/- 24 vs 164 +/- 23 mg/dL, both p <0.001). After artichoke there was a decrease in VCAM-1(1633 +/- 1293 vs 1139 +/- 883 ng/mL, p <0.05) and ICAM-1(477 +/- 123 vs 397 +/- 102 ng/mL, p <0.05), brachial FMV increased (3.3 +/- 2.7 vs 4.5 +/- 2.4%, p <0.01), while controls did not exhibit significant changes in VCAM-1, ICAM-1, E-selectin and brachial FMV. Univariate analysis showed that, in artichoke patients, changes of VCAM-1 and ICAM-1 were significantly related to changes in brachial FMV (respectively: r=-0.66 and r=-0.62; both p <0.05). In conclusion, artichoke dietary supplementation seems to positively modulate endothelial function in hypercholesterolemia.

Adult↗
PubMed2006

Circadian variation in endothelial function is attenuated in postmenopausal women.

OBJECTIVE: The present study was undertaken to investigate the possible existence of an endogenously generated circadian rhythm in endothelial function in women and whether this rhythm is altered after the menopause. METHODS: Healthy non smoking women (11 pre-menopausal and 13 postmenopausal women) were studied during a 22 h period under constant routine conditions; endothelium-dependent (flow-mediated dilation (%FMD)) and -independent (glyceryl-trintrate (GTN)-mediated) function was assessed every 2 and 4 h, respectively, by high-resolution ultrasound of the brachial artery. RESULTS: %FMD and %GTN was significantly higher in pre-menopausal women (9.9+/-1.0%FMD (mean+/-S.E.M.); 18.2+/-1.8%GTN; P<0.01) compared with postmenopausal women (6.5+/-0.5%FMD; 11.5+/-1.6%GTN). A significant day-night variation in %FMD was observed pre-menopausal women (day 9.2+/-0.8%; night 10.4+/-1%; P<0.05) with an attenuated rhythm in postmenopausal women (day 6.8+/-0.6%; night 6.0+/-0.4%). CONCLUSIONS: The findings show a circadian rhythm in %FMD in pre-menopausal women, which disappears after the menopause. The reduction in %FMD and an absence of a day-night variation in %FMD in postmenopausal women may have important implications for the incidence of coronary heart disease in women after the menopause.

Adult↗
PubMed2005

Hemorrhagic shock resuscitation affects early and selective mesenteric artery endothelial function through a free radical-dependent mechanism.

Mesenteric ischemia/reperfusion occurring during hemorrhagic shock and resuscitation (H/R) induces a systemic inflammatory response and damages endothelial cells. Our aim was to investigate whether H/R affects selectively mesenteric vascular reactivity and the roles of free radicals and inducible nitric oxide (NO) synthase (iNOS) in these changes. Rats subjected to H (30 min)/R (60 min) in the presence or absence of the free radical scavenger N-2 mercaptopropionyl glycine (MPG), or the specific inhibitor of iNOS [(3) N-(3-aminomethyl)benzyl) acetaminide; 1400W] were studied. Saline requirements to maintain systemic blood pressure during R (53.4 +/- 5.2 mL/kg/h) were reduced by MPG (26.2 +/- 3.1) and 1400W (37.5 +/- 4.1). H/R reduced maximal mesenteric arteries relaxation to acetylcholine (sham: 70% +/- 5%, H/R: 21% +/- 3%) and this impairment was prevented by MPG (66% +/- 10%) and reduced by 1400W (49% +/- 9%). H/R did not affect the endothelium-independent relaxations. Maximal responses to phenylephrine were reduced in mesenteric arteries by H/R (3.6 +/- 0.5 mN/mm vs. sham 6.5 +/- 0.5), this impairment was prevented by 1400W and MPG. No impaired response to acetylcholine was detected in skeletal muscle arteries. H/R was associated with an increased production of TNF-alpha (169 +/- 8.5 ng/mL vs. sham 38 +/- 5 ng/mL), and this was reduced to 75 +/- 8 ng/mL in MPG-treated rats. Total intestinal content of iNOS mRNA was also increased by H/R and this increase was partly reduced by treatment with MPG. H/R induces an early and selective mesenteric endothelial cell dysfunction through a mechanism that involves oxygen-derived free radicals and NO produced by iNOS. H/R is associated with a mesenteric hyporeactivity through an induction of NOS and may be prevented by scavenging free radicals. This early impairment in endothelial function is associated with a local inflammatory response.

Acetylcholine↗
PubMed2003

Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin.

OBJECTIVES: In this study, we evaluated the effect of S 18886, a specific thromboxane A(2) receptor antagonist, on endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Impaired release of endothelial vasodilator substances and increased release of vasoconstrictor prostanoids both contribute to endothelial dysfunction in atherosclerosis. One unresolved question is whether vasoconstrictor prostanoids are still produced and affect vascular tone or alter endothelium-dependent vasodilation in patients treated with aspirin. METHODS: Twenty patients with stable CAD treated with 100 mg/day aspirin were evaluated in a randomized, double-blinded, placebo-controlled study. Twelve patients received a single oral dose of 10 mg S 18886, and eight patients received placebo. Before and 60 min after a single oral dose of S 18886 or placebo, flow-mediated vasodilation (FMD) was evaluated using an echo-tracking device. Venous occlusion plethysmography was used to evaluate the effects on forearm blood flow (FBF) of a brachial artery infusion of acetylcholine (ACh), sodium nitroprusside (SNP), or norepinephrine before and after treatment. RESULTS: Baseline FBF was not affected by S 18886 or placebo. The vasodilator response to ACh was significantly potentiated by S 18886 as compared with placebo (p = 0.03 by analysis of co-variance), whereas the effects of norepinephrine and SNP were unchanged. Flow-mediated dilation increased from 2.50 +/- 1.14% to 3.84 +/- 1.80% (p < 0.01) after S 18886, but was unchanged after placebo. CONCLUSIONS: Single administration of S 18886 improved FMD and ACh-induced vasodilation in aspirin-treated patients with CAD. These results suggest that release of endogenous agonists of TP receptors may contribute to endothelial dysfunction, despite aspirin treatment, in patients with atherosclerosis.

Acetylcholine↗
PubMed2000

The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency.

OBJECTIVES: Controversy persists with regard to the atherogenic risk associated with adult growth hormone deficiency (GHD). Endothelial dysfunction and enhanced oxidative stress are early features of atherogenesis. Therefore, we have studied the effect of three months of low dose GH replacement therapy (0.03IU/kg/day) on these parameters in GHD adults. SUBJECTS AND METHODS: Eight hypopituitary GHD adults (4 male, 4 female), who were receiving conventional hormone replacement therapy, were studied before and after 3 months of GH replacement (0.03IU/kg/day). All observations obtained were compared with similar measurements made in 8 matched control subjects. All study subjects were non-smokers, normotensive and gave no personal or family history of premature vascular disease. Endothelial function was assessed using a specialised vessel wall tracking system to measure endothelium-dependent, flow-mediated, brachial artery dilatation (FMD). Measurements were repeated following glyceryl-trinitrate (GTN) (endothelium-independent dilatation). Oxidative stress was assessed by directly measuring lipid-derived free radicals in venous blood by electron paramagnetic resonance spectroscopy. Fasting lipids, insulin, plasma glucose and IGF-I were also measured at baseline and following GH replacement. RESULTS: FMD, expressed as a percentage change from resting base-line diameter, was significantly impaired in the pre-treatment GHD patients compared with controls (3.1+/-2.1% vs 6.1+/-0.9%, P<0. 001; means+/-s.d.) indicating endothelial dysfunction. Significant increase in FMD was noted following GH therapy (3.1+/-2.1% vs 6. 5+/-1.9%, P<0.001). Free radicals (arbitrary units) were elevated in the pre-treatment GHD patients compared with controls (0.36+/-0.09 vs 0.11+/-0.12, P<0.05) and fell significantly following GH therapy (0.23+/-0.03 vs 0.36+/-0.09, P<0.05), although they remained elevated compared with controls. Fasting insulin was significantly higher (25.9+/-18.8 vs 13.9+/-6.7mu/l, P<0.05) and IGF-I concentrations lower (10.8+/-4.7 vs 20.2+/-6.3nmol/l, P<0.05) in the pre-treatment GHD subjects. After treatment there were no changes in insulin concentration, although IGF-I levels were normalised (10. 8+/-2.3 vs 23.6+/-11.4nmol/l, P<0.05). CONCLUSIONS: Endothelial dysfunction and enhanced oxidative stress are features of adult GHD. This study suggests plausible mechanisms underlying any proatherogenic tendency in adult GHD and demonstrates improvement of these factors following GH replacement.

Adult↗
PubMed2001

Hyperhomocysteinaemia in young adults is not associated with impaired endothelial function.

A mild to moderate elevation of the total homocysteine concentration (tHcy) is now recognized as a risk factor for vascular disease. It is also associated with endothelial dysfunction in middle-aged and elderly individuals without overt atherosclerotic vascular disease. This is important, as endothelial dysfunction is a well recognized early and potentially reversible marker of the atherosclerotic process. We investigated whether mild hyperhomocysteinaemia was associated with endothelial dysfunction in otherwise healthy young males. We compared endothelial function, by measuring forearm blood flow, in 17 males with mild hyperhomocysteinaemia (defined as tHcy >10 micromol/l) and 14 controls with low tHcy (defined as <5 micromol/l). Forearm blood flow was measured in response to the intra-arterial infusion of acetylcholine (endothelial-dependent response) or sodium nitroprusside (endothelial-independent response). Responses to the vasoactive substances were expressed as the area under the curve of the change in forearm blood flow from baseline. Data are given as mean (95% confidence interval). The two groups were well matched for age, body mass index, pulse rate and blood pressure. tHcy was significantly different between the groups [12.3 (10.4-14.2) micromol/l compared with 4.9 (4.6-5.1) micromol/l; P<0.001]. Concentrations of vitamin B(12) and folate were significantly higher in the control group. There was no difference in basal forearm blood flow between the group with mild hyperhomocysteinaemia and the controls, and both the endothelial-dependent [37.5 (26.2-38.8) and 35.3 (26.1-44.4) arbitrary units respectively] and -independent [26.1 (22.2-29.9) and 25.9 (21.0-30.8) units respectively] responses were not significantly different between the groups. Thus the present study demonstrates that, in healthy adults, mild elevation of tHcy was not associated with impaired endothelial-dependent vasodilation. These data suggest an age effect with regard to homocysteine and endothelial dysfunction. The development of vascular disease in individuals with hyperhomocysteinaemia may only result with higher concentrations or after prolonged exposure.

Acetylcholine↗
PubMed2003

Exercise training in patients with chronic heart failure improves endothelial function predominantly in the trained extremities.

The present study investigates whether lower-limb dominant exercise training in patients with chronic heart failure (CHF) improves endothelial function primarily in the trained lower extremities or equally in the upper and lower extremities. Twenty-eight patients with CHF were randomized to the exercise or control group. The exercise group underwent cycle ergometer training for 3 months while controls continued an inactive sedentary lifestyle. Exercise capacity (6-min walk test) and flow-mediated vasodilation in the brachial and posterior tibial arteries were evaluated. After 3 months, walking performance increased only in the exercise group (488+/-16 to 501+/-14 m [control]; 497+/-23 to 567+/-39 m [exercise, p<0.05]). The flow-mediated vasodilation in the brachial arteries did not change in either group (4.2+/-0.5 to 4.5+/-0.4% [control]; 4.3+/-0.5 to 4.6+/-0.4% [exercise]), but that in the posterior tibial arteries increased only in the exercise group (4.1+/-0.5 to 4.1+/-0.3% [control]; 3.6+/-0.3 to 6.4+/-0.6% [exercise, p<0.01]). Cycle ergometer training improved flow-mediated vasodilation in the trained lower limbs, but not in the untrained upper limbs. Exercise training appears to correct endothelial dysfunction predominantly by a local effect in the trained extremities.

Arm↗
PubMed2005

Non invasive evaluation of endothelial function in patients with Anderson-Fabry disease.

AIM: Fabry's disease is an X-linked recessive abnormality of glycosphingolipid metabolism. Increased levels of endothelial prothrombotic factors have recently been demonstrated in Fabry's disease, whereas endothelial function has not been studied using high resolution ultrasound. METHODS: We enrolled 6 patients (4 male, 2 female; mean age, 37 years) and 12 sex matched control subjects (mean age, 37 years). Patients' exclusion criteria included a prior history of cardiac disease, diabetes and treated or untreated hypertension. Patients underwent: anamnesis, physical examination, EKG, 2-dimensional echocardiography with tissue Doppler, measurement of body weight and height, blood pressure. Biochemistry variables were also considered: fasting blood sugar, total cholesterol, HDL-C, LDL-C, triglycerides, fibrinogen, C reactive protein and homocysteine. Using high resolution ultrasound, we assessed the brachial vasodilator response to reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin (NTG) (endothelium-independent). Flow-mediated dilatation (FMD) was expressed as percentage change in post-stimulus diameter in comparison with the baseline. RESULTS: In baseline condition, there was no significant difference between patients and controls in the brachial artery diameter (3.5+/-0.55 vs 3.1+/-0.4). After reactive hyperemia, the FMD change was significantly higher in controls than in patients (16.5+/-6.3% vs 9.3+/-6.2%, P<0.05). After NTG, endothelium-independent vasodilation did not show a significant difference between cases and controls (15+/-7.7% vs 13.8+/-7.1%). CONCLUSIONS: Our study demonstrated the presence of endothelial dysfunction in patients with Fabry's disease in comparison to controls. We hypothesized that endothelial dysfunction may contribute to the pathogenesis of ischemic events in patients with Fabry's disease.

Adult↗
PubMed1998

Endothelial function of internal mammary artery in patients with coronary artery disease and in cardiac transplant recipients.

The objective of this study was to examine the endothelial function of internal mammary artery in patients with coronary artery disease and in heart transplant recipients. Therefore the response of this artery to increasing concentrations of acetylcholine (1, 10, 20 microg/min for 2.5 minutes each) was assessed in 6 patients in a control group, 16 patients with coronary artery disease (CAD group) matched for risk factors with 16 heart graft recipients (who underwent transplantation for nonischemic heart failure), and 12 patients with coronary artery disease and peripheral vascular disease (PVD group). Diameters of proximal and middle segments of internal mammary artery were measured by quantitative angiography. The responses to the first concentration of acetylcholine were attenuated in these three groups compared with the control group. At the highest concentration of acetylcholine the diameter increase was similar in the control and CAD groups, whereas the responses remained significantly impaired in the transplant and PVD groups. However, after selective infusion of L-arginine (30 mg/min for 11 minutes), the precursor of endothelium-derived nitric oxide, was performed, the responses to acetylcholine were restored in these two latter groups. Endothelin plasma levels were significantly enhanced in the PVD group, which exhibited the most severe impairment in acetylcholine-induced vasodilation. Thus some patients with CAD, mainly those with advanced atherosclerosis, and cardiac transplant recipients exhibit internal mammary artery endothelial dysfunction, and this abnormality seems reversible.

Acetylcholine↗
PubMed2003

Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance.

OBJECTIVES: We sought to investigate the effects of orally administered, long-term, eccentric isosorbide mononitrate (ISMN) on endothelial function. BACKGROUND: Previous studies have shown that nitrate tolerance induced by continuous transdermal glyceryl trinitrate (GTN) is associated with increased vascular superoxide production and endothelial dysfunction. In contrast, it is unclear whether vascular superoxide increases during eccentric administration of oral nitrates, which is a widely used therapeutic dosing regimen. METHODS: New Zealand White rabbits were randomly classified into three groups (n = 10, each) that received either placebo, ISMN at 2 mg/kg body weight per day (ISMN-2), or ISMN at 200 mg/kg body weight per day (ISMN-200) in an eccentric, twice-daily scheme for four months. Animals were sacrificed 3 h after application of the last ISMN dose. RESULTS: The continuously present, lowest ISMN plasma levels (ng/ml) were 4.8 +/- 0.2 in ISMN-2 and 14.5 +/- 4 in ISMN-200 (p = 0.026). Treatment with ISMN had no effect on aortic reactivity to phenylephrine, acetylcholine, or the nitric oxide (NO) donor S-nitroso-N-acetyl-D,L-penicillamine, while the half-maximal effective concentration of ISMN (EC(50)-value in -logM) was shifted from 5.23 +/- 0.03 (placebo) to 4.69 +/- 0.04 (ISMN-200) (p < 0.0001 by analysis of variance). This moderate in vivo nitrate tolerance was not associated with increased aortic superoxide production (5 micromol/l lucigenin). The cumulative (20-min) lucigenin signals (cpm/mg) were 211 +/- 34 (ISMN-200) and 230 +/- 22 (placebo) (p = 0.415). CONCLUSIONS: Long-term treatment with high-dose, eccentric ISMN does not increase vascular superoxide production and/or impair endothelium-dependent vasorelaxation, despite the development of moderate nitrate tolerance. Thus, it is unlikely that long-term anti-ischemic treatment with ISMN aggravates endothelial dysfunction in coronary artery disease.

Acetylcholine↗
PubMed2006

Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines.

BACKGROUND: Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure. OBJECTIVE: We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA. DESIGN: In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading. RESULTS: Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction. CONCLUSIONS: Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.

Adult↗
PubMed1999

Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditions.

It is unknown whether and to what extent changes in various endothelial functions and adrenergic responsiveness are related to the development of microvascular complications in type 1 diabetes. Therefore, endothelium-dependent and endothelium-independent vasodilatation, endothelium-dependent hemostatic factors, and one and two adrenergic vasoconstrictor responses were determined in type 1 patients with and without microvascular complications. A total of 34 patients with type 1 diabetes were studied under euglycemic conditions on two occasions (11 without microangiopathy, 10 with proliferative and preproliferative retinopathy previously treated by laser coagulation, 13 with microalbuminuria, and 12 healthy volunteers also were studied). Forearm vascular responses to brachial artery infusions of N(G)-monomethyl-L-arginine (L-NMMA), sodium nitroprusside, acetylcholine (ACh), clonidine, and phenylephrine were determined. The ACh infusions were repeated during coinfusion of L-arginine. Furthermore, plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen activator antigen levels, von Willebrand factor antigen levels, tissue factor pathway inhibitor (TFPI) activity, and endothelin-1 levels were measured. No differences in endothelium-dependent or endothelium-independent vasodilatation or adrenergic constriction were observed between the diabetic patients and the healthy volunteers. In comparison to the first ACh infusion, the maximal response to repeated ACh during L-arginine administration was reduced in the diabetic patients, except in the patients with proliferative and preproliferative retinopathy previously treated by laser coagulation. In these patients, the combined infusion of L-arginine and ACh resulted in an enhanced response. TFPI activity was elevated, and PAI-1 activity was reduced in the type 1 diabetic patients. Furthermore, PAI-1 activity was positively correlated with urinary albumin excretion (r = 0.48, P < 0.01) and inversely correlated with the vasodilatory response to the highest ACh dose (r = -0.37, P < 0.05). The response to the highest ACh and L-NMMA dose were positively correlated with mean arterial blood pressure (r = 0.32, P < 0.01; r = 0.41, P < 0.01, respectively). Forearm endothelium-dependent and endothelium-independent vasodilatation and adrenergic responsiveness were unaltered in type 1 diabetic patients with and without microvascular complications. Relative to healthy control subjects, endothelium-dependent vasodilatation was depressed during a repeated ACh challenge (with L-arginine coinfusion) in the diabetic patients without complications or with microalbuminuria. In contrast, this vasodilatation was enhanced in the patients with retinopathy. Elevation of TFPI was the most consistent marker of endothelial damage of all the endothelial markers measured.

Adrenergic alpha-Agonists↗