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PubMed2003

Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298-->Asp) variant in determining endothelial function in coronary artery disease.

The products of nitric oxide synthase (NOS) and angiotensin-converting enzyme (ACE) play a critical role in determining vessel wall structure and function. Polymorphisms in both genes have been independently demonstrated to influence propensity to cardiovascular events. The purpose of this study was to determine the influence of the homozygous G849T (Glu298-->Asp) polymorphism in NOS III on peripheral conduit artery endothelial function and to elucidate the modifier role, if any, of a common ACE polymorphism. Three hundred and ninety-seven consecutive subjects presenting to the cardiac catheterization laboratory of the University of Michigan over a period of 18 months were recruited. DNA was extracted and polymerase chain reaction (PCR) analysis for ACE and NOS polymorphisms performed. Patients with homozygosity for G849T at both loci (TT) who belong to DD and II ACE genotype (groups 1 and 2) and those who are negative for this polymorphism (GG) and belong to either DD or II genotype (groups 3 and 4) were identified. The four groups then underwent determination of conduit endothelial function. Heterozygosity of Glu298-Asp or the ID variant of the ACE were not studied. Median FMD value in the TT-DD group was 0.20 (-3.17, 2.01) compared with 2.23% (-0.29, 4.17) in the GG-II group. Median values in the TT-II and the GG-DD groups were 3.04 (-1.16, 6.61) and 2.46% (-1.83, 6.52) respectively. These values were not statistically significant (p > 0.05 by one-way ANOVA). Median nitroglycerin-mediated dilation in the four groups did not differ between the four groups (p = NS by ANOVA). Atherosclerosis burdens as assessed by angiography were not different across the groups. In conclusion, the homozygous NOS III variant (GG) status does not seem to interact additively with the ACE homozygous DD genotype in determining flow-mediated vasodilation in individuals with established atherosclerosis and pre-existent endothelial dysfunction.

Aged↗

PubMed2006

Endothelial function and cardiovascular diseases in HIV infected patient.

The HIV epidemic has dramatically changed the paradigm for the development of drug therapy in the last 15 years. The goal is now not only to provide an effective reduction of plasma viremia , but also to reconstitute the immune deficiency due to the progression of the disease. Significant problems with the metabolism of sugars and lipids lead to the appearance of well-documented disorders such as insulin resistance, abnormalities in lipid metabolism and lipodystrophy in those patients on prolonged therapy with antiretrovirals. The question of whether or not HAART-associated lipid disorders contribute to the premature development of coronary artery disease is of major importance for the HIV community. Endothelial injury is associated with disease-related biochemical abnormalities that are implicated in HIV pathogenesis. The exploration of endothelial function began in the early 1980s at the start of the epidemic. The study of endothelial function in HIV infection and its modifications by HAART is an exciting new field in clinical research; in this review the available information on cardiovascular diseases associated with HIV infection and its treatment are discussed.

Anti-Retroviral Agents↗

PubMed1994

Endothelial function of human gastroepiploic artery in comparison with saphenous vein.

OBJECTIVE: Endothelial function is one of the important determinants of patency rate of a graft material used in coronary revascularisation. The aim of this study was to compare the endothelial reactivity of human gastroepiploic artery versus saphenous vein in response to various vasoactive substances. METHODS: Gastroepiploic artery and saphenous vein rings were mounted in an organ bath containing Krebs-Ringer bicarbonate solution aerated with 95% O2 and 5% CO2 at 37 degrees C. Endothelium dependent responses of acetylcholine, histamine, and bradykinin were examined on the precontracted rings of the vessels. The sensitivity of these two graft materials to the potent vasoconstrictor agent endothelin-1 was also compared. RESULTS: Acetylcholine, histamine, and bradykinin caused dose dependent relaxations in saphenous vein and gastroepiploic artery rings. These agonists were more effective in producing endothelium dependent relaxations in the artery than in the vein. Endothelium removal and pretreatment with nitro-arginine abolished the relaxations completely in saphenous vein but not in gastroepiploic artery, depending on the relaxing agent used. On the other hand, both graft materials showed nearly equal sensitivity to endothelin-1 (EC50 values; 3.5 x 10(-9) M in the vein versus 6.4 x 10(-9) M in the artery, p = NS) which was not affected by endothelium removal. CONCLUSIONS: Gastroepiploic artery exhibited more pronounced relaxation and a different response profile to endogenous vasoactive substances than saphenous vein. The demonstration of higher capacity of the artery to release vasoactive substances in response to various endogenous agents shows that gastroepiploic artery may have a better long term patency rate than saphenous vein.

Acetylcholine↗

PubMed2003

External counterpulsation therapy improves endothelial function in patients with refractory angina pectoris.

OBJECTIVES: The goal of this study was to investigate the influence of short-term external counterpulsation (ECP) therapy on flow-mediated dilation (FMD) in patients with coronary artery disease (CAD). BACKGROUND: In patients with CAD, the vascular endothelium is usually impaired and modification or reversal of endothelial dysfunction may significantly enhance treatment. Although ECP therapy reduces angina and improves exercise tolerance in patients with CAD, its short-term effects on FMD in patients with refractory angina pectoris have not yet been described. METHODS: We prospectively assessed endothelial function in 20 consecutive CAD patients (15 males), mean age 68 +/- 11 years, with refractory angina pectoris (Canadian Cardiovascular Society [CCS] angina class III to IV), unsuitable for coronary revascularization, before and after ECP, and compared them with 20 age- and gender-matched controls. Endothelium-dependent brachial artery FMD and endothelium-independent nitroglycerin (NTG)-mediated vasodilation were assessed before and after ECP therapy, using high-resolution ultrasound. RESULTS: External counterpulsation therapy resulted in significant improvement in post-intervention FMD (8.2 +/- 2.1%, p = 0.01), compared with controls (3.1 +/- 2.2%, p = 0.78). There was no significant effect of treatment on NTG-induced vasodilation between ECP and controls (10.7 +/- 2.8% vs. 10.2 +/- 2.4%, p = 0.85). External counterpulsation significantly improved anginal symptoms assessed by reduction in mean sublingual daily nitrate consumption, compared with controls (4.2 +/- 2.7 nitrate tablets vs. 0.4 +/- 0.5 nitrate tablets, p <0.001 and 4.5 +/- 2.3 nitrate tablets vs. 4.4 +/- 2.6 nitrate tablets, p = 0.87, respectively) and in mean CCS angina class compared with controls (3.5 +/- 0.5 vs. 1.9 +/- 0.3, p <0.0001 and 3.3 +/- 0.6 vs. 3.5 +/- 0.5, p = 0.89, respectively). CONCLUSIONS: External counterpulsation significantly improved vascular endothelial function in CAD patients with refractory angina pectoris, thereby suggesting that improved anginal symptoms may be the result of such a mechanism.

Aged↗

PubMed2004

Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors.

BACKGROUND: Although recommended as initial therapy for patients with dyslipidemia who are taking human immunodeficiency virus protease inhibitors (HIV PIs), the effects of pravastatin on lipoproteins and arterial reactivity have not been elucidated. The purpose of this study was to determine the effects of pravastatin on lipoprotein subfractions and endothelial function in patients with dyslipidemia who are receiving HIV PIs. METHODS: This was a placebo-controlled, double-blind, crossover study comparing pravastatin (40 mg) to placebo in 20 patients who were taking HIV PIs. Lipoprotein subfractions were measured with nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was evaluated with high-resolution ultrasound scanning. RESULTS: At baseline, subjects had an increased concentration of low-density lipoprotein (LDL) particles (1756 +/- 180 nmol/L), which tended to be small (19.9 +/- 0.2 nm), a low concentration of large high-density lipoproteins (HDL; 0.94 +/- 0.07 mmol/L), and an increased concentration of large very low-density lipoproteins (VLDL; 1.90 +/- 0.58 mmol/L). FMD was impaired (4.5% +/- 1.1%). Compared with placebo, pravastatin resulted in a 20.8% reduction in LDL particles (P =.030), a 26.7% reduction in small LDL (P =.100), and a 44.9% reduction in small VLDL (P =.023). Total and non-HDL cholesterol levels decreased by 18.3% (P <.001) and 21.7% (P <.001), respectively. FMD tended to increase in patients receiving pravastatin (0.7% +/- 0.6%); however, the difference between treatment phases was not statistically significant (P =.080). CONCLUSIONS: This is the first double-blind, placebo-controlled study of the effects of statin therapy on lipids, lipoprotein subfractions, and endothelial function in patients taking HIV PIs. Pravastatin reduced concentrations of atherogenic lipoproteins, particularly those most associated with future coronary events.

Adult↗

PubMed2004

Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk.

Preeclampsia is a disorder of pregnancy diagnosed by gestational hypertension and proteinuria. Epidemiological evidence suggests that women who experience preeclampsia are at a greater risk of hypertension and heart disease later in life compared with women who had normal pregnancies. Our objective was to determine whether endothelial function is impaired in postpartum women with a history of preeclampsia in their first pregnancy. We measured forearm blood flow (FBF) by venous occlusion plethysmography in 50 healthy women: 16 with prior preeclampsia, 14 with a prior normotensive pregnancy, and 20 never pregnant controls. The postpartum women participated 6-12 mo after delivery. Heart rate (HR) and blood pressure (BP) were concurrently monitored on the contralateral arm. Hemodynamic variables were assessed at baseline and during a mental stress test known to elicit endothelium-dependent vasodilatation. We found that baseline FBF, HR, systolic BP, and diastolic BP did not significantly differ among the groups, whereas mean arterial pressure in the preeclamptic group was greater than that of the normal pregnancy group (P = 0.03). Stress-induced FBF (percent change over baseline) was reduced in the preeclamptic group compared with both the normal pregnancy and never pregnant groups (P = 0.06) and was significantly attenuated compared with women with prior normal pregnancies (91% vs. 147%, P = 0.006). These data demonstrate that women with a history of preeclampsia exhibit impaired endothelial function up to 1 yr postpartum. This observation may explain their increased risk for hypertension and cardiovascular disease.

Adolescent↗

PubMed2003

Comparison between the effects of mixed dyslipidaemia and hypercholesterolaemia on endothelial function, atherosclerotic lesions and fibrinolysis in rabbits.

We compared the impact of hypercholesterolaemia and mixed dyslipidaemia on vascular function, vascular structure and fibrinolytic balance in rabbits. To this end, vascular reactivity was studied in aortic rings from rabbits fed a control diet, a diet containing 0.5% cholesterol+14% coconut oil (mixed dyslipidaemia) or a diet containing 1% cholesterol (hypercholesterolaemia) for 12-14 weeks. Morphometric analysis of aorta was also performed and plasminogen activator inhibitor-1 (PAI-1) as well as tissue-type plasminogen activator (t-PA) plasma activities were measured. Both diets induced a similar increase in cholesterol plasma levels, although triacylglycerols (triglycerides) were increased in animals with mixed dyslipidaemia. Hypercholesterolaemia was associated with intimal thickening, reduction in acetylcholine-induced relaxation ( P <0.05) and increased vasoconstriction induced by acetylcholine+ N (G)-nitro-L-arginine methyl ester (L-NAME) when compared with controls ( P <0.05). These effects were more marked ( P <0.05) in animals with mixed dyslipidaemia. Incubation with ifetroban, a thromboxane A(2)/prostaglandin H(2) receptor antagonist, increased acetylcholine-induced relaxation ( P <0.05) and reduced acetylcholine+L-NAME contraction ( P <0.05) in both diet groups. In contrast, the presence of PD 145, an endothelin (ET)(A)/ET(B) receptor antagonist, exerted these effects only in rabbits with mixed dyslipidaemia. Both hypercholesterolaemia and mixed dyslipidaemia induced a similar increase in PAI-1 and a similar decrease in t-PA plasma activities. These data suggest that hypertriglyceridaemia can increase the deleterious effects of hypercholesterolaemia on endothelial function and vascular structure. This additional harmful effect exerted by triacylglycerols on endothelial function could, in part, be mediated by ET.

Acetylcholine↗

PubMed2005

Egg consumption and endothelial function: a randomized controlled crossover trial.

BACKGROUND: Because of egg cholesterol content, reduction in egg consumption is generally recommended to reduce risk of cardiovascular disease. Recently, however, evidence has been accumulating to suggest that dietary cholesterol is less relevant to cardiovascular risk than dietary saturated fat. This randomized controlled crossover trial was conducted to determine the effects of egg ingestion on endothelial function, a reliable index of cardiovascular risk. METHODS: Forty-nine healthy adults (mean age 56 years, 40% females) underwent a baseline brachial artery reactivity study (BARS), and were assigned to two eggs or oats daily for 6 weeks in random sequence with a 4-week washout. A BARS was done at the end of each treatment phase, measuring flow-mediated vasodilation (FMD) in the brachial artery using a high-frequency ultrasound. RESULTS: FMD was stable in both egg and oat groups, and between-treatment differences were not significant (egg -0.96%, oatmeal -0.79%; p value >0.05). Six weeks of egg ingestion had no effect on total cholesterol (baseline: 203.8 mg/dl; post-treatment: 205.3) or LDL (baseline: 124.8 mg/dl; post-treatment: 129.1). In contrast, 6 weeks of oats lowered total cholesterol (to 194 mg/dl; p = 0.0017) and LDL (to 116.6 mg/dl; p = 0.012). There were no differences in body mass index (BMI), triglyceride, HDL or SBP levels between egg and oat treatment assignments. CONCLUSION: Short-term egg consumption does not adversely affect endothelial function in healthy adults, supporting the view that dietary cholesterol may be less detrimental to cardiovascular health than previously thought.

Cross-Over Studies↗

PubMed2003

Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state.

The incidence of ischemic heart disease shows a sharp rise after menopause. However, the effects of hormone replacement therapy (HRT) on cardiovascular disease are still controversial. Not only oxidative stress, but also inflammation has been suggested to play an important role in the pathogenesis of cardiovascular events. We compared the effects of HRT on endothelial function, cellular antioxidant system and inflammation between oral and transdermal administration in mild hypercholesterolemic postmenopausal women. Transdermal estradiol replacement was administrated to 12 patients (mean age 53 years) for 12 weeks, and oral conjugated equine estrogen was administrated to 12 patients (mean age 54 years) for 12 weeks. The flow-mediated endothelium-dependent dilation of the brachial artery, serum levels of thioredoxin as a marker of the cytoprotective antioxidant system, and high-sensitivity C-reactive protein (hs-CRP) were measured every 4 weeks. The flow-mediated vasodilation increased with HRT (oral, baseline 4.9 +/- 0.5, 4-week 8.9 +/- 0.7*, 8-week 9.9 +/- 0.6*, 12-week 9.4 +/- 0.7*; transdermal, 4.7 +/- 0.6, 8.3 +/- 0.7*, 9.1 +/- 0.8*, 8.9 +/- 0.9%*, * = p < 0.01 versus baseline). The thioredoxin levels decreased with HRT (oral, 26.1 +/- 7.2, 24.1 +/- 8.2, 22.1 +/- 7.8, 19.1 +/- 7.0*; transdermal, 26.9 +/- 7.4, 23.4 +/- 8.7, 21.1 +/- 7.9, 19.2 +/- 7.2 ng/ml*, * = p < 0.01 versus baseline). There were no differences in the variation of the flow-mediated vasodilation or thioredoxin concentrations between the 2 groups. The hs-CRP levels increased with oral HRT (0.32 +/- 0.12, 0.72 +/- 0.17*, 0.86 +/- 0.23*, 0.88 +/- 0.21 mg/dl*, * = p < 0.01 versus baseline), while transdermal HRT did not elicit any changes (0.35 +/- 0.15, 0.34 +/- 0.17, 0.38 +/- 0.20, 0.36 +/- 0.22 mg/dl). The differences of hs-CRP concentrations between the 2 groups analyzed by 2-way ANOVA were significant (p < 0.01). Oral HRT instigated inflammation, but transdermal did not. Both oral and transdermal HRT, however, improved endothelial function and decreased oxidative stress through affecting the cellular redox state. These differentials in the effects caused by the course of administration may affect the future cardiovascular events.

Administration, Cutaneous↗

PubMed1999

Adding ischaemic hand exercise during occlusion of the brachial artery increases the flow-mediated vasodilation in ultrasound studies of endothelial function.

A non-invasive method has been introduced to study endothelial function by evaluating flow-mediated, endothelium-dependent vasodilation of the brachial artery. One weakness of this method is that the post-occlusion vasodilation response is very small in subjects above the age of 60 years, which is a problem when quantifying endothelial dysfunction above this age. We have therefore evaluated whether a higher post-occlusion flow stimulus and a larger vasodilation response can be achieved by adding ischaemic hand exercise during the occlusion of the brachial artery. The subject population was men (n = 12), aged 60 years, free from cardiovascular disease. B-mode ultrasound images for the measurement of lumen diameter of the brachial artery were recorded before and after reactive hyperaemia induced by occlusion of the artery. Blood flow velocity was recorded intermittently using a Doppler technique. Hyperaemia was induced in two different ways: first by occlusion only and then by adding ischaemic hand exercise during the occlusion. The results showed that flow velocity was higher and the duration of flow increase was longer after ischaemic hand exercise compared with occlusion only. Two minutes after cuff pressure release, the increase in blood flow velocity was significantly higher after ischaemic hand work compared with occlusion only (P < 0.01). The corresponding maximal lumen diameters after cuff pressure release were 4.63 +/- 0.35 and 4.45 +/- 0.34 respectively (P < 0.01). The flow-mediated vasodilation increased significantly from 2.24 +/- 2.00% after occlusion only to 7.42 +/- 3.32% after occlusion plus ischaemic hand exercise (P < 0.01). In conclusion, this study showed that a maximal endothelial-dependent vasodilation was not achieved after occlusion only in these 60-year-old men. Adding ischaemic hand exercise may therefore be of value when quantifying endothelial dysfunction in this age group.

Blood Flow Velocity↗

PubMedDate not supplied

Influence of glucose control and improvement of insulin resistance on microvascular blood flow and endothelial function in patients with diabetes mellitus type 2.

OBJECTIVE: The study was performed to investigate the effect of improving metabolic control with pioglitazone in comparison to glimepiride on microvascular function in patients with diabetes mellitus type 2. METHODS: A total of 179 patients were recruited and randomly assigned to one treatment group. Metabolic control (HbA1c), insulin resistance (HOMA index), and microvascular function (laser Doppler fluxmetry) were observed at baseline and after 3 and 6 months. RESULTS: HbA1c improved in both treatment arms (pioglitazone: 7.52 +/- 0.85% to 6.71 +/- 0.89%, p < .0001; glimepiride: 7.44 +/- 0.89% to 6.83 +/- 0.85%, p < .0001). Insulin-resistance decreased significantly in the pioglitazone group (6.15 +/- 4.05 to 3.85 +/- 1.92, p < .0001) and remained unchanged in the glimepiride group. The microvascular response to heat significantly improved in both treatment groups (pioglitazone 48.5 [15.2; 91.8] to 88.8 [57.6; 124.1] arbitrary units [AU], p < .0001; glimepiride 53.7 [14.1; 91.9] to 87.9 [52.9, 131.0] AU, p < .0001, median [lower and upper quartile]). Endothelial function as measured with the acetylcholine response improved in the pioglitazone group (38.5 [22.2; 68.0] to 60.2 [36.9; 82.8], p = .0427) and remained unchanged in the glimepiride group. CONCLUSIONS: Improving metabolic control has beneficial effects in microvascular function in type 2 diabetic patients. Treatment of type 2 diabetic patients with pioglitazone exerts additional effects on endothelial function beyond metabolic control.

Adult↗

PubMed2005

Moderate vs. high exercise intensity: differential effects on aerobic fitness, cardiomyocyte contractility, and endothelial function.

OBJECTIVE: Current guidelines are controversial regarding exercise intensity in cardiovascular prevention and rehabilitation. Although high-intensity training induces larger increases in fitness and maximal oxygen uptake (VO(2max)), moderate intensity is often recommended as equally effective. Controlled preclinical studies and randomized clinical trials are required to determine whether regular exercise at moderate versus high intensity is more beneficial. We therefore assessed relative effectiveness of 10-week HIGH versus moderate (MOD) exercise intensity on integrative and cellular functions. METHODS: Sprague-Dawley rats performed treadmill running intervals at either 85%-90% (HIGH) or 65%-70% (MOD) of VO2max 1 h per day, 5 days per week. Weekly VO2max-testing adjusted exercise intensity. RESULTS: HIGH and MOD increased VO2max by 71% and 28%, respectively. This was paralleled by intensity-dependent cardiomyocyte hypertrophy, 14% and 5% in HIGH and MOD, respectively. Cardiomyocyte function (fractional shortening) increased by 45% and 23%, contraction rate decreased by 43% and 39%, and relaxation rate decreased by 20% and 10%, in HIGH and MOD, respectively. Ca2+ transient time-courses paralleled contraction/relaxation, whereas Ca2+ sensitivity increased 40% and 30% in HIGH and MOD, respectively. Carotid artery endothelial function improved similarly with both intensities. EC50 for acetylcholine-induced relaxation decreased 4.3-fold in HIGH (p < 0.05) and 2.8-fold in MOD (p < 0.20) as compared to sedentary; difference HIGH versus MOD 1.5-fold (p = 0.72). Multiple regression identified rate of systolic Ca2+ increase and diastolic myocyte relengthening as main variables associated with VO2max. Cell hypertrophy, contractility and vasorelaxation also correlated significantly with VO2max. CONCLUSIONS: The present study demonstrates that cardiovascular adaptations to training are intensity-dependent. A close correlation between VO2max, cardiomyocyte dimensions and contractile capacity suggests significantly higher benefit with high intensity, whereas endothelial function appears equivalent at moderate levels. Thus, exercise intensity emerges as an important variable in future preclinical and clinical investigations.

Acetylcholine↗

PubMed2003

Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles.

Given that combination therapy with statin plus fibrate confers a risk of myopathy, it is worthwhile to determine whether statin or fibrate monotherapy is associated with greater clinical benefit in individuals with combined hyperlipidemia. In this randomized double-blind study, we compared the efficacy of simvastatin and fenofibrate on indexes of endothelial function (flow-mediated dilation (FMD) of the brachial artery) and inflammatory markers (plasma high-sensitivity C-reactive protein (CRP), interleukin-1 beta (IL-1 beta), soluble CD40, and soluble CD40 ligand (sCD40L) levels), as surrogate indicators of future coronary heart disease (CHD), in patients with combined hyperlipidemia. A total of 70 patients with plasma triglyceride levels between 200 and 500 mg/dl and total cholesterol levels of >200 mg/dl were randomly assigned to receive either simvastatin (20 mg/day) (n=35) or micronized fenofibrate (200 mg/day) (n=35) for 8 weeks. Treatment with simvastatin was associated with significantly greater reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), while the decrease in triglycerides was significantly greater in patients receiving fenofibrate. Both fenofibrate and simvastatin markedly reduced plasma levels of high-sensitivity CRP, IL-1 beta, and sCD40L, and improved endothelium-dependent FMD without mutual differences. The changes in plasma inflammatory markers did not correlate with baseline clinical characteristics in both groups. However, the improvement in FMD with fenofibrate treatment correlated inversely with baseline high-density lipoprotein cholesterol (HDL-C) levels, whereas the improvement in FMD with simvastatin treatment was positively related to HDL-C levels. Accordingly, in the subgroup with a baseline HDL-C of < or =40 mg/dl, only fenofibrate significantly improved the endothelium-dependent FMD. On the other hand, in the subgroup with HDL-C >40 mg/dl, only treatment with simvastatin achieved significant improvement in FMD. The data here indicate that in patients with combined hyperlipidemia, both fenofibrate and simvastatin have comparative beneficial effects on various inflammatory markers and differential beneficial effects on endothelial function according to baseline HDL-C levels. These findings should be validated by additional prospective studies, in which patients are stratified by baseline HDL-C prior to randomization.

C-Reactive Protein↗

PubMed2007

N,N-diacetyl-L-cystine improves endothelial function in atherosclerotic Watanabe heritable hyperlipidaemic rabbits.

N,N-diacetyl-L-cystine (DiNAC), a novel immunomodulator, stimulates contact sensitivity/delayed type hypersensitivity reactions in mice induced by oxazolone and reduces atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL) rabbits. Forty-week-old WHHL rabbits were given DiNAC (3 micromol/kg per day) for 8 weeks, and endothelium-mediated dilatation was investigated in vivo using pulse wave analysis. A significant improvement in endothelial function was found after 3 weeks of treatment, which was further improved after 8 weeks. For experiments on isolated blood vessels, 40-week-old rabbits were treated for 3 weeks. Treatment did not affect plasma lipid levels. At termination, aortic rings from the thoracic and abdominal aorta were contracted with phenylephrine in vitro. Concentration-effect curves to acetylcholine and the calcium ionophore A 23187 were used to measure endothelium-mediated vasodilatation, and nitroprusside to elicit endothelium-independent relaxations. Abdominal aorta relaxations were generally larger than in thoracic aorta. DiNAC improved endothelium-dependent relaxations in the abdominal but not in the thoracic aorta. This effect was independent of the degree of atherosclerosis. It is concluded that DiNAC improved endothelial function in atherosclerotic rabbit arteries in vivo and in vitro, and may represent a new treatment modality for atherosclerosis-related diseases.

Acetylcholine↗

PubMedDate not supplied

Endothelial function in different organs.

The endothelial lining represents an organ of 1.5 kg in an adult which is distributed throughout the body and serves multifunctional purposes. It regulates vascular growth processes and adaptations and controls the delicate equilibrium between coagulation-hemostasis and fibrinolysis. The endothelium is not only a simple diffusion barrier between the intravascular and extravascular space of blood and lymph vessels thus regulating permeability (ie, the fluid, metabolite and catabolite exchange), but synthetizes, releases, converts, activates and/or inactivates various vasoactive hormones. Thus, it regulates vascular tone and organ blood supply as well as lymphatic flow and expression of surface receptors for the activation of leukocytes eg, during inflammation. In different organs it has additional, organ specific functions (eg, cerebral endothelial lining/blood brain barrier, endothelium mediated changes in renal, splenic and hepatic function and in skeletal muscle perfusion) by generating various autacoids such as nitric oxide, prostaglandins, endothelins, hyperpolarizing factors, and so on. These autacoids are not only vasoactive compounds but also modulate the activation of transcription factors. The endothelial autacoids exert an important role in vascular homeostasis (eg, by direct inhibition of atherogenesis and by inhibition of proatherogenic genes).

Animals↗

PubMed2004

Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation.

BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory disorder. Several large-scale clinical studies demonstrate that markers of inflammation, such as high-sensitivity C-reactive protein (hsCRP), fibrinogen, and soluble CD40 ligand, are potent and independent predictors of vascular risk. HYPOTHESIS: The study was undertaken to investigate the effect of increasing the statin dose from conventional to aggressive treatment on lipids levels, inflammation, and endothelial function in patients with coronary artery disease (CAD). METHODS: We randomized 97 patients to either 20 mg simvastatin or 80 mg atorvastatin. Plasma levels of lipids, hsCRP, fibrinogen, soluble adhesion molecules, and nitric oxide-total were analyzed at baseline and after 6 months of treatment. RESULTS: Lipid values were significantly reduced in both treatment groups, but with significantly greater reduction in the aggressively treated group. Furthermore, aggressive statin treatment significantly decreased hsCRP and fibrinogen, while only small reductions were seen in the conventionally treated group, resulting in significant differences between the two treatment groups (p < 0.001). Nitric oxide-total increased significantly in both treatment groups, although the increase was more pronounced in the aggressively treated group (22.6 vs. 15.6%). CONCLUSION: Aggressive statin treatment significantly improved lipid status and reduced markers of inflammation and improved endothelial function compared with conventional treatment in patients with CAD. No interaction was observed, and high-dose treatment did not offer additional benefit compared with standard-dose treatment with respect to soluble adhesion molecules.

Arteriosclerosis↗

PubMed2005

Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease.

Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.

Aged↗

PubMed2006

Intensive treatment of risk factors in patients with type-2 diabetes mellitus is associated with improvement of endothelial function coupled with a reduction in the levels of plasma asymmetric dimethylarginine and endogenous inhibitor of nitric oxide synthase.

AIMS: Vascular endothelium is a major organ involved in hyperglycaemia and is affected by plasma asymmetric dimethylarginine (ADMA). ADMA is an endogenous, competitive inhibitor of nitric oxide synthase and is induced by inflammatory cytokines of tumour necrosis factor (TNF)-alpha in vitro. We hypothesized that a tight glycaemic control may restore endothelial function in patients with type-2 diabetes mellitus (DM), in association with modulation of TNF-alpha and/or reduction of ADMA level. METHODS AND RESULTS: In 24 patients with type-2 DM, the flow-mediated, endothelium-dependent dilation (FMD: %) of brachial arteries during reactive hyperaemia was determined by a high-resolution ultrasound method. Blood samples for glucose, cholesterol, TNF-alpha, and ADMA analyses were also collected from these patients after fasting. No significant glycaemic or FMD changes were observed in 10 patients receiving the conventional therapy. In 14 patients who were hospitalized and intensively treated, there was a significant decrease in glucose level after the treatment [from 190+/-55 to 117+/-21 (mean+/-SD) mg/dL, P<0.01]. After the intensive control of glucose level, FMD increased significantly (from 2.5+/-0.9 to 7.2+/-3.0%), accompanied by a significant (P<0.01) decrease in TNF-alpha (from 29+/-16 to 11+/-9 pg/dL) and ADMA (from 4.8+/-1.5 to 3.5+/-1.1 microM/L) levels. The changes in FMD after treatment correlated inversely with those in TNF-alpha (R=-0.711, P<0.01) and ADMA (R=-0.717, P<0.01) levels. CONCLUSION: The intensive correction of hyperglycaemia is associated with the improvement of endothelial function, which is coupled with the decrease in the levels of reduction of plasma TNF-alpha and ADMA in patients with type-2 DM. A strict glycaemic control may exert anti-cytokine and anti-atherogenic effects and may therefore be pathophysiologically important.

Arginine↗