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Results for “endothelial dysfunction”

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PubMed1999

Coronary endothelial dysfunction of isolated hearts subjected to prolonged cold storage: patterns and contributing factors.

BACKGROUND: A key role of endothelial dysfunction in the pathogenesis of early low coronary flow of heart transplants and late cardiac allograft vasculopathy indicates the importance of optimal coronary endothelial preservation during cold heart storage. We designed this study to investigate the effect of prolonged cold storage on endothelial and smooth muscle function of proximal (epicardial) and distal (intramyocardial) coronary arteries. METHODS: Four groups of isolated rat hearts were subjected to cold cardioplegic perfusion and immersed in storage medium at 4 degrees C. In groups 1, 2, and 3, hearts were perfused with and stored in Celsior solution for 10, 15, and 30 hours, respectively. In group 4, hearts were perfused with Plegisol and stored in saline for 15 hours. At the end of cold heart storage, arterial segments were taken from the proximal and distal parts of the left coronary artery and mounted on an isometric wire myograph for functional studies. In fifth group, proximal and distal segments of coronary artery isolated from fresh hearts were used as controls. At the end of control measurements, these vessels were used for storage in vitro at 4 degrees C for 15 hours in saline (group 5A) or Celsior (group 5B). RESULTS: The endothelium-dependent relaxation to acetylcholine was reduced in distal coronary arteries in group 1, and in both proximal and distal coronary artery segments in groups 2, 3, 4, and 5A. Endothelial function was significantly more impaired in both proximal and distal coronary arteries in group 4, as compared with group 2. The impairment of relaxation to acetylcholine was more pronounced following cold storage of the heart than after a similarly long storage of the isolated vessels. The endothelium-independent relaxations to isoprenaline did not differ among all groups. The basal myogenic tone was increased in distal coronary arteries in group 1, and in both proximal and distal coronary arteries in groups 2, 3, 4, and 5A. The sensitivity to the vasoconstricting action of 5-hydroxytryptamine was increased in distal coronary arteries in group 2, and in both proximal and distal coronary arteries in groups 3, 4, and 5A. CONCLUSIONS: Prolonged ischemic cold heart storage induces coronary endothelial dysfunction that is more pronounced in distal than in proximal arteries and is related to the duration of heart storage and the composition of storage medium.

Acetylcholine↗

PubMed2001

Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction.

BACKGROUND: Human immunodeficiency virus protease inhibitors (HIV PIs) are associated with hyperlipidemia, hyperglycemia, and obesity; however, it is not known whether they increase risk of atherosclerotic vascular disease. The purposes of this study were to characterize the lipoprotein abnormalities associated with use of HIV PIs in individuals with HIV infection and to determine the pathophysiological significance of these changes by assessing their effect on endothelial dysfunction. METHODS AND RESULTS: This was a cross-sectional study of 37 adults with HIV-1 infection who were receiving antiretroviral therapy. Twenty-two were taking HIV PIs (group 1); 15 were not (group 2). Lipids and lipoproteins were measured by enzymatic techniques and nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was measured by high-resolution ultrasound. Subjects in both groups were similar in regard to age, time since diagnosis of HIV infection, and CD4 cell count. Group 1 subjects had higher total cholesterol (5.68 versus 4.42 mmol/L, P=0.007) and triglyceride (4.43 versus 1.98 mmol/L, P=0.009) levels, characterized by elevated levels of IDL and VLDL. Subjects in group 1 had impaired FMD (2.6+/-4.6%), indicative of significant endothelial dysfunction. Group 2 subjects had normal FMD (8.1+/-6.7%, P=0.005). In group 1, chylomicron, VLDL, IDL, and HDL cholesterol levels predicted FMD. CONCLUSIONS: Use of HIV PIs is associated with atherogenic lipoprotein changes and endothelial dysfunction. Because these metabolic and vascular changes predispose to atherosclerosis, monitoring and treatment of dyslipidemia in patients taking these medications is warranted.

Adult↗

PubMed2005

Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats.

The aim of the present study was to analyze the possible involvement of vasoconstrictors prostanoids on the reduced endothelium-dependent relaxations produced by chronic administration of aldosterone in Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). For this purpose, acetylcholine (ACh) relaxations in aortic segments from both strains were analyzed in absence and presence of the cyclooxygenase-1 (COX-1) and COX-2 inhibitor indomethacin, the specific COX-2 inhibitor NS-398, the TP receptor antagonist (SQ 29 548), the thromboxane A2 (TXA2) synthase inhibitor furegrelate, and the prostacyclin (PGI2) synthesis inhibitor tranylcypromine (TCP). In addition, COX-2 protein expression was studied by Western blot analysis. Release of prostaglandin E2 (PGE2) and the metabolites of PGF2alpha, TXA2, and PGI2, 13,14-dihydro-15-keto PGF2a, TXB2, and 6-keto-PGF1alpha, respectively, were measured. Treatment with aldosterone did not modify blood pressure levels in any strain. However, aldosterone markedly reduced (P<0.05) ACh-induced relaxations in segments from both strains in a similar extent. Indomethacin, NS-398, SQ 29 548, and TCP enhanced (P<0.05) ACh relaxations in both strains treated with aldosterone. Aortic COX-2 protein expression was higher in both strains of rats treated with aldosterone. In normotensive animals, aldosterone increases the ACh-stimulated aortic production of 13,14-dihydro-15-keto PGF2a, PGE2, and 6-keto-PGF1alpha (P<0.05). In SHR, ACh only increased the 6-keto-PGF1alpha production (P<0.05). It could be concluded that chronic treatment with aldosterone was able to produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive conditions. PGI2 seems to be the main factor accounting for endothelial dysfunction in hypertensive rats, whereas other prostanoids besides PGI2 appear to be involved in endothelial dysfunction under normotensive conditions.

Acetylcholine↗

PubMed2001

Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function.

Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.

Diabetes Mellitus↗

PubMed2006

Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes.

BACKGROUND AND AIMS: Some plasma biomarkers of inflammation and endothelial dysfunction have been recently recognized as important cardiovascular risk factors. Currently, there is little information about the effects of aerobic exercise training on these biomarkers in older adults with type 2 diabetes. We have therefore assessed the effects of a twice-weekly moderate, aerobic exercise programme, without a concomitant weight loss diet, on plasma inflammatory and endothelial dysfunction biomarkers in older type 2 diabetic patients. METHODS AND RESULTS: A group of 16 sedentary, overweight, non-smoking, older patients with type 2 diabetes volunteered to participate in a 6-month, supervised, progressive, aerobic training study, two times per week. Plasma levels of hs-C-reactive protein (hs-CRP), soluble tumour necrosis factor (TNF)-alpha receptors, P-selectin and intercellular adhesion molecule-1 (ICAM-1) were measured before and after physical training. While hs-CRP and soluble TNF-alpha receptors remained essentially unaffected by physical training, plasma concentrations of P-selectin (P<0.001) and ICAM-1 (P<0.01) markedly decreased; physical training also increased HDL cholesterol by 12% (P<0.05) and decreased uric acid levels by approximately 33% (P=0.021). Body weight, waist circumference, blood pressure, haemoglobin A1c, plasma triglyceride and LDL cholesterol concentrations did not change. Interestingly, the exercise-induced changes in ICAM-1 and P-selectin levels remained significant after adjustment for the percent variations of body weight, waist circumference, haemoglobin A1c, HDL cholesterol and uric acid concentrations. CONCLUSIONS: A twice-weekly, 6-month, progressive aerobic-training programme, without a concomitant weight loss diet, is associated with significant decreases in circulating P-selectin and ICAM-1 levels and with a less atherogenic lipid profile in overweight, non-smoking, older type 2 diabetic individuals.

Aged↗

PubMed2006

Non-invasive evaluation of endothelial dysfunction in uncomplicated obesity: relationship with insulin resistance.

Obesity is associated with increased cardiovascular morbidity and amortality. Endothelial dysfunction, involved in the pathogenesis of cardiovascular events, has been demonstrated in obese patients with invasive techniques requiring artery catheterization. The aim of our investigation was to evaluate, with a non-invasive method readily employable on clinical grounds, impaired vasodilatation and its relationship with insulin resistance in uncomplicated obesity. 15 uncomplicated obese subjects (BMI = 36.6 +/- 3.2) and 10 lean controls (BMI = 22.9 +/- 1.25) were enrolled in this study. All subjects underwent measurement of endothelium-dependent (FBFr) vasodilatation by forearm venous occlusion pletysmography after increasing times of ischemia, and measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (M index), by fasting glucose and insulin (HOMA-IR) and by oral glucose tolerance test (ISI index). Endothelium-independent (N-FBFr) vasodilatation was assessed as well. The FBFr was markedly blunted in obese patients versus lean controls (30 s: 2.12 +/- 0.34 vs. 3.63 +/- 0.22, P < 0.01; 60 s: 2.34 +/- 0.42 vs. 3.82 +/- 0.53, P < 0.01; 180 s: 3.20 +/- 0.45 vs. 7.15 +/- 0.35, P < 0.01; 300 s: 4.08 +/- 0.94 vs. 14.1 +/- 0.82, P < 0.001). The N-FBFr was not different in the two groups. High correlation was found between M index and FBFr at all ischemia times. HOMA-IR and ISI were not related with FBFr. The non-invasive evaluation of endothelial dysfunction by a simple and reliable method based on venous occlusive plethysmography shows high correlation between impaired endothelium-dependent vasodilatation and insulin resistance in uncomplicated obesity. This non-invasive test of endothelial function may be routinely performed in the assessment of cardiovascular risk in uncomplicated obesity.

Adult↗

PubMed2003

Vascular endothelial growth factor induced functional and morphologic signs of endothelial dysfunction in isolated arteries from normal pregnant women.

OBJECTIVE: The purpose of this study was to determine the effects of vascular endothelial growth factor on basal tone, endothelium-dependent dilatation, permeability, and morphologic features of endothelium in isolated arteries from normal pregnant women. We hypothesized that vascular endothelial growth factor might induce signs of endothelial dysfunction. STUDY DESIGN: Arteries (approximately 200 microm) were dissected from subcutaneous fat biopsy specimens that were obtained at cesarean delivery and mounted on a pressure arteriograph. Changes in basal tone, dilatation to bradykinin (1 nmol/L to 3 micromol/L) before, during, and after 3 hours of incubation with vascular endothelial growth factor (0.5 or 1 nmol/L), vascular endothelial growth factor (0.5 nmol/L) plus bosentan (a nonselective endothelin receptor A and B antagonist, 1 micromol/L), or vehicle were compared. Scanning electron microscopy was applied for endothelial morphologic features. Permeability to Evans blue dye was evaluated in arteries after incubation with vascular endothelial growth factor, vascular endothelial growth factor plus angiopoietin-1, or vehicle, and in arteries that were obtained from women with preeclampsia. RESULTS: Basal tone was higher after 60 minutes of incubation with vascular endothelial growth factor (0.5 nmol/L) compared with vehicle (29% +/- 5% [n = 10] vs 10% +/- 4% [n = 7], P =.006). Combination of vascular endothelial growth factor with bosentan failed to increase the tone (n = 4). Bradykinin-mediated dilatation was impaired in arteries that were incubated with vascular endothelial growth factor 0.5 nmol/L (max dilatation: 287% +/- 16% vs 160% +/- 23% [n = 10], P =.0001) or vascular endothelial growth factor 1 nmol/L (max dilatation: 207% +/- 21% vs 88% +/- 4% [n = 3], P =.003). Bradykinin-mediated dilatation was similar after incubation with vehicle (n = 7) or the combination of vascular endothelial growth factor plus bosentan (n = 4). Evans blue dye staining was higher after incubation with vascular endothelial growth factor but was reversed by the addition of angiopoietin-1. Scanning electron microscopy demonstrated the development of intercellular gaps. CONCLUSION: Vascular endothelial growth factor impaired bradykinin-mediated dilatation and enhanced basal tone and permeability. This might indicate a potential role for vascular endothelial growth factor in the development of endothelial dysfunction in pregnancy. Angiopoietin-1 inhibited the vascular endothelial growth factor-induced vascular leakage, which may have therapeutic implications in preeclampsia.

Adipose Tissue↗

PubMed1994

Dietary vitamin E increases the resistance to lipoprotein oxidation and attenuates endothelial dysfunction in the cholesterol-fed rabbit.

This study was conducted to determine if vitamin E could reverse or attenuate endothelial dysfunction following an atherogenic diet. Rabbits were initially fed 1% cholesterol for 4 weeks to induce endothelial dysfunction. During the next 4 weeks the rabbits were fed either 1% cholesterol +0.2% vitamin E or 1% cholesterol alone, and were then killed. Endothelium-dependent responses to acetylcholine, calcium ionophore A23187 and sodium nitroprusside (SNP) were studied in the preconstricted perfused rabbit ear. Dietary vitamin E partially reversed the impaired endothelium-dependent responses to acetylcholine associated with cholesterol feeding. The maximum decrease in perfusion pressure in response to acetylcholine was 77.8% +/- 3.6% in control animals, 35.3% +/- 2.6% in cholesterol-fed animals, and 49.1% +/- 4.7% in cholesterol+vitamin E treated animals. The response to A23187 or sodium nitroprusside did not differ between the groups. The susceptibility of rabbit beta-VLDL to oxidation was markedly decreased in the vitamin E treated animals as assessed by the formation of conjugated dienes. The formation of lipid peroxidation products were also significantly inhibited by vitamin E. These data suggest that dietary vitamin E is beneficial in reducing the oxidative injury that may lead to the impairment of nitric oxide (NO)-mediated responses in early hypercholesterolaemia.

Acetylcholine↗

PubMed2003

Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy.

BACKGROUND: Endothelial dysfunction has been described in patients with coronary artery disease (CAD) or chronic heart failure (CHF). Vitamin C administration leads to an improvement of endothelial function by reducing elevated levels of reactive oxygen species. It remains unclear, however, whether the degree of endothelial dysfunction caused by oxidative stress differs between CAD and CHF because of ischemic (ICM) or dilated cardiomyopathy (DCM). METHODS: In patients with CAD (n = 9; left ventricular ejection fraction [LVEF], 64% +/- 3%), ICM (n = 9; LVEF, 25% +/- 4%), DCM (n = 9; LVEF, 25% +/- 3%), and healthy subjects (HS; n = 5; LVEF, 66% +/- 5%) a change in internal radial artery diameter in response to acetylcholine (Ach; 15 and 30 microg/min) was measured with high-resolution ultrasound scanning during a co-infusion of normal saline or vitamin C (25 mg/min). RESULTS: Ach-mediated vasodilation was blunted in patients with CHF (DCM, 90 +/- 20 microm; ICM, 86 +/- 20 microm) and patients with CAD (336 +/- 20 microm) as compared with HS (496 +/- 43 microm; P <.05 vs patients with DCM, ICM, CAD). Vitamin C co-infusion increased Ach-mediated vasodilation by 180 +/- 35 microm (to 270 +/- 30 microm) in DCM (P <.05 vs CAD, HS) and by 294 +/- 40 microm (to 380 +/- 20 microm) in ICM (P <.05 vs DCM, CAD, HS). In patients with CAD, vitamin C increased Ach-mediated vasodilation by 146 +/- 35 microm to normal values, whereas vascular diameter remained unchanged in HS (14 +/- 20 microm; P = not significant). CONCLUSIONS: Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.

Acetylcholine↗

PubMed2005

Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease.

Recent studies demonstrated that glycoprotein (GP) IIb/IIIa receptor antagonists improve endothelial dysfunction of forearm resistance vessels in patients with stable coronary artery disease. However, it remains unclear whether these findings can be extended to the conductance vessel level. In this study, we aimed to evaluate the acute effect of tirofiban on endothelial function of arterial conductance vessels in patients undergoing percutaneous coronary intervention (PCI). Endothelial function was examined by ultrasonographic measurement of flow-mediated vasodilation (FMD) of the brachial artery. Endothelium-independent vasodilation was determined in response to nitroglycerin. Sixty-six patients who underwent PCI were included in the study. Thirty-three patients received a bolus of 10 microg/kg body weight of tirofiban, whereas 33 patients who did not receive tirofiban served as the control group. FMD was measured in all patients before and 30 minutes after PCI. Tirofiban significantly improved FMD (6.0 +/- 0.4% before vs 7.8 +/- 0.5% after PCI, p <0.0001), whereas FMD deteriorated in patients in the control group (6.1 +/- 0.6% before vs 4.7 +/- 0.7% after PCI, p = 0.006). Nitroglycerin-induced dilation remained unaltered in response to PCI. In another group of 11 patients with coronary artery disease, FMD did not change after coronary angiography without coronary intervention. In conclusion, PCI induces endothelial dysfunction in forearm conductance vessels that can be reversed with tirofiban.

Aged↗

PubMed2002

Pulmonary endothelial dysfunction after cardiopulmonary bypass in neonatal pigs.

BACKGROUND: In neonatal pigs cardiopulmonary bypass (CPB) is associated with endothelial dysfunction in isolated large pulmonary arteries. It is, however, of great importance if this functional change extends to the small pulmonary resistance arteries, which are the key regulators of pulmonary flow and pressure. The aim of this study was to assess changes in pulmonary microvascular function after CPB using a clinically relevant pediatric procedure. METHODS: From three groups of neonatal pigs (CPB-, sham- and control group) pulmonary resistance arteries and systemic resistance arteries (from skeletal muscle) were isolated and mounted as ring preparations in wire myographs. Vessel diameters were less than 500 microm. Concentration-response curves were constructed for norepinephrine (NA), vasopressin (Vp), and the thromboxane A2-analog U46619, while the endothelium-dependent and -independent vasodilator functions were assessed as responses to acetylcholine and nitric oxide (NO). RESULTS: Maximum pulmonary vasodilator response to acetylcholine was attenuated after CPB compared with sham-operated and control animals (P=0.04). NO-induced relaxation, and contractile responses to NA, Vp, and U46619 were not influenced by CPB. In systemic arteries no changes in contractile or relaxant responses were seen after CPB. CONCLUSION: CPB seems to induce pulmonary endothelial dysfunction in pulmonary but not peripheral resistance arteries in neonatal piglets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Endothelial dysfunction of conduit arteries in insulin-dependent diabetes mellitus without microalbuminuria.

OBJECTIVE: Previous studies have shown that endothelial dysfunction, an early sign of atherosclerosis, occurs in animal models of diabetes mellitus and in resistance vessels of patients with insulin-dependent diabetes. In the present study we examined whether young patients with insulin-dependent diabetes without microalbuminuria present abnormal endothelial function of large peripheral arteries. METHODS: Twenty-six patients with insulin-dependent diabetes without microalbuminuria were compared with 26 normal controls and 5 patients with insulin-dependent diabetes with microalbuminuria. Brachial artery diameter was measured at rest, during reactive hyperaemic flow (endothelium-dependent dilatation) and after sublingual isosorbide dinitrate (endothelium-independent dilatation). RESULTS: Baseline artery diameter and flow as well as the degree of reactive hyperaemia were similar in all groups compared to controls. Flow-mediated dilatation was lower in patients with diabetes without microalbuminuria (5.8 +/- 7 vs 11 +/- 7%. P = 0.01) as well as in patients with diabetes without microalbuminuria (0.75 +/- 2.5 vs 11 +/- 7%, P = 0.003); nitrate-induced dilatation was normal in patients without microalbuminuria and attenuated in patients with microalbuminuria. In the group of diabetes patients without microalbuminuria, those with disease duration > 10 years and HbAlc > 6% had the worse endothelial function. CONCLUSIONS: Our results demonstrate that endothelial dysfunction of conduit arteries can be detected in patients with insulin-dependent diabetes mellitus without microalbuminuria, probably contributing to the high prevalence of atherosclerosis in these patients.

Adolescent↗

PubMed2004

Deletion of p66shc gene protects against age-related endothelial dysfunction.

BACKGROUND: Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66shc protein controls cellular responses to oxidative stress. Mice lacking p66shc (p66shc-/-) have increased resistance to ROS and a 30% prolonged life span. The present study investigates age-dependent changes of endothelial function in this model. METHODS AND RESULTS: Aortic rings from young and old p66shc-/- or wild-type (WT) mice were suspended for isometric tension recording. Nitric oxide (NO) release was measured by a porphyrinic microsensor. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), superoxide dismutase, and nitrotyrosine-containing proteins was assessed by Western blotting. Nitrotyrosine residues were also identified by immunohistochemistry. Superoxide (O2-) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66shc-/- mice. Accordingly, an age-related decline of NO release was found in WT but not in p66shc-/- mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66shc-/- mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O2- production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66shc-/- mice. CONCLUSIONS: We report that inactivation of the p66shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Endothelial dysfunction in the early stage of atherosclerosis precedes appearance of intimal lesions assessable with intravascular ultrasound.

The objective of this study was to clarify whether morphologic evaluation of the in vivo artery with intravascular ultrasound provides as sensitive a marker as endothelial dysfunction or microscopic histologic assessment. Endothelial dysfunction assessed with the changes in the vessel diameter during acetylcholine infusion has been used as a more sensitive marker of atherosclerosis than the angiographic estimates of morphologic structure of the vessel. Recent advent of intravascular ultrasound has provided such high-resolution images of the vessels that morphologic changes in the vessel structure are sensitively and accurately detected. Twenty-two rabbits were divided into three groups: six rabbits fed a cholesterol-rich diet for 2 weeks as the hypercholesterolemia group, eight rabbits fed with the diet for 8 weeks as the atherosclerosis group, and eight rabbits fed a normal diet as the normal group. After evaluating the atherosclerotic lesions by intravascular ultrasound, the cross-sectional area was measured in the baseline and during the infusion of acetylcholine (0.05, 0.5, and 5 micrograms/kg/min) and nitroglycerin (5 micrograms/kg/min). No atherosclerotic lesions were detectable with intravascular ultrasound in any rabbit despite the presence of microscopic intimal lesions in the vessels in the rabbits of the atherosclerosis group. The cross-sectional area increased during acetylcholine infusion in the rabbits of the normal and the hypercholesterolemia groups. In contrast, in the rabbits of the atherosclerosis group, the cross-sectional area did not significantly increase during acetylcholine infusion at the rate of 0.5 microgram/kg/min and even tended to decrease at the rate of 5 micrograms/kg/min (-3.8% +/- 3.7%, P < 0.05 vs the normal group). Dilating responses to nitroglycerin infusion were similar among all three groups. In conclusion, impairment of the endothelium-dependent vasodilating response assessed with intravascular ultrasound in the in vivo vessel precedes the appearance of echographic atherosclerotic findings. Thus intravascular ultrasound, if used in combination with drug intervention to assess endothelial function, would provide even more accurate assessment of the vessels than conventional intravascular ultrasound alone.

Acetylcholine↗

PubMed2006

Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats.

Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED(50) value was higher in ZDF (-6.80 +/- 0.05 vs. -7.11 +/- 0.05 log(10) mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED(50), -7.16 +/- 0.03 and -7.14 +/- 0.05 log(10) mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.

Acetophenones↗

PubMed2001

Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats.

1. The purpose of the present study was to determine the relationship between endothelial dysfunction and the endogenous inhibitor of nitric oxide synthase NG,NG'-asymmetric dimethylarginine (ADMA) in aged rats. 2. Studies were performed in male adult Sprague-Dawley rats (6 months old; n = 8) and in aged rats (20 months old; n = 8). Serum levels of ADMA and L-arginine were measured by high-performance liquid chromatography and responses of endothelium-intact aortic rings to acetylcholine (ACh) were tested. Nitric oxide synthase activity in kidney tissue and serum concentrations of nitrite, a stable end-product of nitric oxide, were assayed and serum contents of malondialdehyde, derived from lipid peroxidation and serum lipid and creatinine level were determined. 3. Serum levels of ADMA increased significantly in aged rats compared with adult rats (P < 0.01), whereas serum levels of L-arginine were similar in both groups (P = NS). Accordingly, the ratio of L-arginine/ADMA in old rats was lower than that in young rats (P < 0.01). Endothelium-dependent relaxation responses to ACh in aortic rings from aged rats were impaired and these impaired responses were improved by pre-incubation of aortic rings with L-arginine. 4. Nitric oxide synthase activity in the kidney, together with serum concentration of nitrite, was significantly decreased and serum contents of malondialdehyde, cholesterol and triglycerides were increased in old compared with young rats. However, the serum creatinine level was not significantly different between adult and aged rats. 5. Endogenous ADMA may be a contributor to age-related endothelial dysfunction and increases in endogenous ADMA may be linked to lipid peroxidation in aged rats.

Acetylcholine↗

PubMed2003

[Endothelial dysfunction and intima-media thickness in relation to cardiovascular risk factors in patients without clinical manifestations of atherosclerosis].

INTRODUCTION: Endothelial dysfunction and increased intima-media thickness are early findings in the development of atherosclerosis that can be assessed non-invasively by echography. The aim of this study was to investigate endothelial function and intima-media thickness, and the relation between these processes and cardiovascular risk factors in patients without clinical atherosclerosis. PATIENTS AND METHOD: Fifty-two subjects were studied, 39 with one or more cardiovascular risk factors and 13 with none. Vascular echography was performed to analyze endothelium-dependent vascular dilatation in the brachial artery and intima-media thickness in the common carotid artery. RESULTS: Compared to patients without risk factors, patients with cardiovascular risk factors more frequently had impaired vascular dilatation after ischemia, 11.98 4.61% vs 2.77 2.57%, (P<.0.001; mean difference = 9.21%, 95% CI of the difference 6.33-12.07%) and a greater intima-media thickness, 0.085 0.024% vs 0.057 0.014 cm (P < 0.0001; mean difference = 0.028 cm, 95% CI of the difference, 0.017-0.04 cm). There was a significant negative correlation between intimal-media thickness and endothelial dysfunction (r = -0.357; P<0.01). Linear regression analysis showed that intima-media thickness was independently related to age and the presence of hypertension, while endothelial function was related only with the presence of hypertension, smoking, and hyperlipoproteinemia. CONCLUSIONS: In patients without clinical atherosclerotic disease, cardiovascular risk factors were associated with impaired endothelial function and increased intima-media thickness. There was a negative correlation between endothelial-dependent vascular dilatation and intima-media thickness.

Aged↗

PubMed2000

Ischemic preconditioning and infarct mass: the effect of hypercholesterolemia and endothelial dysfunction.

In an experimental model of atherosclerosis we investigated whether rabbits fed an atherogenic diet (0.25% cholesterol, 3% coconut oil) develop endothelial dysfunction accompanied with increased infarct mass compared to normal fed rabbits and, whether hypercholesterolemia would interfere with the beneficial outcome of ischemic preconditioning observed in normal rabbits. After four weeks on either a normal or an atherogenic diet, New Zealand White rabbits (n=7 in each group) were subjected to 30 min of myocardial ischemia by occlusion of a branch of the left anterior descending coronary artery (LAD) followed by 2 hours of reperfusion (infarct studies). For ischemic preconditioning experiments, LAD was additionally occluded twice for 5 min followed by 10 min reperfusion before the long-lasting (30 min) ischemia. Infarct mass was evaluated by triphenyl-tetrazolium staining. Besides the assessment of aortic endothelium-dependent function and NO-release, aortic and cardiac vessels were inspected for atherosclerotic lesions. Total cholesterol serum levels in rabbits on an atherogenic diet were significantly higher (15.3+/-2.7 mmol/L) than those on a standard diet (0.65+/-0.08 mmol/L). The aortas and heart vessels were without any histological evidence of atherosclerosis, whereas endothelial dysfunction and significantly reduced calcium-ionophore stimulated endothelial NO-release were found in isolated aortic rings of hypercholesterolemic animals. Rabbits on a standard diet showed an infarct mass (related to the area at risk) of 41+/-33%, which was reduced to 21+/-2% by ischemic preconditioning (49% decrease, p<0.05). In rabbits on an atherogenic diet, infarct mass was significantly increased to 63+/-3% (52% increase versus standard diet). Interestingly, hypercholesterolemia did not affect the beneficial influence of ischemic preconditioning; infarct mass (21+/-3%, p<0.05 vs hypercholesterolemia) was similar to rabbits on a standard diet with ischemic preconditioning. Our results show that experimental hypercholesterolemia increases infarct mass in nonpreconditioned hearts but it does not interfere with the reduction of infarct mass elicited by preconditioning. This may suggest that NO produced by the endothelium is not a prime factor in the cardioprotective mechanism of preconditioning.

Animals↗