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PubMed2004

Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation.

Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors. Cardiovascular morbidity is elevated even in young women with PCOS. Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP) and endothelial dysfunction have recently been linked to development of atherosclerosis. We compared high-sensitivity (hs)CRP concentrations and endothelium dysfunction in 37 women with PCOS and 25 control subjects matched as a group for age and body mass index (BMI). Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli. Serum LH, testosterone, androstenedione, and fasting insulin levels were significantly higher in the PCOS group than the control group. The PCOS group was more insulin resistant than age- and BMI-matched control women. CRP concentrations were higher in PCOS women than the healthy control group (0.25 vs. 0.09 mg/dl). hsCRP concentrations were correlated with BMI, insulin sensitivity indices (homeostasis model assessment and quantitative insulin sensitivity check index), and endothelium-dependent vasodilation. The groups were well matched for baseline brachial artery diameter. There was a significant difference in endothelium-dependent (flow- mediated dilation) and endothelium-independent (sublingual nitroglycerin) vascular responses between the women with PCOS and the normal healthy control group (P = 0.002 and P = 0.01, respectively). Endothelium-dependent vasodilation was correlated with hsCRP concentrations and insulin resistance. In conclusion, this study is the first to demonstrate increased levels of hsCRP, endothelial dysfunction, and the relation with insulin resistance in young and normal-weight women with PCOS. Clinical strategies aimed at reducing insulin resistance may prevent early atherosclerosis in women with PCOS.

Adult↗

PubMed2001

Heart failure, redox alterations, and endothelial dysfunction.

Heart failure is characterized by neurohumoral alterations, such as activation of the sympathetic nervous system, stimulation of the renin-angiotensin system, increased activity of the endothelin system, increased production of norepinephrine, and increased circulating levels of cytokines. Oxidative stress is associated with the formation of reactive oxygen species (ROS). The myocardium has enzymes that stimulate ROS generation and enzymes with antioxidant effects. Several studies have suggested that ROS are increased in the failing heart. ROS may contribute to the pathophysiology of heart failure by initiating myocyte apoptosis and exerting direct negatively inotropic effects through the reduction of cytosolic intracellular free calcium. However, mechanisms such as endothelial dysfunction and inflammation have also been involved in the progression of heart failure. Antioxidants (eg, vitamin C) seem to improve endothelial functionality and reduce the inflammatory response in patients with heart failure. Therefore, in this review, we analyzed the involvement of ROS in the cellular and molecular mechanisms associated with endothelial dysfunction in heart failure.

Animals↗

PubMed2001

Endothelial dysfunction and decreased exercise tolerance in interferon-alpha therapy in chronic hepatitis C: relation between exercise hyperemia and endothelial function.

BACKGROUND: We previously reported that reversible endothelial dysfunction is caused by interferon-alpha therapy (IFN) in patients with chronic hepatitis C. In experimental studies, limb blood flow during exercise is reported to be dependent on endothelium-derived nitric oxide. HYPOTHESIS: The purpose of this study was to confirm the effect of IFN on endothelial function and to investigate whether exercise hyperemia is dependent on endothelial function in humans. METHODS: We performed symptom-limited exercise treadmill testing and measured flow-mediated vasodilation (FMD, endothelium-dependent vasodilation) and sublingual glyceryl-trinitrate-induced dilation (GTN-D, 0.3 mg, endothelium-independent vasodilation) in the brachial artery by using high-resolution ultrasound in 10 patients with chronic active hepatitis C (age 53 +/- 11 years, 2 men, 8 women) before and immediately after administration of recombinant interferon 2b (10 million U/day) for 4 weeks. RESULTS: There were no significant abnormal findings in any patients in routine studies of 24-h ambulatory electrocardiogram monitoring, two-dimensional echocardiography, and exercise treadmill testing both before and after treatment. Leg fatigue and exhaustion were the reasons for termination of exercise treadmill testing in each patient. Pressure rate product was calculated at rest and peak exercise. Interferon-alpha therapy significantly (p<0.05) decreased FMD (6.8 +/- 3.1 vs. 1.9 +/- 2.6%), exercise treadmill testing tolerance time (437 +/- 89 vs. 395 +/- 62 s) and peak pressure rate product (283 +/- 41 vs. 241 +/- 47 mmHg x beats/min x 10(-2)), but not GTN-D (13.4 +/- 5.4 vs. 17.0 +/- 5.5%). The change of FMD due to IFN significantly and highly correlated with exercise treadmill testing tolerance time (r = 0.86, p<0.001), but not with change of peak pressure rate product, suggesting that FMD is more closely related to the condition of the peripheral circulation than is cardiac performance. CONCLUSION: These results suggest that IFN in patients with chronic hepatitis C impairs endothelial function and exercise tolerance, and that endothelial function might be at least partly involved in exercise hyperemia in humans.

Adult↗

PubMed2001

Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.

BACKGROUND: Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular endothelial dysfunction (VED). METHODS: We carried out cross-sectional analysis of 23 dialysed and 16 non-dialysed CRF patients, 28 healthy controls, and 20 patients with stable angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen. RESULTS: Endothelium-dependent vasodilatation (EDV) was lower in angina, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared with controls, vWf (P<0.005) and adhesion molecules (vCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r=-0.43 to +0.70, all P<0.05). CONCLUSIONS: Endothelial dysfunction is unrelated to LDL oxidation, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.

Adult↗

PubMed2005

Systemic endothelial dysfunction as an early predictor of adverse outcome in heart failure.

OBJECTIVE: Endothelial dysfunction is an early event in the natural progression of heart failure. Increased oxidative stress has been linked to impaired endothelial function and both may play a prognostic role. METHODS AND RESULTS: Endothelium-dependent and endothelium-independent vasodilatation were determined in 289 patients with mild left ventricular dysfunction by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. Vascular effects of the coadministration of the antioxidant vitamin C at pharmacological doses (24 mg/min) were assessed. Occurrence of death, heart transplantation, and readmission with worsening heart failure were recorded as clinical outcome parameters during a follow-up period of 4.8 years. Patients experiencing adverse events (n=79) had lower vasodilator responses to acetylcholine (P<0.001) and to sodium nitroprusside (P=0.03) compared with patients without events. However, beneficial effects of vitamin C did not differ between both groups. Cox proportional hazards model demonstrated that age (P=0.001), renal function (P=0.001), and blunted acetylcholine-induced vasodilatation (P=0.007) remained independent predictors of adverse outcome. CONCLUSIONS: Impaired peripheral endothelial function independently predicts long-term adverse outcome in patients with early-stage heart failure. The findings suggest that assessment of peripheral endothelial function may represent an additional mean for risk stratification and therapy management in these patients.

Acetylcholine↗

PubMed2000

Endothelial dysfunction in the pulmonary vascular bed.

The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.

Animals↗

PubMed2005

Enhanced oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats exposed to fine particles.

The association between ambient particulate matter (PM) and cardiovascular diseases has been demonstrated in epidemiological studies. Recent studies suggest that diabetic patients are at greater risk for PM-associated cardiovascular events. Although diabetes and PM exposure individually have been reported to be associated with increased oxidative stress, inflammation, and endothelial dysfunction, it is not clear whether PM may induce synergistic interaction effects on these parameters in diabetics. Strepotozotocin-induced diabetic (n=4) and healthy (n=4) rats were intratracheally administered with PM2.5 collected from a busy traffic area in a dose of 200 microg suspended in 0.5 mL phosphate-buffered saline (PBS). The same number of rats was exposed to PBS as controls. Cell and differential counts and protein and lactate dehydrogenase activity were determined in bronchoalveolar lavage. Markers of 8-hydroxydeoxy-guanosine (8-OHdG), endothelin-1 (ET-1), and [nitrate+nitrite], an indicator of nitric oxide (NO) production, in addition to C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in peripheral blood were also determined. Our results showed that diabetic rats were associated with increased 8-OHdG, IL-6, and ET-1 decreased [nitrate+nitrite]. In nondiabetic rats PM exposure was also associated with increased 8-OHdG, IL-6, TNF-alpha, and CRP but decreased [nitrate+nitrite]. Interestingly, increases of 8-OHdG and ET-1 after PM exposure were more prominent in diabetic rats than in nondiabetic rats. The general linear model further indicated that there were interactions between diabetes and PM on 8-OHdG (P<0.01) and ET-1 (P=0.08). We suggest that PM exposure may enhance the risk of cardiovascular diseases through interaction between PM and diabetes on excess reactive oxygen species generation and endothelial dysfunction. These findings provide further support for previous epidemiological studies.

Animals↗

PubMedDate not supplied

Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme.

Hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain triggers several pathways of injury involved in the pathogenesis of diabetic complications [protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product (AGE) formation] by inhibiting glyceraldehyde- 3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. On the other hand, it inhibits GAPDH by poly(ADP-ribosy)lation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC isoforms, hexosaminase pathway flux, and AGE formation is prevented by blocking PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in preclinical models. PARP activation is present in microvasculature of human diabetic subjects. The oxidative/nitrosative stress-PARP pathway leads to diabetes-induced endothelial dysfunction, which may be an important underlying mechanism for the pathogenesis of other diabetic complications (cardiomyopathy, nephropathy, neuropathy, and retinopathy). This review focuses on the role of PARP in diabetic complications and the unique therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.

Animals↗

PubMed2000

Endothelial dysfunction in diabetes mellitus.

Diabetes mellitus and impaired glucose tolerance are linked to increased cardiovascular morbidity and mortality. Vascular disease is directly associated with plasma glucose levels, and reduction of these levels forestalls to a certain extent the vascular complications of diabetes, such as myocardial infarction, nephropathies, and retinopathies. In addition to hyperglycemia, there are other risk factors that play a prominent role, such as hypertension, hyperlipidemia, and genetic factors. Endothelial dysfunction is one of the major factors in the development of cardiovascular disease. The vascular endothelium regulates the blood flow by tightly controlling the coagulation system, cell-cell interaction, and vascular tone. These functions are disturbed in diabetic patients. In diabetics, endothelin-1 levels are increased, leading to vasoconstriction. Endothelin levels are directly related to plasma glucose levels. In addition, the endothelial cell-NO axis is disturbed. NO release and function are impaired. This seems to be dependent upon hyperglycemia and genetic factors. Impaired NO function also results in vasoconstriction. Furthermore, enhanced vascular permeability is seen in diabetics. This appears to be related to impaired endothelial cell relaxation and reactive oxygen species as well as advanced glycosylated end products (AGEs). The complex changes seen in diabetes and even prediabetes are therefore related to numerous derailments related to endothelial dysfunction, and no single therapeutic approach is likely to solve the problem of vascular complications.

Diabetes Mellitus↗

PubMed2001

Vascular endothelial dysfunction: does tetrahydrobiopterin play a role?

Tetrahydrobiopterin is one of the most potent naturally occurring reducing agents and an essential cofactor required for enzymatic activity of nitric oxide synthase (NOS). The exact role of tetrahydrobiopterin in the control of NOS catalytic activity is not completely understood. Existing evidence suggests that it can act as allosteric and redox cofactors. Suboptimal concentration of tetrahydrobiopterin reduces formation of nitric oxide and favors "uncoupling" of NOS leading to NOS-mediated reduction of oxygen and formation of superoxide anions and hydrogen peroxide. Recent findings suggest that accelerated catabolism of tetrahydrobiopterin in arteries exposed to oxidative stress may contribute to pathogenesis of endothelial dysfunction present in arteries exposed to hypertension, hypercholesterolemia, diabetes, smoking, and ischemia-reperfusion. Beneficial effects of acute and chronic tetrahydrobiopterin supplementation on endothelial function have been reported in experimental animals and humans. Furthermore, it appears that beneficial effects of some antioxidants (e.g., vitamin C) on vascular function could be mediated via increased intracellular concentration of tetrahydrobiopterin. In this review, the potential role of tetrahydrobiopterin in the pathogenesis of vascular endothelial dysfunction and mechanisms underlying beneficial vascular effects of tetrahydrobiopterin will be discussed.

Animals↗

PubMed1999

The protective effect of K+ channel openers on beta-amyloid induced cerebrovascular endothelial dysfunction.

Amyloid angiopathy is characterized by amyloid beta-peptide (A beta) deposition and may contribute to the cerebrovascular abnormalities that precede the onset of Alzheimer's Disease (AD). That aberrant potassium (K+) channel function occurs in AD patients is supported by deleterious effects of A beta on normal fibroblast K+ channels and prevention of A beta-induced toxicity by potassium channel openers (KCOs) in neuronal cell culture. We report here that KCOs protect cerebral and peripheral vessels against the endothelial damage induced by A beta. Pressurized posterior cerebral artery and aortic ring segments from the rat were constricted and then relaxed with the endothelium-dependent vasodilator acetylcholine before and after incubation with A beta (10(-6) M), or pre-treatment with KCOs before the addition of beta-amyloid. Vessels treated with A beta exhibited features of endothelial dysfunction: enhanced vasoconstriction and diminished endothelium-dependent vasodilation. Pre-treatment with KCOs significantly antagonized the A beta effect in both cerebral and aortic vessel segments. This protection was provided by both KCa and KATP channel openers. Endothelial damage by A beta and protection by KCOs was verified by electron microscopy. The K+ channel blocker, TEA, reversed the protective effect of KCO. The results suggest that potassium channel openers protect against A beta induced endothelial dysfunction and that KCOs may have a role in the treatment of degenerative cerebrovascular disease as seen in stroke, AD and aging.

Acetylcholine↗

PubMed1997

Endothelial dysfunction and cardiorenal injury in experimental salt-sensitive hypertension: effects of antihypertensive therapy.

BACKGROUND: Pharmacological control of hypertension has contributed to a significant decrease in cardiovascular morbidity and mortality, although the beneficial effect on cardiac and renal diseases has been far more modest than the reduction in stroke. The endothelium plays a crucial homeostatic role in the regulation of vascular tone thrombogenesis and vascular remodeling. We studied the relationship between endothelial dysfunction and cardiorenal injury in hypertensive rats and evaluated the effects of two classes of antihypertensive agents commonly used in the clinical setting, a diuretic (DIU) and an ACE inhibitor (CEI). METHODS AND RESULTS: Dahl salt-sensitive rats (DS) given high dietary salt (4% NaCl) developed hypertension (systolic blood pressure [SBP], 218+/-9 versus 147+/-3 mm Hg in DS given 0.5% NaCl; P<.001), which was associated with impaired endothelium-dependent relaxations (EDRs) in aortic rings (ED50, 5.44+/-.18 versus 7.51+/-.10; P<.05) and mesenteric vessels (area under the curve, 299+/-11 versus 217+/-11 arbitrary units; P<.05). Hypertensive DS also demonstrated depressed nitric oxide synthase activity in the aorta (0.76+/-.15 versus 2.83+/-.17 nmol x min(-1) x g protein(-1); P<.05), left ventricular hypertrophy (0.43+/-.02 versus 0.29+/-.02 g ventricular weight/100 g body weight; P<.05), glomerular injury (histological injury score: 151+/-8 versus 11+/-2; P<.05), and increased urinary protein excretion (95+/-21 versus 25+/-5 mg/24 hours; P<.05). Treatment of DS rats with the CEI perindopril (4.56 mg x kg(-1) x d(-1)) did not affect SBP (225+/-6 mm Hg) but modestly improved EDR (ED50: 6.07+/-.37; P<.05 versus hypertensive DS) as well as proteinuria and glomerular histology. Addition of the DIU indapamide (1.44 mg x kg(-1) x d(-1)) normalized SBP (151+/-2 mm Hg; P<.05), EDR (ED50, 7.33+/-.08; P<.05), left ventricular hypertrophy (0.27+/-.01 g/100 g body weight; P<.05), and proteinuria (31+/-4 mg/24 hours; P<.05) and prevented glomerular injury (injury score: 30+/-2; P<.05). Monotherapy with DIU reduced SBP (175+/-3 mm Hg; P<.05) and normalized EDR and left ventricular hypertrophy but did not provide effective renal protection. In hypertensive DS, impaired EDR and left ventricular hypertrophy were positively correlated with SBP. In addition, we found a significant correlation between cardiac hypertrophy and endothelial dysfunction. Indeed, a hierarchical regression analysis revealed that impaired aortic EDR, and therefore decreased aortic compliance, positively contributed to left ventricular hypertrophy in addition to but independently of SBP [F(2,37)=6.29; P=.004]. CONCLUSIONS: These studies suggest a dissociation of the endothelial, cardiac, and renal effects of antihypertensive therapy in hypertension and may explain the variable success of antihypertensive regimens in treating hypertension while preventing cardiac and renal damage.

Acetylcholine↗

PubMedDate not supplied

Levels of plasma total adrenomedullin are related with two acute phase inflammatory reactants (fibrinogen and sialic acid) but not with markers of endothelial dysfunction in Type 1 diabetes Adrenomedullin and vascular risk factors in Type 1 DM.

Adrenomedullin (AM), an ubiquitous regulatory peptide with different actions, is known to be elevated in different clinical situations, including diabetes mellitus (DM), but its potential role in the pathogenesis of diabetic vascular complications is not clear. In the present study, we examined plasma total AM levels, and their association with different markers of endothelial dysfunction and with other established risk factors for cardiovascular diseases, in patients with Type 1 DM. We studied a total of 155 patients, 117 patients without any kind of vascular complications, 24 patients with retinopathy only, and 14 patients with retinopathy and microalbuminuria but normal renal function. None of them had clinical evidence of atherosclerotic disease. Compared with the control group (64 healthy participants), patients had raised fibrinogen, soluble E-selectin ((s)E-selectin), vascular cellular adhesion molecule (VCAM), angiotensin converting enzyme (ACE), and von Willebrand factor (vWf) (P<.001 in all cases), but plasma total AM, endothelin (ET), sialic acid, and homocysteine were not raised. In the diabetic group, AM levels correlated significantly with sialic acid (r=.16; P<.05), but a more significant correlation was found with fibrinogen (r=.30; P<.001). No correlation was found with the other parameters studied. In summary, plasma total AM levels seem to correlate with inflammatory markers but not with endothelial dysfunction markers in Type 1 diabetic patients without atherosclerotic disease.

Adrenomedullin↗

PubMed2002

Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies.

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy one can detect neurohormonal activation and signs for intravascular volume expansion. These so called pseudotolerance mechanisms may compromise nitroglycerin's vasodilatory effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin's vasorelaxant potency suggesting changes in intrinsic mechanisms of the tolerant vasculature itself may also contribute to tolerance. More recent experimental work defined new mechanisms of tolerance such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of the intracellular second messenger protein kinase C. As potential superoxide producing enzymes, the NADPH oxidase and the nitric oxide synthase have been identified. Nitroglycerin-induced stimulation of oxygen-derived free radicals together with NO derived from nitroglycerin may lead to the formation of peroxynitrite, which may be responsible for the development of tolerance as well as for the development of cross tolerance to endothelium-dependent vasodilators. The oxidative stress concept of tolerance and cross tolerance may explain why radical scavengers such as vitamin C or substances which reduce oxidative stress, such as ACE-inhibitors, AT1 receptor blockers or folic acid, are able to beneficially influence both tolerance and nitroglycerin-induced endothelial dysfunction. New aspects concerning the role of oxidative stress in nitrate tolerance and nitrate induced endothelial dysfunction and the consequences for the NO/cyclicGMP downstream target, the cGMP-dependent protein kinase will be discussed.

Animals↗

PubMedDate not supplied

The link between microalbuminuria, endothelial dysfunction and cardiovascular disease in diabetes.

Microalbuminuria (MA) i.e. slightly elevated albumin excretion in the urine, is now considered to be an atherosclerotic risk factor. MA predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. Although microalbuminuria is associated with a certain degree of sub-clinical artherosclerotic damage, it is not known how early in the atherosclerotic process microalbuminuria appears. Epidemiological studies have shown an association between MA and insulin resistance, obesity, salt sensitivity and dyslipidaemia in patients with essential hypertension and diabetes. Patients with microalbuminuria are also characterised by an increased prevalence of left ventricular hypertrophy and retinal microvascular lesions. Microalbuminuria, is associated with an excess of other cardiovascular risk factors. The mechanisms linking microalbuminuria and risk for cardiovascular disease are not fully understood, but in subjects at risk it may be related to increased transvascular leakiness of albumin in systemic as well as renal vessels. A recent concept is that microalbuminuria is a marker of extensive endothelial dysfunction or generalised vasculopathy, which may lead to heightened atherogenic states. One possible explanation is that endothelial dysfunction might promote increased penetration of atherogenic lipoprotein particles in the arterial wall, but glycaemic status, insulin resistance, procoagulant state and adhesion molecules have all been implicated in the pathogenesis. Current evidence suggests that tight blood pressure control may reduce the risk of microalbuminuria in diabetic patients with hypertension and that inhibitors of the rennin-angiotensin system (RAS) can prevent or delay the progression of microalbuminuria to overt nephropathy in normotensive persons. ACE inhibitors are currently recognised as first-line antihypertensive therapy in diabetic patients with proteinuria, and these agents afford unique benefits in modifying the progression and severity of cardiovascular disease (CVD) as well as of diabetic nephropathy. Whether albuminuria is a risk factor or just a marker for CV disease, it identifies the high-risk diabetic patient who should be targeted for early, aggressive intervention against proven risk factors. If persistent microalbuminuria is confirmed, strict blood pressure control with added RAS inhibition should be pursued in an attempt to stabilise or even reduce microalbuminuria, preserve kidney function and possibly improve cardiovascular risk.

Albuminuria↗

PubMed1998

Endothelial dysfunction in hypertension.

The endothelium modulates the tone of the underlying vascular smooth muscle by releasing relaxing factors, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). In most types of hypertension, endothelium-dependent relaxations are impaired because of a reduced production and/or action of endothelium-derived NO and EDHF. In essential hypertension, endothelium-dependent relaxations are reduced because of a concomitant release of vasoconstrictor prostanoids (endoperoxides and thromboxane A2). These prostanoids may be produced in the vascular smooth muscle rather than in the endothelium. The endothelial dysfunction observed in hypertension is likely to be a consequence rather than a cause of the disease, representing premature aging of the blood vessels due to the chronic exposure to the high blood pressure. The endothelial dysfunction can be improved by antihypertensive therapy, favoring the prevention of the occurrence of vascular complications in hypertension.

Animals↗

PubMed2003

Cerebral endothelial dysfunction in diabetes: intravital microscopic analysis using streptozotocin-induced diabetic rats.

Endothelial function of cerebral microvessel in diabetes was evaluated using streptozotocin (STZ)-induced diabetic rats (blood glucose of >/=300 mg/dl). At 36 weeks after STZ injection, the rats were anesthetized with sodium pentobarbital. The cerebral microcirculation in control and STZ groups was directly observed, using intravital fluorescence videomicroscopy. To evaluate the endothelial function in vivo, the number of leukocytes adhering to postcapillary venules were counted, and cerebral arteriolar responses to acetylcholine (ACh) and nitroglycerine (NTG) were examined. The results showed that the leukocyte adhesion to cerebral postcapillary venular endothelium increased significantly in STZ-rats, compared with control rats. The vasodilatory responses of cerebral arterioles (20-30 microm) to ACh decreased significantly in STZ-rats, compared with control rats (p<0.01), but the responses to NTG did not alter in diabetes. These results indicate that the impaired responses should occur on the endothelial cell. In conclusion, endothelial dysfunction induced in diabetes are characterized by impaired endothelium-dependent vasodilation and increased leukocyte adhesion to endothelial cells.

Acetylcholine↗

PubMed1995

Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease.

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.

Adult↗