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Results for “endothelial dysfunction”

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PubMed2000

Cyclo-oxygenase-1 and -2 contribution to endothelial dysfunction in ageing.

Experiments were designed to investigate the role of cyclo-oxygenase isoforms in endothelial dysfunction in ageing. Aortic rings with endothelium of aged and young (24 vs 4 month-old) Wistar rats, were mounted in organ chambers for the recording of changes in isometric tension. In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.3 microM), NS-398 (a preferential COX-2 inhibitor; 1 microM), SQ-29548 (a thromboxane-receptor antagonist; 1 microM), nor valeryl-salicylate (VAS, a preferential inhibitor of COX-1; 3 mM). In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01 - 1 microM ACh), followed by a contraction (3 - 100 microM ACh). Indomethacin, NS-398 and SQ-29548, but not VAS, augmented the first phase. Indomethacin, VAS, NS-398 and SQ-29548 decreased the contractions to high ACh concentrations. Then, the sensitivity to thromboxane receptor activation was investigated with U-46619. The results show comparable EC(50) values in young and aged rats. In aged rats, the ACh-stimulated release of prostacyclin, prostaglandin F(2alpha) and thromboxane A(2) was decreased by either indomethacin, NS-398, VAS or endothelium removal. However, in young animals, the ACh-stimulated release of prostacyclin and prostaglandin F(2alpha) were smaller than in older animals and remained unaffected by NS-398. Aortic endothelial cells from aged - but not young - rats express COX-2 isoform, while COX-1 labelling was observed in endothelial cells from both young and aged rats. These data demonstrate the active contribution of COX-1 and -2 in endothelial dysfunction associated with ageing.

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

PubMed2001

HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184+/-5 versus 204+/-6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II-induced vasoconstriction. Angiotensin type 1 (AT(1)) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription-polymerase chain reaction. Atorvastatin treatment downregulated aortic AT(1) receptor mRNA expression to 44+/-12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63+/-7% of control. Aortic AT(1) receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62+/-12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT(1) receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138+/-7% of control) and an enhanced ecNOS activity in the vessel wall (209+/-46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT(1) receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT(1) receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.

Angiotensin Receptor Antagonists↗

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↗

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↗

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↗

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↗

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↗

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↗

PubMed2001

Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats.

BACKGROUND: Postmenopausal estrogen deficiency is associated with an increased cardiovascular risk, hypertension, and oxidative stress. Angiotensin type 1 (AT(1)) receptor regulation is involved in the pathogenesis of atherosclerosis. To characterize vascular function, oxidative stress, and AT(1) receptor regulation during estrogen deficiency, ovariectomized spontaneously hypertensive rats (SHR) were investigated in comparison with sham-operated animals and with ovariectomized rats receiving estrogen replacement therapy with 17beta-estradiol. METHODS AND RESULTS: Arterial blood pressure was similar in all 3 groups investigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Estrogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vascular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. Estrogen substitution normalized the production of free radicals in the vessel wall. Vascular AT(1) receptor expression was significantly upregulated by estrogen deficiency, as shown by quantitative reverse transcription-polymerase chain reaction, whereas endothelial NO synthase mRNA expression and NO release were unchanged. Five-week treatment of the animals with the AT(1) receptor antagonist irbesartan prevented endothelial dysfunction in ovariectomized rats and normalized the vascular production of free radicals. CONCLUSIONS: In SHR, estrogen deficiency leads to increased vascular free radical production and enhanced angiotensin II-induced vasoconstriction via increased vascular AT(1) receptor expression, resulting in endothelial dysfunction. Estrogen replacement therapy and AT(1) receptor antagonism prevent these pathological changes. Therefore, estrogen deficiency-induced AT(1) receptor overexpression and oxidative stress may play an important role in cardiovascular diseases associated with menopause.

Angiotensin II↗

PubMed2002

Endothelial dysfunction in chronic heart failure: clinical and therapeutic implications.

Chronic heart failure is a complex clinical syndrome in which abnormal vascular endothelial function has been shown to occur at both the experimental and clinical levels. Alterations in endothelial function may contribute to the increased vasomotor tone and to the vascular remodeling process observed in patients with chronic heart failure. Reduced shear stress, increased activity of the various vasoconstricting neurohormonal systems, and increased levels of proinflammatory cytokines promote endothelial dysfunction in chronic heart failure. This article summarizes the major mechanisms implicated in the pathophysiology of abnormal endothelial function in chronic heart failure, as well as the novel therapeutic interventions aimed at reducing endothelial dysfunction in patients with the syndrome.

Journal Article↗

PubMed2002

Mechanisms of amelioration of glucose-induced endothelial dysfunction following inhibition of protein kinase C in vivo.

Inhibition of protein kinase C (PKC) activity has been shown to improve the endothelial dysfunction associated with hyperglycemia and diabetes. The mechanisms by which inhibition of PKC activity ameliorates endothelial dysfunction in diabetes are not well understood. We investigated the relationship between PKC inhibition and leukocyte-endothelium interaction in the microcirculation of the rat mesentery exposed to 25 mmol/l D-glucose for 12 h. D-Glucose significantly increased leukocyte rolling and adherence in mesenteric postcapillary venules. This proinflammatory action of D-glucose was inhibited by superfusion of the mesentery with 30 nmol/l bisindolylmaleimide-I, a potent, selective PKC inhibitor (P < 0.01 vs. glucose alone after 90 min of superfusion). Immunohistochemical localization of the cell adhesion molecules P-selectin and intercellular adhesion molecule (ICAM)-1 on the endothelial cell surface was increased by 25 mmol/l D-glucose (P < 0.001 vs. control tissue from rats injected with saline), which was significantly reduced by bisindolylmaleimide-I (P < 0.001 vs. glucose alone). In addition, we studied adhesion of isolated neutrophils to rat superior mesenteric artery (SMA) vascular segments stimulated with 25 mmol/l D-glucose for 4 h in vitro. Pretreatment of the SMA vascular segments with either superoxide dismutase enzyme (100 units/ml) or bisindolylmaleimide-I (30 nmol/l) equally inhibited the increased neutrophil adherence to SMA endothelium in response to glucose. These data demonstrate that inhibition of PKC activity reduces leukocyte-endothelium interactions by suppressing surface expression of endothelial cell adhesion molecules in response to increased oxidative stress. These results provide a novel mechanism by which inhibition of PKC activity improves endothelial cell function in hyperglycemia and diabetes.

Animals↗

PubMed2001

Coronary vasodilation and improvement in endothelial dysfunction with endothelin ET(A) receptor blockade.

The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ET(A) receptor activation. We hypothesized that ET(A) receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclerosis or its risk factors. Epicardial diameter (D) and Doppler flow velocity were measured, and coronary vascular resistance (CVR) was calculated during intracoronary infusions of acetylcholine (ACH) and sodium nitroprusside (SNP), and during cold pressor testing, before and after a 60-minute intracoronary infusion of the ET(A) receptor antagonist BQ-123. BQ-123 dilated the coronary circulation; D increased by 5.6+/-1.0% (P<0.0001), and CVR fell by 12+/-3% (P<0.01). The D response to ACH, corrected for the SNP response, improved in segments that constricted with ACH at baseline (P=0.03), whereas segments that initially dilated with ACH did not change with BQ-123 (P=NS). Improvement in D and CVR responses to ACH with BQ-123 inversely correlated with baseline ACH responses (r=-0.44 [P=0.006] and r=-0.78 [P=0.001], respectively), indicating greater improvement in those with endothelial dysfunction. Similarly, cold pressor testing-mediated epicardial vasoconstriction (-2.0+/-1.1%) was reversed after BQ-123 (+1.0+/-0.7%), especially in dysfunctional segments (from -5.6+/-0.9% to +2.2+/-0.9%, P<0.001). There was no correlation between any risk factor and the response to BQ-123. An arteriovenous difference in ET-1 levels developed after BQ-123, which was consistent with enhanced cardiac clearance of ET-1, probably via ET(B) receptors. Thus, ET-1 acting via the ET(A) receptor contributes to basal human coronary vasoconstrictor tone and endothelial dysfunction. This suggests that ET(A) receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.

Acetylcholine↗