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Results for “Endothelial function”

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PubMed1993

Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass.

BACKGROUND: Increased pulmonary vascular resistance is common in congenital heart disease and is exacerbated by cardiopulmonary bypass (CPB). We investigated whether CPB is responsible for pulmonary endothelial dysfunction and contributes to postoperative pulmonary hypertension. METHODS AND RESULTS: We infused the endothelium-dependent vasodilator acetylcholine (ACH) into the pulmonary circulation of pulmonary hypertensive children with congenital heart disease either before (n = 12) or after (n = 22) surgical repair on CPB. The dose response to ACH (10(-9) to 10(-6) M) was recorded for all hemodynamic variables. Nine additional postoperative patients were studied with ACH followed by inhalation of 80 ppm nitric oxide, an endothelium-independent smooth muscle relaxant. Plasma levels of cyclic GMP (cGMP) were measured before and after ACH and nitric oxide administration. Pulmonary vasodilation with 10(-6) M ACH was seen in all preoperative patients but was markedly attenuated in postoperative patients. Baseline pulmonary vascular resistance (5.6 +/- 1.0 U x m2) fell 46 +/- 5% in preoperative patients but declined only 11 +/- 4% from baseline (5.8 +/- 0.9 U x m2) in postoperative patients (P < .002). However, inhalation of 80 ppm nitric oxide after ACH infusion in postoperative patients lowered pulmonary vascular resistance by 33 +/- 4% (P < .0002 compared with postoperative ACH response) with minimal effects on the systemic circulation. This finding suggests that the capacity for smooth muscle relaxation and pulmonary vasodilation was present in postoperative patients but could not be induced by ACH. Plasma levels of cGMP in postoperative patients were unchanged after acetylcholine infusion but rose more than threefold during pulmonary vasodilation with nitric oxide (P < .0001). This finding is consistent with the purported role of cGMP as the second messenger effecting smooth muscle relaxation in this process. CONCLUSIONS: CPB may be responsible for postoperative dysfunction of the pulmonary endothelial cell and may contribute to postoperative pulmonary hypertension in children. Inhaled nitric oxide is a potent pulmonary vasodilator after CPB with minimal systemic circulatory effects. It may have important diagnostic and therapeutic applications in patients with congenital heart disease.

Acetylcholine↗

PubMed2005

The effect of statin therapy on endothelial function in type 2 diabetes without manifest cardiovascular disease.

OBJECTIVE: Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes and is preceded by endothelial dysfunction. Flow-mediated dilation (FMD) is a noninvasive technique for measuring endothelial dysfunction. We aimed to determine the effect of long-term statin therapy versus placebo on FMD in patients with type 2 diabetes without manifest CVD. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind trial was performed with 250 type 2 diabetic patients. Patients were given 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, the 0.4 mg cerivastatin was replaced by 20 mg simvastatin, without deblinding the study. The primary end point was the change in FMD, measured by B-mode ultrasound, after 2 years. RESULTS: Determinants of baseline FMD were diabetes duration, common carotid intima-media thickness, and brachial artery diameter. FMD at baseline was 1.51% in the placebo group and 1.66% in the statin group and did not change significantly after 2 years. CONCLUSIONS: The 2-year statin therapy had no effect on FMD in type 2 diabetes. Statin-induced improvement of cardiovascular risk in patients with type 2 diabetes may be mediated through mechanisms other than increased nitric oxide availability.

Blood Flow Velocity↗

PubMed2004

A walnut diet improves endothelial function in hypercholesterolemic subjects: a randomized crossover trial.

BACKGROUND: Epidemiological studies suggest that nut intake decreases coronary artery disease (CAD) risk. Nuts have a cholesterol-lowering effect that partly explains this benefit. Endothelial dysfunction is associated with CAD and its risk factors and is reversed by antioxidants and marine n-3 fatty acids. Walnuts are a rich source of both antioxidants and alpha-linolenic acid, a plant n-3 fatty acid. METHODS AND RESULTS: To test the hypothesis that walnut intake will reverse endothelial dysfunction, we randomized in a crossover design 21 hypercholesterolemic men and women to a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced approximately 32% of the energy from monounsaturated fat. Participants followed each diet for 4 weeks. After each intervention, we obtained fasting blood and performed ultrasound measurements of brachial artery vasomotor function. Eighteen subjects completing the protocol had suitable ultrasound studies. Compared with the Mediterranean diet, the walnut diet improved endothelium-dependent vasodilation and reduced levels of vascular cell adhesion molecule-1 (P<0.05 for both). Endothelium-independent vasodilation and levels of intercellular adhesion molecule-1, C-reactive protein, homocysteine, and oxidation biomarkers were similar after each diet. The walnut diet significantly reduced total cholesterol (-4.4+/-7.4%) and LDL cholesterol (-6.4+/-10.0%) (P<0.05 for both). Cholesterol reductions correlated with increases of both dietary alpha-linolenic acid and LDL gamma-tocopherol content, and changes of endothelium-dependent vasodilation correlated with those of cholesterol-to-HDL ratios (P<0.05 for all). CONCLUSIONS: Substituting walnuts for monounsaturated fat in a Mediterranean diet improves endothelium-dependent vasodilation in hypercholesterolemic subjects. This finding might explain the cardioprotective effect of nut intake beyond cholesterol lowering.

Adult↗

PubMed2003

Soy protein with isoflavones has favorable effects on endothelial function that are independent of lipid and antioxidant effects in healthy postmenopausal women.

BACKGROUND: Controversy exists about the ability of soy protein and isoflavones to modulate vascular reactivity and biochemical cardiovascular disease risk markers in healthy, normolipidemic postmenopausal women. OBJECTIVE: The objective was to investigate whether the consumption of soy protein with isoflavones would result in improved vascular reactivity and decreased biochemical markers of endothelial dysfunction and inflammation, independent of enhanced lipid and antioxidant effects. DESIGN: Healthy postmenopausal women (n = 28) were enrolled in a randomized, double-blind, crossover study, and they consumed 25 g of 3 protein products/d for 6 wk each, with intervening washout periods. The products were isolated soy protein with isoflavones, ethanol-washed isolated soy protein with trace isoflavones, and total milk protein, which supplied 107, 2, and 0 mg total isoflavone (aglycone) units/d, respectively. We studied vascular function by using brachial artery reactivity values, plasma concentrations of vasoactive factors, endothelial inflammatory markers, and plasma isoflavone concentrations. The resistance of whole plasma and isolated LDL to copper-mediated oxidation was measured by conjugated diene formation. RESULTS: Postocclusion peak flow velocity of the brachial artery was significantly (P = 0.03) lower after treatment with isolated soy protein with isoflavones, which is consistent with a vasodilatory response, than after treatment with total milk protein. Plasma isoflavones and metabolites were significantly (P < 0.01) higher after treatment with isolated soy protein with isoflavones. There were no significant changes in biochemical cardiovascular disease risk markers or conjugated diene formation between the 3 dietary groups. CONCLUSION: Daily consumption of soy protein with isoflavones can result in positive vascular effects that are independent of lipid and antioxidant effects in healthy postmenopausal women.

Antioxidants↗

PubMed2004

Effect of classic preconditioning and diazoxide on endothelial function and O2- and NO generation in the post-ischemic guinea-pig heart.

OBJECTIVES: A hypothesis was tested that a reaction product between superoxide (O2-) and nitric oxide (NO) mediates post-ischemic coronary endothelial dysfunction that ischemic preconditioning (IPC) protects the endothelium by preventing post-ischemic cardiac O2- and/or NO formation, and that the opening of the mitochondrial ATP-dependent potassium channel (mKATP) plays a role in the mechanism of IPC. METHODS: Langendorff-perfused guinea-pig hearts were subjected either to 30 min global ischemia/30 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min wash-out of mKATP opener, diazoxide (0.5 microM). Coronary flow responses to acetylcholine (ACh) and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Myocardial outflow of O2- and NO, and functional recoveries were followed during reperfusion. RESULTS: IR impaired the ACh response by approximately 60% and augmented cardiac O2- and NO outflow. Superoxide dismutase (150 U/ml) and NO synthase inhibitor, l-NMMA (100 microM) inhibited the burst of O2- and NO, respectively, and afforded partial preservation of the ACh response in IR hearts. NO scavenger, oxyhemoglobin (25 microM), afforded similar endothelial protection. IPC and diazoxide preconditioning attenuated post-ischemic burst of O2-, but not of NO, and afforded a complete endothelial protection. Diazoxide given after 30-min ischemia increased the O2- burst and was not protective. The effects of IPC and diazoxide preconditioning were not affected by HMR-1098 (25 microM), a selective blocker of plasmalemmal KATP, and were abolished by glibenclamide (0.6 microM) and 5-hydroxydecanoate (100 microM), a nonselective and selective mK(ATP) blocker, respectively. 5-Hydroxydecanoate produced similar effects, whether it was given as a continuous treatment or was washed out prior to IR. CONCLUSION: The results suggest that in guinea-pig heart: (i) a reaction product between O2- and NO mediates the post-ischemic endothelial dysfunction; (ii) the mK(ATP) opening serves as a trigger of the IPC and diazoxide protection; and (iii) the mK(ATP) opening protects the endothelium in the mechanism that involves the attenuation of the O2- burst at reperfusion.

Animals↗

PubMed2005

Indinavir impairs endothelial function in healthy HIV-negative men.

BACKGROUND: Potent antiretroviral treatment has drastically reduced mortality in HIV-infected patients but may accelerate atherosclerotic disease, which could be partially mediated via endothelial dysfunction. METHODS: In 8 HIV-negative healthy males, leg blood flow responses to intraartery infusions of methacholine chloride (Mch), sodium nitroprusside, and NG-mono-methyl-L-arginine (L-NMMA) were measured before and after 4 weeks of daily oral indinavir. In the same subjects, we also assessed the effect of indinavir on lipids, insulin sensitivity, markers of inflammation, as well as oxidative stress. RESULTS: After 4 weeks of indinavir, the endothelium-dependent response to methacholine chloride was impaired (195% +/- 38% vs 83% +/- 13%, P < .05), the response to NG-mono-methyl-L-arginine (nitric oxide-dependent tone) was nearly abrogated (-30% +/- 4% vs -1% +/- 11%, P < .05), whereas the endothelium-independent response to sodium nitroprusside remained unchanged. Fasting insulin levels increased from 5.8 +/- 1.2 to 7.0 +/- 1.4 microU/mL (P < .05), and HOMA-IR scores increased from 1.3 +/- 0.3 to 1.6 +/- 0.3 U (P < .05). There were no changes in blood pressure, lipids, markers of inflammation, or oxidative stress. CONCLUSIONS: Four weeks of the HIV-1 protease inhibitor indinavir, in the absence of HIV-1 infection, causes vascular dysfunction most likely at the level of endothelial nitric oxide production. The vascular dysfunction may be mediated partially by the concomitant induction of insulin resistance but other mechanisms cannot be ruled out.

Adult↗

PubMed2004

Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene.

Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.

Acetylcholine↗

PubMed2007

Endothelial function and white matter hyperintensities in older adults with cardiovascular disease.

BACKGROUND AND PURPOSE: The presence of white matter hyperintensities on brain MRI is common among elderly individuals. Previous research suggests that cardiovascular risk factors are associated with increased white matter hyperintensities. Examining the role of direct physiological measures of vascular function will help to clarify the vascular mechanisms related to white matter hyperintensities. The aim of the present study was to examine the association between endothelial-dependent and endothelial-independent vasodilatation and white matter hyperintensity volume. METHODS: Twenty-five older adults with a range of cardiovascular diseases underwent brain MRI and completed assessments of blood vessel integrity using endothelial-dependent and independent flow-mediated dilation of the brachial artery. A semi-automated pixel-based method was used to quantify total brain volume and white matter hyperintensity volume, with white matter hyperintensity volume corrected for total brain volume. The association between measures of flow-mediated dilation and log-transformed white matter hyperintensities was examined. RESULTS: Correlation analysis revealed that endothelial-dependent vasodilatation was significantly and inversely associated with white matter hyperintensity volume. In contrast, endothelial-independent vasodilatation was not associated with white matter hyperintensities. Neither endothelial-dependent nor endothelial-independent vasodilatation was associated with total brain volume. CONCLUSIONS: These data provide preliminary evidence that the integrity of the vascular endothelium is associated with white matter hyperintensities in older adults with cardiovascular disease. Impaired vascular function may be one mechanism that contributes to the development of white matter hyperintensities in the brain. Additional longitudinal research combining measures of vessel function, neuroimaging and cognition will be helpful in clarifying this potential mechanism.

Aged↗

PubMed2004

Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease.

OBJECTIVE: Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors. METHODS AND RESULTS: Sixteen CAD patients had reduced CD34(+)/CD133(+) (0.0224+/-0.0063% versus 0.121+/-0.038% mononuclear cells [MNCs], P<0.01) and CD133(+)/VEGFR-2(+) cells, consistent with EPC phenotype (0.00033+/-0.00015% versus 0.0017+/-0.0006% MNCs, P<0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2+/-1/well) compared with 16 healthy subjects at high risk (13+/-4/well, P<0.05) or 14 at low risk (22+/-3/well, P<0.001) for CAD. G-CSF 10 microg/kg per day for 5 days increased CD34(+)/CD133(+) cells from 0.5+/-0.2/microL to 59.5+/-10.6/microL and CD133(+)/ VEGFR-2(+) cells from 0.007+/-0.004/microL to 1.9+/-0.6/microL (both P<0.001). Also increased were CD133(+) cells that coexpressed the homing receptor CXCR4 (30.4+/-8.3/microL, P<0.05). Endothelial cell-forming clusters in 10 patients increased to 27+/-9/well after treatment (P<0.05), with a decline to 9+/-4/well at 2 weeks (P=0.06). CONCLUSIONS: Despite reduced EPCs compared with healthy controls, patients with CAD respond to G-CSF with increases in EPC number and homing receptor expression in the circulation and endothelial out-growth in culture. Endothelial progenitor cells (EPCs) are reduced in coronary artery disease. Granulocyte colony-stimulating factor (CSF) administered to patients increased: (1) CD133+/VEGFR-2+ cells consistent with EPC phenotype; (2) CD133+ cells coexpressing the chemokine receptor CXCR4, important for homing of EPCs to ischemic tissue; and (3) endothelial cell-forming clusters in culture. Whether EPCs mobilized into the circulation will be useful for the purpose of initiating vascular growth and myocyte repair in coronary artery disease patients must be tested in clinical trials.

AC133 Antigen↗

PubMed2001

Effect of coronary bypass and cardiac valve surgery on systemic endothelial function.

Seventeen patients scheduled for a cardiac procedure necessitating cardiopulmonary bypass underwent serial perioperative assessment of brachial artery flow-mediated dilation. Patients who underwent coronary bypass surgery had a sustained systemic endothelial dysfunction in the perioperative period, whereas those undergoing cardiac valve surgery experienced transient postoperative systemic endothelial dysfunction.

Adult↗

PubMed2006

[Klotho gene and endothelial function].

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g. arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, skin atrophy). We have demonstrated that mice deficient for the klotho gene show endothelial dysfunction as manifested by an attenuated response of aortic relaxation in response to acetylcholine stimulation. Systemic nitric oxide production was also significantly reduced in klotho deficient mice. Oxidative stress was increased in klotho deficient mice. The klotho gene delivery improves multiple aging phenotypes. Our findings establish the basis for the therapeutic potential of klotho gene delivery in age-related diseases.

Aging↗

PubMed2004

Beneficial effects of quinaprilat on coronary vasomotor function, endothelial oxidative stress, and endothelin activation after human heart transplantation.

BACKGROUND: We evaluated the potential of angiotensin-converting enzyme inhibition (ACEI) to modulate resting coronary vasomotor tone and endothelial dysfunction, and to decrease vascular oxidative stress and endothelin (ET)-1 activity in human heart transplant recipients. METHODS: Coronary vasomotor responses and transcardiac metabolism of glutathione, oxidized glutathione, and ET-1 were determined before and after quinaprilat infusion in 32 heart transplant recipients. Furthermore, the potential effects of ACEI on endothelial oxidative stress, ET-1 activity, and nitrosoglutathione formation were investigated using endothelial cell cultures. RESULTS: Epicardial diameter increased in response to quinaprilat by 6% +/- 1% (proximal segments; P<0.05) and 14% +/- 3% (distal segments; P<0.01). Coronary flow velocity increased by 2.2 +/- 0.2 (P<0.03). Coronary vasodilation to quinaprilat was negatively correlated with preexisting functional and structural coronary alterations. Quinaprilat selectively improved epicardial vasomotor response in segments with endothelial dysfunction, whereas microvascular endothelial dysfunction was unchanged. Transcardiac glutathione and big ET levels decreased after quinaprilat, whereas oxidized glutathione and ET-1 concentrations remained unchanged. Cell culture studies showed antioxidative effects of quinaprilat, revealed concentration-dependent down-regulation of endothelial ET-1 release, and indicated formation of nitrosoglutathione by quinaprilat. CONCLUSION.: ACE regulates resting coronary vasomotor tone. Quinaprilat reduces vascular oxidative stress and ET-1 activity and mediates formation of nitrosoglutathione, effects that might contribute to long-term vasculoprotective effects of ACEI after heart transplantation.

Adult↗

PubMed2003

Increase in nitric oxide bioavailability improves endothelial function in endothelin-1 transgenic mice.

BACKGROUND: Endothelin-1 (ET-1) has been described as a very potent vasoconstrictor. Nevertheless, transgenic mice overexpressing ET-1 have been shown to exhibit normal blood pressure. We thus hypothesized that vascular ET-1 effects may be antagonized by increased activity of other regulatory systems, such as the increase in bioavailability of the endothelial counterpart of ET-1, nitric oxide (NO). METHODS: Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine (10(-10)-10(-4) mol/l), sodium nitroprusside (10(-10)-10(-4) mol/l), ET-1 (10(-10)-10(-7) mol/l) and big ET-1 (10(-10)-10(-7) mol/l), respectively, in ET-1 transgenic mice and corresponding controls. To unmask the impact of the NO system, we furthermore analysed vessel rings incubated in vitro with the NO-synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) mol/l). RESULTS: Maximum endothelium-dependent relaxation was enhanced in ET-1 transgenic mice (93+/-3% vs 84+/-4% for wild-type littermates; P<0.05) and was inhibited by preincubation with L-NAME in both ET-transgenic mice and wild-type littermates (11+/-5% vs 9+/-4% maximum relaxation, respectively). Endothelium-independent relaxation was similar among all groups. Maximum vascular contraction to ET-1 and big ET-1 was reduced in ET-1 transgenic mice (P<0.05 vs wild-type littermates). Preincubation with L-NAME reduced this difference, indicating the involvement of augmented NO availability. Correspondingly, urinary nitrate/nitrite excretion was significantly elevated in ET-1 transgenic mice. CONCLUSIONS: These data suggest that in transgenic mice overexpressing ET-1, increased NO bioavailability counteracts the contractile potency of elevated ET-1 levels and leads to an improvement of endothelium-dependent relaxation. Thus, in the presence of an activated ET system, up-regulation of NO production may be capable of maintaining vascular tone in a normal range and therefore may prevent the development of hypertension.

Acetylcholine↗

PubMed2004

Oral snuff impairs endothelial function in healthy snuff users.

AIMS: Oral snuff is a less dangerous drug and therefore a good substitute for cigarette smoking. The aim of this study was to determine whether oral moist snuff induces acute endothelial dysfunction. Previous studies have shown that endothelial dysfunction predicts cardiovascular morbidity. METHODS AND RESULTS: Twenty healthy middle-aged snuff users underwent ultrasound assessment of endothelial-dependent flow-mediated dilatation (FMD) of the brachial artery. FMD measurements were performed in duplicate at baseline and then 20 and 35 min after the administration of 1 g portion-bag-packed moist snuff or placebo. Ten of the subjects were examined twice according to a randomized cross-over procedure, once with snuff and once with placebo. All images were arbitrarily analysed off-line by a single blinded observer. FMD values declined significantly from 3.4 +/- 2.0% to 2.3 +/- 1.3% (P < 0.05) 35 min after the administration of 1 g oral moist snuff. Heart rate, systolic and diastolic blood pressure increased significantly (P < 0.05) after snuff administration. All parameters remained unchanged after placebo. CONCLUSIONS: Oral moist snuff significantly impaired FMD of the brachial artery. As endothelial dysfunction predicts cardiovascular morbidity, use of oral snuff should be discouraged.

Administration, Oral↗

PubMed2002

Inhibitory effect of glucocorticoid on coronary artery endothelial function.

Acute and chronic stresses are implicated in cardiovascular diseases including coronary artery disease. The present study was designed to examine the direct effects of the stress hormone cortisol on nitric oxide (NO) release and endothelial NO synthase (eNOS) expression in cultured bovine coronary artery endothelial cells (BCAEC). Nitrate, nitrite, and NO (NO(x)) were measured by the chemiluminescence method. At 24 h after treatment, cortisol (1 nM-10 microM) produced a dose-dependent decrease in NO(x) release, which was attenuated in the presence of the 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone (3 microM). In accordance, eNOS protein levels were significantly decreased by cortisol in a dose-dependent manner. Cortisol pretreatment significantly increased the rate of eNOS protein degradation in the presence of cycloheximide. In addition, cortisol pretreatment decreased ATP-induced intracellular Ca(2+) elevation and NO(x) release in BCAEC. The presence of glucocorticoid receptors in BCAEC was demonstrated by Western blot. The results suggest that cortisol, through activation of glucocorticoid receptors, suppresses NO(x) release in BCAEC by downregulating eNOS proteins and inhibiting intracellular Ca(2+) mobilization. Decreased NO(x) is likely to result in an increase in contraction of coronary arteries, leading to a decrease in coronary blood flow.

Adenosine Triphosphate↗

PubMed2003

Interval sprint training enhances endothelial function and eNOS content in some arteries that perfuse white gastrocnemius muscle.

The purpose of this study was to test the hypothesis that interval sprint training (IST) selectively increases endothelium-dependent dilation (EDD) and endothelial nitric oxide synthase and/or superoxide dismutase-1 protein content in arteries and/or arterioles that perfuse the white portion of rat gastrocnemius muscle (WG). Male Sprague-Dawley rats completed 10 wk of IST (n = 62) or remained sedentary (Sed) (n = 63). IST rats performed six 2.5-min exercise bouts, with 4.5 min of rest between bouts (60 m/min, 15% incline), 5 days/wk. EDD was assessed from acetylcholine (ACh)-induced increases in muscle blood flow measured in situ and by ACh-induced dilation of arteries and arterioles [first to third order (1A-3A)] that perfuse red gastrocnemius muscle (RG) and WG. Artery protein content was determined with immunoblot analysis. ACh-induced increases in blood flow were enhanced in WG of IST rats. eNOS content was increased in conduit arteries, gastrocnemius feed artery, and fourth-order arterioles from WG and fifth-order arterioles of RG but not in 2As from RG. EDD was examined in 2As and 3As from a subset of IST and Sed rats. Arterioles were canulated with micropipettes, and intraluminal pressure was set at 60 cmH2O. Results indicate that passive diameter (measured in 0 calcium PSS) of WG 2As was similar in IST and Sed, whereas diameter of WG 3As was greater in IST (96 +/- 8 microm) than Sed (73 +/- 4 microm). WG 2As and 3As of IST rats exhibited greater spontaneous tone, but sensitivity to stretch, phenylephrine, and sodium nitroprusside was similar to Sed arterioles. ACh-induced dilation was enhanced by IST in WG 2As but not in RG 2As or WG 3As. We conclude that IST induces vascular adaptations nonuniformly among arteries that perfuse WG muscle.

Animals↗

PubMed2000

Endothelial function and hemostasis.

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.

Arteriosclerosis↗

PubMed1996

Peripheral artery structure and endothelial function in heart failure: effect of ACE inhibition.

Chronic heart failure (CHF) induces peripheral vasoconstriction and impairs endothelium-dependent relaxation of large arteries. We investigated in a rat model of CHF (coronary artery ligation) 1) whether endothelial dysfunction also exists in resistance arteries, 2) whether this is associated with vascular morphological changes, and 3) the effect of angiotensin-converting enzyme (ACE) inhibition on these parameters. After 1 mo or 1 yr, CHF reduced the vasodilatory response to acetylcholine of isolated, perfused femoral and mesenteric artery segments. This impairment was more marked in femoral than in mesenteric arteries. However, CHF did not induce any arterial remodeling. Chronic treatment with the ACE inhibitor perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density. Thus at the level of small peripheral arteries, CHF induces an endothelial dysfunction but does not affect vascular structure. ACE inhibition prevents the CHF-induced endothelial dysfunction and induces vascular remodeling. These changes could contribute to the observed beneficial effects of ACE inhibitors on hemodynamics and survival in CHF.

Acetylcholine↗