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PubMed1993

The effects of warm versus cold blood cardioplegia on endothelial function, myocardial function, and energetics.

BACKGROUND: Recent interest in the use of normothermic blood cardioplegia is based on theoretical advantages over the traditional method of hypothermic myocardial protection. This study was designed to compare the effects of warm and cold blood cardioplegia on left ventricular functions and energetics and coronary responsiveness. MATERIALS AND METHODS: Two groups of mongrel dogs (n = 7 each) underwent either normothermic cardiopulmonary bypass (CPB) with continuous warm (37 degrees C) blood cardioplegia or hypothermic (26 degrees C) CPB with a single dose of cold (4 degrees C) blood cardioplegia supplemented with topical cooling during 30 minutes of aortic clamping. There was no deterioration in the endothelium-dependent and -independent coronary relaxation as tested by the infusion of acetylcholine and nitroglycerin after cardioplegic arrest for either group. At 60 minutes of reperfusion, both groups had complete recovery of left ventricular contractility as measured by the preload recruitable stroke work area derived from the measurement of the ventricular pressure (micromanometer catheter) and volume (conductance catheter) relation. The analysis of myocardial energetics in terms of the myocardial oxygen consumption-pressure volume area relation did not reveal any significant changes between the y-intercepts and the slopes of the two groups. CONCLUSIONS: For 30 minutes of aortic cross-clamp time, continuous warm cardioplegia did not provide any benefit over a single injection of cold cardioplegia in coronary endothelial and smooth muscle function, myocardial function, and energetics.

Animals↗

PubMed1992

Iloprost preserves endothelial function against cyclosporin A and sensitises microvessels towards endothelium-dependent and -independent vasodilatation.

The effects of iloprost have been investigated on the endothelial damage produced by cyclosporin-A (Cy-A) and on the microvascular reactivity to sodium nitroprusside (SNP), acetylcholine (ACh) and isoprenaline (ISO) following iloprost treatment i.e. in the absence of effective plasma levels, using the hamster cheek pouch. It has been shown that iloprost protects the microvascular arteriolar endothelium from functional damage by Cy-A and that iloprost infusion for 12-14 hr sensitizes the arterioles to ACh, SNP and ISO, an effect which is evident 5 hr but not 24 hr following treatment and in the case of ACh is abolished by indomethacin.

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

PubMed1998

Effects of a high-cholesterol diet on vascular and endothelial function in rat aorta.

We have examined the effects of high cholesterol (1%) or normal diet for 8 weeks on vascular and endothelial responsiveness of rat aorta. The cholesterol diet produced a small but significant elevation of plasma cholesterol levels (vehicle: 0.95 +/- 0.13 mmol/l, n = 11; cholesterol fed; 1.40 +/- o.12 mmol/1, n = 14; p < 0.05). There were significant differences between control and high cholesterol groups in the contractile response to noradrenaline in rat aortic rings, both in terms of maximum response and potency. Both the potency of noradrenaline (NA) (pD2 values; vehicle diet: 7.84 +/- 0.08; cholesterol diet: 8.27 +/- 0.09; p < 0.01) and the maximum response (vehicle diet: 0.78 +/- 0.05 g; cholesterol diet: 0.95 +/- 0.06 g; p < 0.05) were significantly greater in the high-cholesterol group. There were no significant differences between control and high cholesterol groups in endothelium-independent relaxations to sodium nitroprusside (SNP). When responses were correlated with plasma cholesterol levels, there was a significant negative correlation with maximum endothelium-dependent relaxation to ACh (r = 0.53, n = 16, p < 0.05), so that the maximum relaxation decreased with increasing plasma levels of cholesterol. There were no significant correlations between cholesterol levels and endothelium-independent relaxation to SNP or between cholesterol levels and vascular contractions to NA. In conclusion, cholesterol-fed normal Wistar rats show functional changes in vascular responsiveness even with a relatively small elevation of plasma cholesterol levels.

Animals↗

PubMed1993

Endothelial damage of the venous graft in CABG. Influence of solutions used for storage and rinsing on endothelial function.

A significant proportion of early graft occlusions after aortocoronary revascularization using autologous saphenous vein grafts (SVG) are due to mechanical and/or metabolic or biochemical endothelial lesions. The morphological examination of the endothelium, usually carried out using light microscopy or by various types of scanning electron microscopy (SEM), does not give any indication of the functioning of the endothelium (E). Functionally intact E is capable of producing endothelium-derived relaxing factor (EDRF); a practicable in vitro test is the relaxation of pre-contracted vein segments (VS) in response to acetylcholine (ACh) application. To study the effect of the solution used to rinse and store the SVG between removal and implantation on the functional characteristics of the E, we performed in vitro tests on macroscopically intact VS removed from the saphenous vein of 30 male patients who underwent elective CABG surgery. Isolated VS rings were incubated for 60 min in heparinized whole blood (HWB), Bretschneider's cardioplegic solution (HTK), human albumin solution (HAS), or Ringer's solution (RS) and compared with the results obtained immediately after the removal of untreated control samples (C) taken from the same patients. After equilibration in carbogen aerated Krebs-Henseleit solution and precontraction by 3 x 10(-7) M noradrenaline (NE), relaxation induced by 10(-6) M ACh was measured. Only the samples stored in HWB (13.4 +/- 0.4 mN) showed similar maximal contractions with NE to those in the control group (14.4 +/- 0.5 mN), i.e. all those segments which showed both contractions with NE and relaxation with ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed2003

Protective effect of chronic vitamin C treatment on endothelial function of apolipoprotein E-deficient mouse carotid artery.

Endothelium-dependent relaxations are impaired in carotid artery of apolipoprotein E-deficient (apoE-/-) mice. This impairment seems to be due to increased formation of superoxide anions and inactivation of endothelial nitric oxide (NO). In the present study, we tested hypothesis that chronic treatment with vitamin C may prevent endothelial dysfunction by increasing release of NO from endothelial cells. C57BL/6 and apoE-/- mice were treated for 26 weeks with Western-type fat diet with and without 1% vitamin C. Vasomotor function of isolated carotid arteries was studied by video dimension analyzer. Expression of endothelial NO synthase (eNOS) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) protein were evaluated by Western blotting. Levels of cGMP and cAMP were measured by radioimmunoassay. In apoE-/- mice, vitamin C significantly augmented relaxations to acetylcholine (10-9-10-5 mol/l), but did not affect relaxations to NO donor diethylammonium-(Z)-1-(N,N-diethylamino) diazen-1-1,2-diolate (DEA-NONOate; 10-9-10-5 mol/l). In contrast, vitamin C reduced relaxations to acetylcholine and DEA-NONOate in C57BL/6 mice. Interestingly, vitamin C significantly increased basal cGMP levels in C57BL/6 mice but did not affect cGMP formation in apoE-/-. Vitamin C treatment did not affect expression of eNOS protein, whereas elevated expression of PECAM-1 protein in apoE-/- mice was returned to normal level. Our findings demonstrate that chronic treatment with vitamin C prevents endothelial dysfunction of carotid artery induced by hypercholesterolemia. This effect seems to be mediated by preservation of NO bioavailability in endothelial cells.

Animals↗

PubMed2006

Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation.

Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, such as hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions and the underlying mechanisms have not been explored previously. In lone AF or AF associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (ED function) and ventilation during the recovery phase of handgrip (metaboreflex) exercise for subjects receiving placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and the ergoreflex activity more pronounced in AF + HP and AF + DM compared with lone AF. Vitamin C and CV significantly improved both flow-mediated dilatation and metaboreflex activity in lone AF and AF + HP, and vitamin C did not produce any additive effect when administered after CV. In AF + DM, neither vitamin C nor CV was effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone AF and greater when the arrhythmia is associated with HP. In DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF. In AF, a cause-effect link exists between ED dysfunction and metaboreflex activity. Ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.

Aged↗

PubMed2005

[Noninvasive assessment of endothelial function in hemodialyzed hypertensive patients by laser Doppler flowmetry].

BACKGROUND: End stage renal disease and hypertension are associated with higher cardiovascular mortality. Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. The authors investigated the endothelium-dependent and -independent vasodilation in the forearm skin microcirculation and the plasma markers of endothelial damage in hypertensive hemodialysed patients and in normotensive control subjects. METHODS: Laser Doppler flowmetry with iontophoresis of acetylcholine and sodium nitroprusside and the postocclusive reactive hyperemia test was performed in 22 normal control subjects and in 21 hemodialysed patients with hypertension. Levels of endothelin-1, big-endothelin, and von Willebrand Factor were measured, as well. RESULTS: The average hyperemic response to the two doses of acetylcholine iontophoresis was 474 +/- 83%; 836 +/- 97% in the control subjects, and 160 +/- 26%; 360 +/- 67% in the hemodialysed patients group (p < 0.05). The vasodilation after the two doses of sodium nitroprusside was 381 +/- 60%, 782 +/- 81% in the control group and 186 +/- 42%; 379 +/- 63% in the dialysed patients group (p < 0.05 compared to control, respectively). The average peak flow during the postocclusive reactive hyperemia test was significantly lower in hemodialysed hypertensives (234 +/- 48%) compared to healthy control subjects (434 +/- 36%, p < 0.05). Levels of endothelin-1, big endothelin, von Willebrand Factor and von Willebrand Factor activity were significantly higher in the patient group compared to the control subjects. CONCLUSIONS: In hemodialysed hypertensive patients, both endothelium-dependent and -independent vasodilation are impaired. Markers of endothelial damage are elevated referring the progression of vascular disease.

Biomarkers↗

PubMed2000

An in vitro cell culture system to study the influence of external pneumatic compression on endothelial function.

PURPOSE: External pneumatic compression (EPC) is an effective means of prophylaxis against deep venous thrombosis. However, its mechanism remains poorly understood. Understanding of the biological consequences of EPC is an important goal for optimizing performance of the EPC-generating device and providing guidance for clinical use. We present a new in vitro cell culture system (Venous Flow Simulator) that simulates blood flow and vessel collapse conditions during EPC, and we examine the influence of these factors on endothelial cell (EC) fibrinolytic activity and vasomotor function. METHODS: An in vitro cell culture system was designed to replicate the hemodynamic shear stress and vessel wall strain associated with induced blood flow during different modes of EPC. Human umbilical vein endothelial cells were cultured in the system and subjected to intermittent flow, vessel collapse, or a combination of the two. The biologic response was assessed through changes in EC morphology and the expression of fibrinolytic factors tissue plasminogen activator, plasminogen activator inhibitor type 1, profibrinolytic receptor (annexin II), and vasomotor factors endothelial nitric oxide synthase and endothelin-1. RESULTS: The cells remained attached and viable after being subjected to intermittent pulsatile flow (F) and tube compression (C). In F and F + C, cells aligned in the direction of flow after 6 hours. Northern blot analysis of messenger RNA shows that there is an upregulation of tissue plasminogen activator expression (1.95 +/- 0.19 in F and 2.45 +/- 0.46 in FC) and endothelial nitric oxide synthase expression (2.08 +/- 0.25 in F and 2.11 +/- 0.21 in FC). Plasminogen activator inhibitor type 1, annexin II, and endothelin 1 show no significant change under any experimental conditions. The results also show that pulsatile flow, more than vessel compression, influences EC morphology and function. CONCLUSION: Effects on ECs of intermittent flow and vessel collapse, either individually or simultaneously, were simulated with an in vitro system of new design. Initial results show that intermittent flow associated with EPC upregulates EC fibrinolytic potential and influences factors altering vasomotor tone. The system will facilitate future studies of EC function during EPC.

Blood Flow Velocity↗

PubMed2002

Endothelial function studies in pulmonary vascular disease: determination of angiotensin converting enzyme activity in humans (review).

Angiotensin converting enzyme (ACE, kininase II) is an endothelial luminal ectoenzyme. The majority of ACE has been found on the pulmonary capillary endothelium (PCE). Pulmonary capillary endothelium-bound (PCEB)-ACE has been extensively studied by means of indicator dilution techniques in animals and man. We have recently developed and applied methodologies for assaying pulmonary capillary endothelium-bound (PCEB) angiotensin converting enzyme (ACE) activity in man. This article provides a summary of our studies in human subjects utilizing similar methodology. Trace amounts of the specific ACE substrate, (3)H-benzoyl-Phe-Ala-Pro ((3)H-BPAP; 40 microCi or 2 nmol), was injected as a bolus into the subclavian vein of patients and immediately blood was withdrawn from a radial arterial catheter. Plasma concentrations of surviving substrate and product ((3)H-benzoyl-Phe) were estimated and BPAP utilization was calculated during a single transpulmonary passage. To investigate the PCE in this manner we tested the hypothesis that PCEB-ACE is depressed in patients diagnosed with acute lung injury and estimated interaction of an ACE inhibitor (enalaprilat) with PCE in human subjects. An inverse correlation was found between the pulmonary endothelium-bound ACE activity (v) and the lung injury score (r=0.379; p<0.01). Similarly, an inverse correlation was found between the pulmonary capillary perfusion index (CPI) and the lung injury score (r=0.284, p<0.05). PCEB-ACE activity in the group of patients with mild lung injury was significantly different from the group of control patients (0.44 +/- 0.048 vs. 1.15 +/- 0.05; p<0.01). Trace amounts (1.5 microg/kg) of enalaprilat had no significant effect on mean arterial pressure (91 +/- 6 vs. 84 +/- 7 vs. 88 +/- 6 mmHg for T(1), T(2) and T(3), respectively), but significantly decreased PCEB-ACE activities. When normalized to pre-drug (T(1)) activity levels, enalaprilat inhibited PCEB and SE ACE activity at T(2) by 74 +/- 6 and 68 +/- 6%, respectively. PCEB-ACE measurements can be used in clinical practice for estimating PCE functions and can provide new insight into the physiology of the pulmonary circulation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

[Relation of polymorphism of genes controlling endothelial function and blood pressure and the occurrence of vascular complications in type 2 diabetes].

Genetic polymorphisms of factors regulating the function of endothelium and blood pressure are recently intensively studied also in type 2 diabetes because endothelial dysfunction and arterial hypertension are risk factors of atherosclerosis. The following review deals with relations of polymorphisms in the renin-angiotensin-aldosterone (RAAS) system, polymorphisms of NO-synthase (NOS) as well as the gene for atrial natriuretic peptide (hANP). So far most information was assembled on the influence of polymorphisms of RAAS genes, in particular the gene coding the angiotensin converting enzyme (ACE), on complications of type 2 diabetes. A relationship with the development of coronary disease was described in ACE genes, the receptor for angiotensin II--type 1 (AT1R), angiotensinogen and in several NOS polymorphisms. Also the relationship of polymorphisms of genes ACE, AT1R, NOS and hANP was described in relation to the development of hypertension which is an important risk factor for macrovascular and microvascular complications of diabetes. In some investigations the relationship of polymorphisms of ACE and AT1R genes and the development of diabetic nephropathy was described where a significant acceleration of the process of atherogenesis occurs. As type 2 diabetes mellitus and atherosclerosis are polygenically determinal diseases, it will be in particular necessary to investigate in future the concurrent influence of several gene polymorphisms and their interactions with the diabetic milieu intérieur on the development of macrovascular and microvascular complications of diabetes.

Angiotensinogen↗

PubMed2005

Adiponectin predicts insulin resistance but not endothelial function in young, healthy adolescents.

BACKGROUND: Adiponectin, an adipocyte-derived hormone found in lower concentration with greater adiposity, is suggested to reduce the risk of insulin resistance, atherosclerosis, and cardiovascular disease. We tested this hypothesis in a healthy, nonobese population. METHODS AND RESULTS: Brachial artery flow-mediated endothelial-dependent vasodilation and distensibility, measures of vascular function relevant to the early atherosclerotic process, were determined in 294 adolescents (aged 13-16 yr) using high-resolution vascular ultrasound. Fasting insulin concentration and the homeostasis model assessment of insulin resistance were used to estimate insulin resistance. Fat mass was measured by bioelectric impedance analysis; fasting serum adiponectin concentration by RIA; and lipid profile, fasting insulin, glucose, and C-reactive protein concentrations using standard laboratory techniques. Adiponectin concentration was associated with insulin resistance independent of potential confounding factors (e.g. -1.3% change in fasting insulin concentration per 10% increase in adiponectin concentration; 95% confidence interval, -2.4% to -0.1%; P = 0.03), but not with flow-mediated endothelial-dependent vasodilation or arterial distensibility. CONCLUSIONS: Lower adiponectin concentration was associated with lower insulin sensitivity in a healthy, nonobese population. Our study supports the hypothesis that adiponectin benefits insulin sensitivity from a young age but, in contrast to experimental models and data from older subjects, does not affect vascular changes associated with early atherosclerosis.

Adiponectin↗

PubMed2005

Mechanisms of increased vascular oxidant stress in hyperhomocys-teinemia and its impact on endothelial function.

Elevated plasma levels of homocysteine are associated with an increased generation of reactive oxygen species in aortas of hyperhomocysteinemic animals and in endothelial cells. This may contribute to endothelial dysfunction observed in hyperhomocysteinemia, and promote atherosclerotic vascular disease. Homocysteine seems to promote the formation of reactive oxygen species primarily by a biochemical mechanism involving endothelial nitric oxide synthase, as increased endothelial lipid peroxidation and oxidation of the redox-sensitve dye 2',7'-dichlorofluoresceine could only be observed after incubation of endothelial cells with L-, but not with D-homocysteine, and could be prevented by inhibition of endothelial nitric oxide synthase. An increased oxidation rate of aminothiols in plasma, as observed in patients with hyperhomocysteinemia, further contributes to increased generation of reactive oxygen species. These effects are amplified by a homocysteine-specific inhibition of cellular antioxidant enzymes, like superoxide dismutase and the cellular isoform of gluthatione peroxidase. All mechanisms together result in increased levels of superoxide anion and peroxyl radicals in the vasculature that react with nitric oxide to form peroxnitrites. This abolishes nitric oxide's bioactivity and contributes to endothelial dysfunction. In addition, increased vascular oxidant stress in hyperhomocysteinemia has been shown to activate proinflammatory signaling pathways in endothelial cells, like the transcription factor NF-kappaB. This leads to increased endothelial expression of chemokines and adhesion molecules that promote the recruitment, adhesion and transmigration of circulating leukocytes to the vessel wall. All these mechamisms may contribute to the increased risk for cardiovascular diseases associated with hyperhomocysteinemia.

Animals↗

PubMed1995

Lack of correlation between microalbuminuria and endothelial function in essential hypertensive patients.

OBJECTIVE: To evaluate whether microalbuminuria, defined as urinary albumin excretion between 30 and 300 mg/24 h, is associated with endothelial dysfunction in essential hypertensive patients. DESIGN: We correlated urinary albumin excretion with vasodilatation in response to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) agonists in the forearm vascular bed in essential hypertensive patients with (n = 13) and without (n = 23) microalbuminuria and matched normotensive controls (n = 21). METHOD: We studied forearm vascular responses (strain-gauge plethysmography) to intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5 and 15 ng/100 ml forearm tissue/min) and of sodium nitroprusside (1, 2, 4ng/100 ml forearm tissue per min). Minimal forearm vascular resistances (the ratio between mean arterial pressure and maximal forearm vasodilation induced by 13 min of ischaemia + 1 min of exercise) were also evaluated. RESULTS: Responses to acetylcholine, but not to sodium nitroprusside, were significantly blunted and minimal forearm vascular resistances were increased in hypertensive patients compared with controls. However, no correlation was found between urinary albumin excretion and vasodilatation in response to acetylcholine or to sodium nitroprusside or between urinary albumin excretion and minimal forearm vascular resistances. CONCLUSIONS: In hypertensive patients, increased urinary albumin excretion is associated neither with functional nor with structural dysfunction in the forearm vasculature.

Acetylcholine↗

PubMed2004

Advanced glycation and endothelial functions: a link towards vascular complications in diabetes.

The formation of advanced glycation end-products (AGEs), also called the Maillard reaction, occurs ubiquitously and irreversibly in patients with diabetes mellitus, and its consequences are especially relevant to vascular dysfunctions. The interaction of AGEs with their receptors (RAGE) has been implicated in the development of vascular complications. This interaction elicits remarkable vascular cell changes analogous to those observed in diabetes mellitus, including angiogenic and thrombogenic responses of endothelial cells, increased oxidative stress, and functional alterations in vascular tone control. This review focuses on AGEs formation, the interaction with their specific receptors and how the triggered intracellular events determine functional alterations of vascular endothelium. Finally, some potential pharmacological approaches undertaken to circumvent the deleterious effects of AGEs are also discussed.

Animals↗

PubMed2002

Blockade of angiotensin II type 1 receptors suppressed free radical production and preserved coronary endothelial function in the rabbit heart after myocardial infarction.

The hypothesis that blockade of angiotensin II type 1 (AT1) receptors after myocardial infarction prevents coronary endothelial vasomotor dysfunction by suppressing oxygen free radical production was examined. Rabbits underwent coronary ligation or a sham operation with or without infusion of valsartan, an AT 1 receptor blocker. Two weeks after the operation, the heart was isolated from each rabbit and perfused with buffer in the Langendorff mode, and coronary flow responses to acetylcholine and sodium nitroprusside were assessed. The ratio of heart weight to body weight and the lipid peroxide level in the myocardium were increased by 30 and 50%, respectively, 2 weeks after infarction. The coronary flow response to acetylcholine (10(-8) to 10(-5) M) was reduced by 50% in the hearts with infarction compared with the sham controls, although coronary flow responses to sodium nitroprusside were similar. The coronary flow response to acetylcholine in the hearts with infarction was restored by concurrent infusion of N -2-mercaptopropionyl-glycine, a free radical scavenger. Valsartan (10 mg/kg/d) infused after infarction prevented both ventricular remodeling and elevation of the tissue lipid peroxide level and preserved coronary flow response to acetylcholine. In conclusion, long-term AT1 receptor blockade after infarction protects the coronary arteries from endothelial vasomotor dysfunction through suppression of free radical production.

Acetylcholine↗

PubMed2004

Effects of voluntary exercise on cerebral thrombosis and endothelial function in spontaneously hypertensive rats (SHRSP/Izm).

1. Effects of voluntary exercise on blood pressures, oxidative stress, urinary nitric oxide (NO) level and expression of endothelial NO synthase (eNOS) mRNA were studied in stroke-prone spontaneously hypertensive rats (SHRSP/Izm). 2. SHRSP at the age of 6 weeks were divided into four groups: (i) the control group, sedentary group; (ii) the L-NAME group, which was the sedentary control group given L-NAME (5 mg/kg per day) in drinking water; (iii) the exercise group, which was allowed to run voluntarily on running wheel attached to the metal cages; and (iv) the exercise plus L-NAME group which was loaded exercise and given L-NAME solution for 3 weeks. 3. The bodyweight and systolic pressure of rats were increased with age and the bodyweight of the rats in an exercise plus L-NAME group was less than control but systolic pressure in the exercise group were significantly lower than control. 4. Thrombotic tendency assessed by He-Ne laser method in an exercise group was significantly decreased compared with the rest of the groups. 5. Urinary nitrite/nitrate level was significantly increased in the exercise group compared with before (6 weeks) and after exercise (9 weeks), but there were no significant differences in the rest of groups. 6. eNOS mRNA expression of aorta in the exercise group measured after exercise was significantly higher than the other groups. 7. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) level after exercise was significantly decreased in the exercise group compared with before exercise. 8. These results suggested that voluntary exercise decreased thrombotic tendency by increasing NO level through enhanced expression of eNOS mRNA and antioxidative effects.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model.

The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model (streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NOx- (NO2-+NO3-)/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NOx-/cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110gamma subunits of PI3-K were not. The clonidine-induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction (and the resulting hypertension) in type 2 diabetes.

Acetylcholine↗

PubMed2003

Influence of intracoronary shunt size on coronary endothelial function during off-pump coronary artery bypass.

OBJECTIVE: The insertion of intracoronary shunts during off-pump coronary artery bypass surgery may induce severe endothelial dysfunction in the target arteries. The purpose of this study was to determine the role of the ratio of the shunt diameter to the target artery diameter in the development of endothelial dysfunction and to develop guidelines for selecting the most appropriate shunt size. METHODS: Nine swine (25 +/- 4 kg) were used for this study. Three ClearView shunts 3 mm, 2 mm, and 1.25 mm in diameter were inserted proximally to distally via 3 arteriotomies into the right coronary artery to obtain oversizing with the 3-mm shunt, undersizing with the 1.25-mm shunt, and a satisfying congruence with the 2-mm shunt. The shunts were left in place for 15 minutes, and the levels of bleeding were quantified. Coronary rings upstream and downstream from the arteriotomies were then harvested and placed in organ chambers to study endothelium-dependent relaxations to serotonin and bradykinin. Noninstrumented coronary arteries served as controls. RESULTS: A decrease of endothelium-dependent relaxation occurred with the 3-mm shunts (P <.005), which were associated with an adequate hemostasis. A decrease of endotheliumdependent relaxation occurred with the 2-mm shunts (P <.05), which were associated with intermittent bleeding, and no significant decrease of endothelium-dependent relaxation occurred with 1.25-mm shunts (P >.05), which were associated with continuous bleeding. CONCLUSIONS: Intracoronary shunts are associated with different disadvantages, depending on the mismatch to the target coronary artery, and whatever their size, shunts are not the ideal device for safely obtaining a satisfactory hemostasis. These results support our clinical attitude of the selective use of intracoronary shunts.

Anastomosis, Surgical↗