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Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure.

BACKGROUND: Cardiovascular disease is a major cause of mortality amongst patients with chronic renal failure (CRF). L-arginine has been used to improve endothelial function by increasing nitric oxide (NO) bioavailability and in animal models this in turn has attenuated the progression of atherosclerosis. We examined whether dietary L-arginine supplementation improved endothelial function in children with CRF. METHODS: A randomized, double-blind, placebo-controlled, crossover trial of L-arginine was conducted in 21 normotensive children aged 11.5 +/- 3 (7 to 17) years with CRF (GFR 27.4 +/- 13.2 mL/min/1.73 m(2)) in whom endothelial dysfunction had previously been demonstrated. We examined the effect of L-arginineon the endothelial response to shear stress (NO-dependent) using a non-invasive technique of high-resolution ultrasound. Each subject was studied before and after 4 weeks of L-arginine (2.5 g/m(2) or 5 g/m(2) x 3/day) or placebo, separated by a rest period of 4 weeks. Brachial artery diameter was measured at rest, during increased flow (endothelial-dependent dilation) and after 25 microg of glyceryl trinitrate (endothelial-independent dilation) at each visit. RESULTS: After oral L-arginine, plasma L-arginine levels rose from 82 +/- 20 to 179 +/- 110 micromol/L (P < 0.001). No significant change in endothelial-dependent dilation during L-arginine (7.96 +/- 2.35 to 7.71 +/- 3.22%; P> 0.05) or placebo (8.2 +/- 2.89 to 8.3 +/- 3.14%; P> 0.05) was noted. There was no change in endothelial-independent dilation. CONCLUSION: Endothelial function was not improved with L-arginine, suggesting that dietary supplementation is not a useful clinical approach in children with CRF.

Administration, Oral↗

Effect of tetrahydrobiopterin on selective endothelial dysfunction of epicardial porcine coronary arteries induced by cardiopulmonary bypass.

BACKGROUND: We hypothesized that cardiopulmonary bypass induces a selective alteration of the coronary arterial endothelial cell signal transduction which could be explained by a state of depletion and/or decreased activity of endogenous tetrahydrobiopterin (BH(4)). The aim of this study was to assess the effects of cardiopulmonary bypass and BH(4) on the endothelial function of epicardial coronary arteries in a swine model of cardiopulmonary bypass. METHODS: Swine underwent 90 min of cardiopulmonary bypass alone (N=19) or in association with a brief cardioplegic arrest with (N = 6) or without (N = 5) in vivo BH(4) administration, followed by a 60-min period following weaning from cardiopulmonary bypass and were compared to a control group (N = 7). Endothelium-dependent relaxations of epicardial coronary artery rings were studied using standard organ chamber experiments in the presence or absence of in vitro BH(4) or superoxide dismutase (SOD) and catalase. RESULTS: Cardiopulmonary bypass caused a statistically significant reduction of endothelium-dependent relaxations to serotonin (p < 0.0001), bradykinin (p < 0.001), UK14304 (p < 0.0001) and calcium ionophore (p < 0.01) in epicardial porcine coronary arteries. In vitro and in vivo BH(4) supplementation improved endothelium-dependent relaxations to serotonin and bradykinin, which were left unchanged by SOD-catalase administration. Cardiopulmonary bypass was associated with a decrease in nitric oxide availability (p = 0.002) and increased oxidative stress (p < 0.001), which were both restored by in vivo BH(4) administration (p < 0.001). CONCLUSION: Treatment with BH(4) improves the endothelial dysfunction of porcine epicardial coronary arteries, restores nitric oxide availability and reduces the oxidative stress associated with cardiopulmonary bypass.

Animals↗

Glomerular endothelial dysfunction in chronic kidney disease.

A dysfunctioning glomerular endothelium was demonstrated in chronic kidney disease (CKD) patients by means of in vitro endothelial cell cytotoxicity test and of in vivo intrarenal hemodynamic study. An enhanced endothelial cell cytotoxicity in CKD patients was 26.5 +/- 12% as compared to 0.4 +/- 1% of control. An altered intrarenal hemodynamics revealed 1) a reduction in renal plasma flow, 190 +/- 67 mL/min/1.73 m2 versus control 595 +/- 45 mL/min/1.73 m2, and in peritubular capillary flow, 149 +/- 55 mL/min/1.73 m2 versus control 479 +/- 46 mL/min/1.73 m2, 2) an elevated intraglomerular hydrostatic pressure, 55 +/- 2 mmHg versus control 51 mmHg, elevated afferent arteriolar resistance, 13184 dyne x s x cm(-5) versus control 2443 +/- 154 dyne x s x cm(5), and elevated efferent arteriolar resistance, 13591 +/- 7591 dyne x s x cm(-5) versus control 3062 +/- 177 dyne x s x cm(-5). Both enhanced endothelial cell cytotoxicity and altered intrarenal hemodynamics reflect glomerular endothelial dysfunction which is likely responsible for the renal disease progression in CKD.

Case-Control Studies↗

Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients: a monitoring test of endothelial dysfunction for clinical practice?

OBJECTIVES: The present study aims to investigate whether laser Doppler flowmetry can be used to monitor improvements in vascular function during statin therapy. BACKGROUND: Endothelial dysfunction is an early feature of atherosclerosis in hypercholesterolemic patients and can be improved by statins. There are several methods to assess endothelial function in vivo, none of them being feasible in everyday practice. METHODS: Skin perfusion, measured by laser Doppler flowmetry, was assessed at rest and during reactive hyperemia. Nineteen hypercholesterolemic patients (age 42 to 73 years, total cholesterol 5.4 to 9.6 mmol/l) were studied before and during statin therapy. To further investigate the mechanisms, postischemic skin hyperemia was measured before and after intradermal injection of the nitric oxide synthase inhibitor L-NAME and its inactive isoform D-NAME (0.5 micromol/10 microl each). On a separate day, the healthy volunteers were reexamined before and 2 h after 1,000 mg aspirin. RESULTS: Postischemic skin blood flow was markedly reduced in hypercholesterolemic patients (45 +/- 11%) compared with healthy controls (238 +/- 20%, p < 0.0001) and improved after statin therapy (113 +/- 15%, p = 0.0005 vs. pre-treatment). In the healthy volunteers, the hyperemic responses were not significantly different after L-NAME and D-NAME. Aspirin reduced hyperemia from 274 +/- 49% to 197 +/- 40% (p = 0.025). CONCLUSIONS: Reactive hyperemia of the skin microcirculation can be easily and reproducibly assessed by laser Doppler flowmetry. Vasodilator prostaglandins are the major mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and can be enhanced by cholesterol-lowering therapy. Thus, laser Doppler flowmetry may represent a tool to assess and monitor vascular function during therapy in everyday practice.

Adult↗

Endothelial dysfunction in hypertension is independent from the etiology and from vascular structure.

The aim of our study was to evaluate the relationships between endothelial function, small resistance artery structure, and blood pressure in patients with primary or secondary hypertension. Sixty subjects were included in the study: 9 patients with pheochromocytoma, 10 with primary aldosteronism, 17 with renovascular hypertension, and 13 with essential hypertension with 11 normotensive subjects who served as controls. Clinic and 24-hour ambulatory blood pressure (ABPM) were evaluated. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph and the media/lumen ratio was calculated. A dose-response curve to acetylcholine was performed at cumulative concentrations from 10(-9) to 10(-5) mol/L. The vasodilator response to acetylcholine was similarly impaired in the four groups of hypertensive patients (ANOVA P<.05 versus normotensive controls), without any significant difference among them. In subcutaneous small arteries of patients with either primary aldosteronism or renovascular hypertension, a marked increase in media:lumen ratio was observed, while in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in essential hypertension. No significant correlation between media-lumen ratio or clinic blood pressure and maximum acetylcholine-induced vasodilatation was observed. On the contrary, a significant, albeit not very close, correlation between ABPM values and maximum acetylcholine-induced vasodilatation was observed (r=34, P<.05 with 24-hour systolic blood pressure, r=0.36, P<.05 with 24-hour diastolic blood pressure). In conclusion, endothelial dysfunction seems to be independent from the degree of vascular structural alterations and from the etiology of hypertension, and it is probably more linked to the hemodynamic load.

Acetylcholine↗

Cyclosporin-induced endothelial dysfunction and hypertension: are nitric oxide system abnormality and oxidative stress involved?

Hypertension is a major side effect of cyclosporin (CsA). While the mechanism(s) responsible are unclear, CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to the CsA effect on the endothelial-derived factors controlling vasomotor tone. Endothelial nitric oxide (NO) is crucial in the maintenance of a state of basal vasodilation, and recent studies have suggested an NO-mediated counterregulatory mechanism protective from CsA-induced vasoconstriction. Our study evaluates endothelial nitric oxide synthase (ecNOS) gene status (PCR analysis) and plasma levels of NO metabolites (ELISA) in kidney and heart transplant patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolises NO, plasma hydroperoxides from cholesterol esters and from triglycerides and peroxynitrite were also evaluated (HPLC) as an index of the presence of superoxides and of "oxidative stress". Quantification of monocyte ecNOS mRNA and NO metabolites plasma levels from patients and controls (C) demonstrated NO system upregulation in patients notwithstanding the hypertension. The mean ecNOS to beta-actin ratio was 1.80 +/- 0.85 in patients vs 0.40 +/- 0.09 in C (P < 0.04). NO metabolites were 34.03 +/- 14.32 microM in patients vs 11.53 +/- 5.64 microM in C (P < 0.001). Hydroperoxides from cholesterol esters and from triglycerides were also increased in patients, 3.4 +/- 1.4 vs 1.3 +/- 0.6 integrated area units (i. a. u.), P < 0.007 and 10.6 +/- 6.4 vs 1.3 +/- 0.8 i. a. u., P < 0.008, respectively, as well as the peroxynitrite plasma level, 0.32 +/- 0.11 microM/l vs undetectable in C. This study confirms a CsA-induced NO system upregulation in transplanted patients. However, the NO-mediated counterregulatory system to CsA-induced vasoconstriction, present in normals, could be canceled in patients by CsA-induced superoxide (O2-) and free radical production which, by increasing NO metabolism, could contribute to CsA-induced vasoconstriction and hypertension and predispose to atherosclerosis.

Adult↗

Fenofibrate improves age-related endothelial dysfunction in rat resistance arteries.

This study was designed to test the hypothesis that fenofibrate, the peroxisome proliferator-activated receptor alpha (PPARalpha) activator, improves age-related endothelial dysfunction in small mesenteric arteries (SMA). Adult and aged rats were treated with fenofibrate and then endothelium-dependent relaxations of SMA; expressions of endothelial NO synthase (eNOS), cyclo-oxygenase (COX-1 and COX-2) and superoxide dismutases (SOD) (Cu/Zn SOD, Mn SOD and EC SOD) proteins and release of TXB(2) and 6-keto-PGF(1alpha) were assessed. Fenofibrate improved endothelium-dependent vasodilatation of arteries from old rats and decreased participation of endothelial vasoconstrictor products, sensitive to COX-1 and COX-2 inhibitors and acting on Tp receptor. Fenofibrate decreased expressions of COX-1 and COX-2, and generation of TXA(2). Release of vasodilator PGI(2) and U46619-induced contraction remained unaltered. Neither NO-mediated vasodilatation nor eNOS expression was affected. The addition of the scavengers, SOD and catalase increased relaxation only in SMA from control rats. Finally, fenofibrate did not change expressions of Cu/Zn SOD and Mn SOD but it increased EC SOD towards that observed in arteries from adult rats. Fenofibrate improves endothelial function in resistance arteries from aged rats by decreasing expression of COX-1 and COX-2 together with enhancing anti-oxidant capacity of the vessel wall probably through the increased expression of EC SOD. This study provides evidence that PPARalpha may have clinical applications toward maintaining endothelial function during ageing.

Aging↗

Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies.

Endothelium-derived NO is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis. Cardiovascular risk factors are associated with an imbalance of the redox equilibrium towards oxidative stress and, therefore, impair the integrity of the endothelium, leading to endothelial activation which involves blunted endothelium-dependent vasodilation (vasodilator dysfunction) as well as inflammatory processes extending to the milieu within the whole vasculature, making plaques prone to rupture. In prospective studies endothelial dysfunction is associated with increased incidence of cardiovascular events. Thus, the prevention of endothelial dysfunction can determine a strong advantage in the clinical outcome of patients with cardiovascular risk factors. Several non-pharmacological interventions can prevent endothelial dysfunction or improve impaired endothelium-dependent vasodilation. Probably the most effective non-pharmacological measure is represented by aerobic physical activity, which can reduce production of oxidative stress associated to increasing age. Moreover, physical activity can improve endothelial dysfunction even in patients with cardiovascular risk factors such as essential hypertension. In addition several other approaches, including vitamin and fish oil supplementation, or tea and red wine consumption, can lead to an improvement of endothelium-dependent vasodilation, possibly by a restoration of NO availability. It is worth noting that most of non-pharmacological measures act by preventing or reducing oxidative stress.

Biological Factors↗

Endothelial dysfunction in heart transplanted patients with graft vasculopathy.

The pathological mechanism of cardiac transplant vasculopathy (TVP) is uncertain. We tested the hypothesis that the endothelial function, in terms of the release of endothelium-derived relaxing factor, is impaired in patients with angiographic evidence of transplant vasculopathy. In a pilot study, the effects of the substances used (substance P, acetylcholine, nitroglycerin) were assessed as regards tone of pre-contracted human coronary arteries in vitro, obtained from recipient hearts during cardiac transplantation. The study shows that substance P is a "pure' endothelium-dependent dilator of epicardial human coronary arteries, whereas acetylcholine has a more complex effect on vascular tone involving both a direct effect on the endothelium and the smooth muscle cells. In a second pilot study, the effects of intracoronary infusions of substance P (5-100 pmol.min-1) and acetylcholine (2-50 nmol.min-1) on flow velocity were compared in 10 patients undergoing cardiac catherization after heart transplantation. Flow velocity was determined by a 3F Doppler catheter placed into the proximal segment of the left anterior descending artery (LAD). Both drugs increased concentration-dependent flow velocity; substance P and acetylcholine maximally increased flow velocity by about 85 +/- 24% and 143 +/- 15%, respectively (P < 0.05). In a third study, 23 patients undergoing diagnostic cardiac catheterization were included approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of TVP. Coronary flow velocity (by Doppler) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary injections of substance P (20 pmol), nitroglycerin (0.1 mg), and papaverine (8 mg). Substances were injected through the central lumen which was placed into the LAD. Increases in flow velocity in response to substance P were significantly less in patients with TVP than in patients without evidence of TVP. Moreover, flow-mediated vasodilation in response to papaverine was almost abolished in patients with TVP. Vasodilation in response to nitroglycerin and maximal increase in flow velocity in response to papaverine was similar in both groups. These results suggest that TVP is associated with endothelial dysfunction, which may contribute to the pathogenesis of TVP and its vascular complications.

Acetylcholine↗

Endothelial dysfunction early after heart transplantation. Assessment with intravascular ultrasound and Doppler.

BACKGROUND: Allograft vasculopathy after heart transplantation is thought to represent a response to endothelial injury in the graft vessels. To assess endothelial function before the onset of anatomic disease, coronary vasomotor responses to adenosine, acetylcholine, and nitroglycerin were evaluated in transplant recipients by intravascular ultrasound imaging and Doppler flow studies. METHODS AND RESULTS: Nine patients were studied 1 year after heart transplantation. Acetylcholine provoked significant vasoconstriction to 82% of maximal coronary diameter but was associated with an increase in mean coronary blood flow from 63.1 to 204 ml/min. Coronary blood flow increased fivefold in response to adenosine, a normal response. CONCLUSIONS: The vasomotor response to acetylcholine at 1 year after heart transplantation is consistent with endothelial dysfunction in the epicardial conduit vessels. Microvascular function as judged by coronary flow reserve appears to be normal.

Acetylcholine↗

Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction.

Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg. kg(-1). d(-1) enalapril (WKY-E group) or a combination of 50 mg. kg(-1). d(-1) hydralazine and 7.5 mg. kg(-1). d(-1) hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10(-)(5) mol/L ACh in the presence of norepinephrine: WKY-O, -14+/-2 mV; WKY-E, -22+/-3 mV; WKY-H, -15+/-2 mV; and WKY-Y, -28+/-0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45+/-6%; WKY-E, 63+/-8%; WKY-H, 43+/-4%; and WKY-Y, 72+/-4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K(+) channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system.

Acetylcholine↗

Endothelial dysfunction in response to psychosocial stress in monkeys.

The current study was designed to evaluate the effects of a disrupted social environment on the endothelial integrity of various vascular segments in male cynomolgus monkeys (Macaca fascicularis). Each of 20 single-caged adult monkeys was fed a diet comparable to a person's ingestion of 240 mg cholesterol/day for a 10-week baseline period and then was introduced as a stranger into a four-member social group for 3 days. Half of the monkeys received a beta-adrenergic blocking agent (metoprolol) via subcutaneous implant 2 days before and during group housing. The social manipulation produced persistent sympathetic arousal as evidenced by significantly elevated heart rates among untreated monkeys (p less than 0.01) but not among their metoprolol-treated counterparts, whose heart rate declined (p less than 0.05). After the social manipulation, all monkeys were necropsied and evaluated for endothelial incorporation of immunoglobulin G (as an indicator of cell death), endothelial cell replication, the presence of adherent leukocytes, and arterial low density lipoprotein permeability and concentration. At branching sites in the thoracic aorta, immunoglobulin G incorporation and endothelial cell replication were significantly greater in untreated monkeys than in metoprolol-treated monkeys (p less than 0.01 for both analyses); no differences existed at nonbranch sites. Endothelial cell replication in the coronary arteries (where immunoglobulin G incorporation was not examined) was also greater among untreated than among metoprolol-treated monkeys. No significant differences were observed between treatment groups in arterial low density lipoprotein permeability or leukocyte adherence; estimates of arterial low density lipoprotein concentrations were higher among untreated than among metoprolol-treated monkeys, but only in the abdominal portion of the aorta. These results indicate that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by treatment with a beta-adrenergic blocking agent.

Animals↗

Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction.

The goal of the present study was to test the hypothesis that the CuZn isoform of superoxide dismutase (CuZnSOD) protects against angiotensin II (Ang II)-induced endothelial dysfunction. Vascular responses of carotid arteries from control, CuZnSOD-deficient (CuZnSOD(+/-)), and CuZnSOD transgenic mice were examined in vitro after overnight incubation with either vehicle or Ang II (1 or 10 nmol/L). In control mice, acetylcholine produced concentration-dependent relaxation that was not affected by 1 nmol/L Ang II. In contrast, relaxation to acetylcholine in arteries from CuZnSOD+/- mice was markedly and selectively attenuated after incubation with 1 nmol/L Ang II (eg, 100 micromol/L acetylcholine produced 93+/-6% and 44+/-15% relaxation in vehicle- and Ang II-treated arteries, respectively). A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to acetylcholine in arteries from control mice (eg, 100 micromol/L acetylcholine produced 96+/-4% and 45+/-7% relaxation in vehicle- and Ang II-treated vessels, respectively). In contrast, 10 nmol/L Ang II had no effect on responses to acetylcholine in carotid arteries from CuZnSOD transgenic mice (or in control mice treated with the superoxide scavenger Tiron [1 mmol/L]). Superoxide levels in control mice were higher in aorta treated with Ang II than with vehicle and were markedly reduced in CuZnSOD transgenic mice. These findings provide the first direct evidence that CuZnSOD limits Ang II-mediated impairment of endothelial function and that loss of 1 copy of the CuZnSOD gene is sufficient to enhance Ang II-induced vascular dysfunction.

Acetylcholine↗

Vascular endothelial dysfunction tested by blunted response to endothelium-dependent vasodilation by salbutamol and its related factors in uncomplicated pre-menopausal obese women.

BACKGROUND: Vascular endothelial dysfunction (VED) plays a pivotal role in the pathogenesis of atherosclerosis and is associated with insulin resistance and visceral obesity. We examined the predicting factors of VED in uncomplicated premenopausal obese women using analysis of endothelium-dependent vasodilation by radial artery pulse wave obtained through applanation tonometry. METHODS: The subjects included a group of 33 obese women body mass index ((BMI) > or = 25) and another age-matched control group of 25 nonobese women (BMI: 18.5-22.9) of Asian origin. All uncomplicated premenopausal (20-45 y) obese women were sedentary (<1 h/week of physical activity). Anthropometric measurements were performed, and regional distributions of adipose tissue and metabolic variables were measured. Endothelial function was measured by pulse wave analysis after salbutamol administration, which reflects endothelium-mediated vasodilation, contributed partially by nitric oxide release from beta2-adrenergic stimulation. Radial artery wave forms were recorded and from a derived aortic wave forms augmentation index (AIx, defined as the pressure difference between the first and second peaks of the central arterial wave form, expressed as a percentage of the pulse pressure) was calculated. The subjects received sublingual nitroglycerine (NTG) (0.6 mg), followed by nebulized salbutamol (2.5 mg). RESULTS: AIx fell significantly after the administration of salbutamol, which causes endothelium-dependent vasodilatation. This value was significantly reduced in obese women compared with the controls (10.3+/-6.7 vs 17.2+/-6.8%, P=0.0003). NTG, which causes endothelium-independent vasodilatation, did not produce significant changes (P=0.917). As for our obese subjects, the visceral adipose tissue area was a significant predictor of VED independent of BMI, percent body fat, and other metabolic variables including high-sensitivity C-reactive protein (beta = -0.141, P=0.002, Adj-R(2)=0.41). CONCLUSION: Increased abdominal adiposity is a powerful independent predictor of VED in uncomplicated obese women. Further studies are warranted to determine the pathophysiological link between visceral adipose tissue and VED.

Abdomen↗

Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia.

Mildly elevated plasma homocysteine levels are an independent risk factor for atherothrombotic vascular disease in the coronary, cerebrovascular, and peripheral arterial circulation. Endothelial dysfunction as manifested by impaired endothelium-dependent regulation of vascular tone and blood flow, by increased recruitment and adhesion of circulating inflammatory cells to the endothelium, and by a loss of endothelial cell antithrombotic function contributes to the vascular disorders linked to hyperhomocysteinemia. Increased vascular oxidant stress through imbalanced thiol redox status and inhibition of important antioxidant enzymes by homocysteine results in decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation. This plays a central role in the molecular mechanisms underlying the effects of homocysteine on endothelial function. Supplementation of folic acid and vitamin B12 has been demonstrated to be efficient in lowering mildly elevated plasma homocysteine levels and in reversing homocysteine-induced impairment of endothelium-dependent vasoreactivity. Results from ongoing intervention trials will determine whether homocysteine-lowering therapies contribute to the prevention and reduction of atherothrombotic vascular disease and may thereby provide support for the causal relationship between hyperhomocysteinemia and atherothrombosis.

Arteriosclerosis↗

Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients.

BACKGROUND: Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction and inflammation through oxidative stress. Statins and angiotensin type 1 receptor blockers have been shown to reduce oxidative stress and inflammation, improving endothelial function. METHODS AND RESULTS: Twenty type 2 diabetic patients ate 3 different test meals: a high-fat meal, 75 g glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, endothelial function, nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 were assayed during the tests. Subsequently, diabetics took atorvastatin 40 mg/d, irbesartan 300 mg/d, both, or placebo for 1 week. The 3 tests were performed again between 5 and 7 days after the start of each treatment. High-fat load and glucose alone produced a decrease in endothelial function and increases in nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6. These effects were more pronounced when high-fat load and glucose were combined. Short-term atorvastatin and irbesartan treatments significantly counterbalanced these phenomena, and their combination was more effective than either therapy alone. CONCLUSIONS: This study confirms an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function and inflammation, suggesting oxidative stress as a common mediator of such an effect. Short-term treatment with atorvastatin and irbesartan may counterbalance this phenomenon; the combination of the 2 compounds is most effective.

Anticholesteremic Agents↗

The ACE-DD genotype is associated with endothelial dysfunction in postmenopausal women.

OBJECTIVE: To evaluate the effects of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the angiotensinogen M235T and the angiotensin II type 1 receptor A1166C polymorphisms, and hormone therapy used on endothelial function in postmenopausal women without manifestation of coronary artery disease. DESIGN: Sixty-four postmenopausal women (42 hormone therapy users and 22 hormone therapy nonusers) without clinical manifestation of coronary artery disease were evaluated using external vascular ultrasonography to measure endothelium-dependent (hyperemic response, flow-mediated dilatation) and -independent (nitroglycerin) dilatation. Genotypes were determined by polymerase chain reaction amplification. RESULTS: Women with the ACE-DD genotype displayed a lower flow-mediated dilatation compared to those with the ACE-II genotype (8.4% +/- 3.9% vs 12.6% +/- 5.4%, P = 0.04). Endothelial function was not associated with the angiotensinogen M235T and anglotensin II type 1 receptor A1166C polymorphisms. ACE polymorphism seems to modulate endothelial function among postmenopausal women without hormone therapy (8.2% +/- 5.1% vs 18.4% +/- 5.9% for the DD and the II genotype, respectively, P = 0.02). However, in hormone therapy users, flow-mediated dilatation was similar according to the ACE genotypes. CONCLUSIONS: Our findings suggest that ACE-I/D polymorphism is related to endothelial dysfunction in postmenopausal women. Furthermore, a potential interaction between estrogen users and ACE polymorphism on endothelial function may be present.

Alleles↗

Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers.

OBJECTIVES: This study was designed to assess the effect of flavanol-rich food on the circulating pool of bioactive nitric oxide (NO) and endothelial dysfunction in smokers. BACKGROUND: Studies suggest that smoking-related vascular disease is caused by impaired NO synthesis and that diets rich in flavanols can increase bioactive NO in plasma. METHODS: In smokers (n = 11), the effects of flavanol-rich cocoa on circulating NO species in plasma (RXNO) measured by reductive gas-phase chemiluminescence and endothelial function as assessed by flow-mediated dilation (FMD) were characterized in a dose-finding study orally administering cocoa containing 88 to 370 mg flavanols and in a randomized double-blind crossover study using 100 ml cocoa drink with high (176 to 185 mg) or low (<11 mg) flavanol content on two separate days. In addition to cocoa drink, ascorbic acid and NO-synthase inhibitor L-NMMA (n = 4) were applied. RESULTS: There were significant increases in RXNO (21 +/- 3 nmol/l to 29 +/- 5 nmol/l) and FMD (4.5 +/- 0.8% to 6.9 +/- 0.9%, each p < 0.05) at 2 h after ingestion of 176 to 185 mg flavanols, a dose potentially exerting maximal effects. These changes correlated with increases in flavanol metabolites. Cocoa-associated increases in RXNO and FMD were reversed by L-NMMA. Ascorbic acid had no effect. CONCLUSIONS: The circulating pool of bioactive NO and endothelium-dependent vasodilation is acutely increased in smokers following the oral ingestion of a flavanol-rich cocoa drink. The increase in circulating NO pool may contribute to beneficial vascular health effects of flavanol-rich food.

Adult↗