Increased Bioavailability of Nitric Oxide After Lipid-Lowering Therapy in Hypercholesterolemic Patients : A Randomized, Placebo-Controlled, Double-blind Study (original) (raw)
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Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients
2000
We tested the effects of vitamin C and atorvastatin treatment on endothelium-dependent and endothelium-independent vasodilation in 18 hypercholesterolemic patients (ten men and eight women, aged 20 -46 years) in comparison with 12 normal volunteers (seven men and five women, aged 20-45 years). The responses of the forearm blood flow (FBF) to acetylcholine (ACh) (7.5, 15 and 30 mg/min), sodium nitroprusside (SNP) (0.8, 1.6, 3.2 mg/min) and L-NMMA (2, 4, 8 mmol/min) were evaluated at baseline and after 1 month of atorvastatin (10 mg/day) treatment. Drugs were infused into the brachial artery and FBF was measured by strain-gauge plethysmography. At baseline, the response to ACh was significantly attenuated in hypercholesterolemics versus controls: at the highest dose (30 mg/min), FBF was 27.09 3.4 versus 11.5 91.9 ml·100 ml tissue − 1 ·min − 1 respectively (PB 0.0001). No significant differences were found between groups during SNP infusion. The atorvastatin treatment significantly improved ACh-stimulated FBF: at highest dose the FBF increased to 14.9 91.5 ml·100 ml tissue − 1 ·min − 1 (PB 0.0001). Similarly, the L-NMMA endothelial effects were significantly enhanced by lipid-lowering treatment, supporting the improvement of basal nitric oxide. Vitamin C increased ACh-vasodilation in the same way before and after atorvastatin treatment. In conclusion, the endothelial dysfunction in hypercholesterolemics is due to an oxidative stress and atorvastatin rapidly improves both basal and stimulated endothelium-dependent vasodilation.
2000
There is controversy regarding the relation between hypertriglyceridemia (HTG) and endothelial function. This study was designed to investigate endothelial function in a patient group with chronic HTG, before and during lipid-lowering therapy by atorvastatin. In addition, the effects of acute HTG on endothelial function were studied in normolipidemic individuals. Eight male patients with chronic HTG were studied before and after 6 weeks of lipid-lowering treatment with 80 mg atorvastatin once daily. Ten age-matched control subjects were studied at baseline and immediately after a high-dose infusion of artificial triglycerides. The endothelium-dependent response to serotonin was attenuated in the HTG group, whereas the response to acetylcholine was comparable to the response in the control group. The response to the endothelium-independent vasodilator nitroprusside was comparable in both groups. In response to atorvastatin therapy, serum triglyceride and cholesterol levels decreased significantly by 43% (paired t test, Pϭ0.017) and 38% (paired t test, Pϭ0.012), respectively. After 6 weeks of treatment, the forearm blood flow response to serotonin improved from 63% to 106% (ANOVA, PϽ0.001). Induction of acute HTG in the control subjects did not affect the forearm blood flow responses to serotonin and nitroprusside; however, the response to acetylcholine was paradoxically increased. In conclusion, patients with chronic HTG have an impaired endothelium-dependent vasodilation to serotonin that is normalized after 6 weeks of lipid-lowering therapy by atorvastatin. (Arterioscler Thromb Vasc Biol. 2000;20:744-750.)
The American Journal of Cardiology, 2003
T here currently is great interest in the early treatment of patients with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) in the setting of an acute coronary syndrome, 1 and investigators have postulated that improved endothelial function may contribute to early benefits that occur before lesion regression. The beneficial effects of statins on endothelial function in patients with coronary disease 2,3 may relate to a decrease in serum cholesterol 4 -6 or to direct effects of these agents on the vasculature. 7-9 The present report examines the non-lipidlowering effects of atorvastatin on vascular function in patients with coronary artery disease.
Cardiovascular Therapeutics, 2012
Aim: Endothelial dysfunction is a marker for development and progression of atherosclerosis. Statin therapy improves endothelial function in cardiovascular patients by reducing LDL-cholesterol and by pleiotropic effects. B-group vitamin supplementation restores endothelial function mainly by reducing homocysteine-induced oxidative stress. Thus, we evaluated the effect of rosuvastatin, B-group vitamins and their combination on endothelial function in high-risk cardiovascular patients. Methods: Thirty-six patients with cardiovascular disease were randomly, double-blinded assigned to either rosuvastatin 10 mg (group R, n = 18) or vitamin supplementation consisting of folic acid 1 mg, vitamin B12 0.4 mg, and B6 10 mg (group V, n = 18) for 6 weeks. After 6 weeks all patients received rosuvastatin and vitamin supplementation in combination for additional 6 weeks. Endothelial function was assessed by flow-mediated vasodilation (FMD) at baseline and after 6-and 12-week treatment. Results: At baseline, FMD, plasma lipids, vitamins, and homocysteine were comparable between both groups. After 6 weeks, FMD improved in both groups (from 4.4 ± 1.6 to 6.9 ± 1.4% group R, P = 0.0004 and from 4.9 ± 1.8 to 6.4 ± 1.8% group V, P = 0.0002). This improvement in FMD was mainly associated with a decrease of plasma lipids in group R and a decrease of homocysteine in group V. After 12 weeks, the combined therapy with rosuvastatin and vitamins further improved FMD to the normal range in 26/33 patients compared to 5/36 at baseline (P < 0.0001). Conclusions: In conclusion, both treatments, rosuvastatin and B-group vitamin supplementation, improved endothelial function in high-risk cardiovascular patients. The combination of both therapies had an additive effect on endothelial function suggesting different mechanisms of action.
American Heart Journal, 2002
Background: Low levels of high-density lipoprotein (HDL) cholesterol increase the risk of coronary artery disease (CAD), and recent clinical studies suggest that interventions in low-HDL patients are beneficial. The purpose of this study was to examine the effect of increased HDL levels on endothelium-dependent vasodilation. Methods: We studied patients with CAD with a low-density lipoprotein (LDL) level of <100 mg/dL. Patients with an HDL level of <36 mg/dL were treated with niacin (n = 11), and patients with an HDL level of >36 mg/dL were followed as controls (n = 10). Baseline and 3-month follow-up studies of flow-mediated dilation (FMD) and blood lipid levels were obtained. Results: HDL levels increased from 30.1 ± 1.2 to 40.5 ± 1.2 mg/dL in the niacin-treated patients (P < .001) but remained unchanged in the control patients. At baseline, FMD was impaired in both the treated (6.5% ± 1%) and the control (7.3% ± 1%) patients compared with 10 healthy subjects (16% ± 2%, P < .01). After 3 months, FMD improved in the niacin-treated patients (11.8% ± 1%, P = .001) but remained unchanged in the control patients (6.2% ± 1%). Exposure of cultured human vascular endothelial cells to HDL in vitro enhanced expression of endothelial nitric oxide synthase (eNOS), as shown by immunoblotting. Conclusions: In patients with CAD and well-controlled LDL levels, elevation of HDL with niacin improves endothelial function. HDL increases eNOS protein expression in cultured vascular endothelial cells. Taken together, these observations suggest that HDL-mediated increases in eNOS expression may contribute to the observed enhancement in vasorelaxation and thus support a previously unrecognized mechanism for the beneficial cardiovascular effects of HDL.
Cardiovascular Research, 1999
Objective: Dihydropyridine calcium antagonists have been shown to retard atherogenesis in animal models and to prevent the development of early angiographic lesions in human coronary arteries. Endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. We investigated whether nifedipine could improve endothelial function in hypercholesterolemia, independently of changes in blood pressure or plasma lipids. Methods: First, we compared in vivo forearm vascular responses to the endotheliumdependent and independent vasodilators serotonin (5-HT) and sodium nitroprusside (SNP) in 11 patients with familial hypercholesterolemia before and after 6-weeks treatment with nifedipine GITS (60 mg, OD) and in 12 matched controls. In a subgroup of six control subjects forearm vascular function was also assessed before and after 6-weeks nifedipine GITS treatment. In vitro, we subsequently explored possible mechanisms underlying the effect of nifedipine on endothelial function. We investigated the effects of nifedipine on 3 both NO production by recombinant endothelial NO synthase (eNOS) and endothelial cells, using H-arginine conversion, as well as on superoxide generation by endothelial cell lysates, using lucigenin enhanced chemiluminescence. Results: In hypercholesterolemia 5-HT-induced vasodilation was impaired (4769% increase in forearm bloodflow vs. 9968% in controls). Treatment with nifedipine completely restored 5-HT-induced vasodilation (113613%), whereas it did not influence basal forearm vasomotion or SNP-induced vasodilation. Nifedipine did not alter forearm vascular responses in control subjects and did not alter blood pressure or plasma lipids. In vitro, we found no direct effect of nifedipine on NO production by recombinant eNOS or endothelial cells. However, we did observe a reduction in endothelial superoxide generation. Conclusions: Our data show that nifedipine improves endothelial function in hypercholesterolemia. It is suggested from our in vitro experiments that this effect is due to reduced NO degradation.
Cardiovascular Research, 1999
Objective: Hypercholesterolemia has been shown to impair endothelium-mediated, nitric oxide (NO)-dependent responses to acetylcholine (ACh), serotonin, substance P and flow-mediated dilation. We have recently shown that NO contributes to metabolic vasodilation in the human forearm. We sought to determine whether metabolic vasodilation is impaired in healthy subjects with hypercholesterolemia. Methods: We compared the forearm blood flow (FBF) responses to isotonic exercise, ACh and the endotheliumindependent vasodilator sodium nitroprusside in young, otherwise healthy volunteers with hypercholesterolemia and controls before and G after the NO inhibitor N-monomethyl-L-arginine (L-NMMA). FBF was measured using venous occlusion plethysmography. Hypercholesterolemic (n520) and control (n520) subjects were age-and gender-matched. Results: Total cholesterol (6.960.3 vs. 4.660.1 mmol / l, P,0.0001), low density lipoprotein (4.960.4 vs. 2.760.1 mmol / l, P,0.001) and triglyceride (1.360.2 vs. 0.860.1 mmol / l, P50.005) levels were higher in the hypercholesterolemic group. Basal FBF and resistance were similar in the two groups. Hypercholesterolemia impaired the peak FBF response to ACh (11.161.9 vs. 17.662.2 ml / 100 ml / min, P50.03), and reduced the peak response to sodium nitroprusside (6.060.4 vs. 8.160.6 ml / 100 ml / min, P,0.01). However, hypercholesterolemia did not affect peak hyperemic FBF (13.161.0 vs. 13.261.0 ml / 100 ml / min, P51.0) or the FBF volume repayment during the 1 or 5 min after exercise. Resting FBF was reduced by L-NMMA to a similar degree (by 33% vs. 40%, P50.17) in both groups. Although L-NMMA reduced peak hyperemic FBF (by 16% vs. 17%, P50.93) and the volume repaid after exercise in both groups, there were no differences between the two groups. Conclusions: Exercise-induced metabolic vasodilation is in part dependent on NO release. Hypercholesterolemia impairs NO-mediated vasodilation, but is not associated with a reduction in exercise-induced hyperemia. This may indicate that multiple compensatory mechanisms are operative in skeletal muscle metabolic vasodilation.
Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy, 2000
The objective of this study was to investigate the vascular and biochemical effects of a formulated product in the form of a bar enriched with a combination of nutrients known to enhance the synthesis or activity of endothelium-derived nitric oxide (EDNO). Individuals with hypercholesterolemia manifest impaired flow-mediated vasodilation, which is largely due to a reduction in EDNO activity. Oral supplementation with large amounts (6-21 g/day) of L-arginine, the precursor of EDNO, have been shown to improve endothelium-mediated vasodilation in hypercholesterolemia. Such large doses are effective but may be impractical to take in capsule form. Accordingly, we have developed a nutrient bar enriched with L-arginine as well as other ingredients that additively enhance EDNO activity. A pilot study in 41 hypercholesterolemic individuals indicated that the bar was well tolerated, had no adverse effects on serum chemistries or lipid profile, and normalized endothelial vasodilator function. ...
Brazilian Journal of Medical and Biological Research, 2002
The objective of the present study was to identify disturbances of nitric oxide radical ( · NO) metabolism and the formation of cholesterol oxidation products in human essential hypertension. The concentrations of · NO derivatives (nitrite, nitrate, S-nitrosothiols and nitrotyrosine), water and lipid-soluble antioxidants and cholesterol oxides were measured in plasma of 11 patients with mild essential hypertension (H: 57.8 ± 9.7 years; blood pressure, 148.3 ± 24.8/90.8 ± 10.2 mmHg) and in 11 healthy subjects (N: 48.4 ± 7.0 years; blood pressure, 119.4 ± 9.4/75.0 ± 8.0 mmHg). Nitrite, nitrate and S-nitrosothiols were measured by chemiluminescence and nitrotyrosine was determined by ELISA. Antioxidants were determined by reverse-phase HPLC and cholesterol oxides by gas chromatography. Hypertensive patients had reduced endothelium-dependent vasodilation in response to reactive hyperemia (H: 9.3 and N: 15.1% increase of diameter 90 s after hyperemia), and lower levels of ascorbate (H: 29.2 ± 26.0, N: 54.2 ± 24.9 µM), urate (H: 108.5 ± 18.9, N: 156.4 ± 26.3 µM), ß-carotene (H: 1.1 ± 0.8, N: 2.5 ± 1.2 nmol/mg cholesterol), and lycopene (H: 0.4 ± 0.2, N: 0.7 ± 0.2 nmol/mg cholesterol), in plasma, compared to normotensive subjects. The content of 7-ketocholesterol, 5acholestane-3ß,5,6ß-triol and 5,6a-epoxy-5a-cholestan-3a-ol in LDL, and the concentration of endothelin-1 (H: 0.9 ± 0.2, N: 0.7 ± 0.1 ng/ml) in plasma were increased in hypertensive patients. No differences were found for · NO derivatives between groups. These data suggest that an increase in cholesterol oxidation is associated with endothelium dysfunction in essential hypertension and oxidative stress, although · NO metabolite levels in plasma are not modified in the presence of elevated cholesterol oxides.