Background-The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known. Methods and Results-We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3Ϯ3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.
The objective of this study was to evaluate the influence of ingested L-arginine, L-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a highcholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with L-arginine, L-citrulline, and͞or antioxidants. L-arginine plus L-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma NO 2 ؊ ؉ NO 3 ؊ and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including L-arginine, L-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.antioxidant ͉ nitric oxide ͉ amino acids ͉ endothelial nitric oxide synthase A therosclerosis is an inflammatory disease (1) characterized by vascular endothelial cell dysfunction and diminished production of NO (2-5). Endothelial NO synthase (eNOS) gene transfer can reduce atherogenesis in hypercholesterolemic animals (6). NO is a widespread signaling molecule in the cardiovascular system, which functions in multiple ways to protect against the initiation and progression of atherosclerosis (7-9). For example, NO aids in preventing the adhesion and aggregation of blood cells and platelets along the endothelial cell lining in blood vessels (7,8) and is a potent inhibitor of vascular smooth muscle cell proliferation (10). NO is a potent antioxidant that can elicit antiinflammatory effects by scavenging certain reactive oxygen species (11-13), and it can prevent the oxidation of low-density lipoprotein cholesterol and thereby retard the progression of atherosclerosis (5, 14). Moreover, NO deficiency is generally associated with up-regulation of oxidation-sensitive genes, whereas increased NO production leads to decreased expression of oxidation-sensitive genes (7,15). NO is synthesized by NOS, which utilizes L-arginine as substrate and produces L-citrulline as the second reaction product. L-arginine can be synthesized from L-citrulline in endothelial and other cell types, thereby providing a recycling pathway for the conversion of L-citrulline to NO via L-arginine (16)(17)(18)(19).The oral administration of L-arginine to animals (7, 12, 20-26) and humans (5,8,(27)(28)(29) has been demonstrated to slow the progressi...
OBJECTIVE—We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2α (8-epi-PGF2α), an oxidative stress marker. RESEARCH DESIGN AND METHODS—A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of β-cell function, HbA1c, C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2α, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS—After 8 weeks of glimepiride treatment, significant reductions were observed in HbA1c (from 8.4 ± 1.9 to 6.9 ± 1.0%), HOMA-IR (from 2.54 ± 2.25 to 1.69 ± 0.95%), and plasma TNF-α concentrations (from 4.0 ± 2.0 to 2.6 ± 2.5 pg/ml). MCR-g was significantly increased from 3.92 ± 1.09 to 5.73 ± 1.47 mg · kg−1 · min−1. Plasma adiponectin increased from 6.61 ± 3.06 to 10.2 ± 7.14 μg/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS—Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA1c without changing extrapancreatic β-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-α may underlie the improvement of insulin resistance with glimepiride.
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