Search

Background: Atherosclerosis-related diseases are leading causes of morbidity among patients undergoing hemodialysis. The effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on the endothelial function of hemodialyzed patients are not known., Methods and Results: For 16 weeks, we prescribed simvastatin (low dose: 5 mg or moderate dose: 10 mg) to 28 patients (low dose: n=14, 61.2 ± 8.6 years, moderate dose: n=14, 60.8 ± 10.2 years) and chose 9 patients (61.5 ± 5.2 years) without prescriptions as controls. We compared the effects of statin on lipids, flow-mediated endothelium-dependent and nitroglycerin-induced endothelium-independent dilatation (%FMD, %NTD), and markers of oxidant stress and atherosclerosis. Serum HDL-cholesterol and triglycerides did not change significantly in any of the three groups; however, LDL-cholesterol was decreased at 16 weeks in both simvastatin groups. The %FMD and plasma NOx increased at 1 and 16 weeks in both statin groups, but not in the control group (P<0.01). The %NTD did not change. Oxidized LDL, VCAM-1, and 8-isoprostane decreased significantly after 16 weeks in both statin groups; however, TNF-α and interleukin 6 did not change. In the control group, no significant changes in these parameters were observed. Multiple regression analyses showed that the (short) period of hemodialysis and (young) age are significant factors associated with %FMD improvement., Conclusions: A statin improved impaired endothelial function in the arteries of chronic dialysis patients, in part by enhancing NO bioavailability within one week. Improved endothelial function is in line with the anti-atherosclerotic effects observed in patients undergoing chronic hemodialysis., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: We have reported that inducible nitric oxide synthase (iNOS) is present only in deep areas of plaque in atherosclerosis. However, the role of iNOS in the development of atherosclerosis is not well known. We therefore investigated the relevance of iNOS inhibition., Methods and Results: Seven groups of male rabbits were fed a 0.5% high-cholesterol diet (HCD) for 8 weeks. Gp1-HCD was fed HCD only; Gp2-O17 was fed HCD with ONO1714, an iNOS inhibitor; Gp3-AG was fed HCD with amino-guanidine (AG), an iNOS inhibitor; Gp4-AR was fed HCD with l-arginine; Gp5-AR-O17 was fed HCD with l-arginine with ONO1714; Gp6-LNA was fed HCD with l-NAME (a NOS inhibitor); and Gp7-LN-O17 was fed HCD with l-NAME plus ONO1714. ONO1714 decreased atherosclerosis by about 70% (area occupied by lesions: 3.0+/-0.4% in Gp2-O17 versus 10.3+/-1.6% in Gp1-HCD) and also decreased atherosclerosis in Gp7-LN-O17. The ONO compound enhanced the atheroprotective effect of l-arginine. Amino-guanidine also showed an anti-atherosclerotic effect. Tone-related basal NO release and acetylcholine-induced NO-dependent relaxation were improved in Gp2-O17 and Gp5-AR-O17. O(2)(-) release was decreased in Gp2-O17 and Gp7-LN-O17., Conclusion: ONO1714 retards the progression of atherosclerosis in rabbits. Although the up-regulation of endothelial nitric oxide synthase (eNOS) and the decrease of O(2)(-) may play roles in this retardation, the inhibition of iNOS may be the principal factor, alone was not sufficient.

Background: Approximately 80% of cases of ischemic heart disease (IHD) occur in patients with nonstenotic coronary arteries, and few studies have systematically assessed exercise testing (TMT) as a predictor of risk in the elderly., Methods: TMT was carried out using a protocol for the independent and active elderly (n=176). After 4.1+/-0.5 years follow-up, logistic regression analysis was performed for each coronary risk factor such as diabetes mellitus (DM) and hypercholesterolemia (HC). According to the results, patients were divided into Gp HC, hypercholesterolemic patients; Gp DM, diabetics; Gp HC+DM, hypercholesterolemic diabetics; and Gp C, nonhyperlipidemic and nondiabetics. Sensitivity and specificity of TMT for IHD (significant stenosis or acute coronary syndrome) were analyzed., Results: Odds ratios for each risk factors are as follows: DM, 4.167; HC, 4.485; and DM+HC, 8.652. Notably, TMT was 17.59. Age was a significant risk, but hypertension was not. Positive ischemic signs in TMT were observed in 52.7%, 28.6%, 33.3%, and 16.3% in the Gp HC+DM, HC, DM, and C groups, respectively. Only three participants complained of chest pain during the TMT. Significant stenosis was observed in 75.0%, 71.4%, 69.2%, and 60.0% of coronary angiography (CAG)-receiving patients of Gp HC, DM, HC+DM, and C. During the observation term, acute coronary syndromes occurred in 4.7%, 3.3%, 5.5%, and 0% of patients in the Gp HC, DM, HC+DM, and C groups, respectively. The sensitivity of TMT for IHD was higher than 66.7% and specificity was higher than 94.1% in each group., Conclusion: An exercise tolerance test in the elderly, especially for diabetics and hypercholesterolemic patients, is useful for the diagnosis of IHD.

Background: The remarkable anti-atherosclerotic effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model., Objective: We have investigated the effect of pitavastatin, a newly developed statin, on atherosclerosis in rabbits., Methods and Results: Oophorectomized female NZW rabbits were fed 0.3% cholesterol chow for 12 weeks with or without pitavastatin (0.1mg/kg per day) (Gp.NK and HCD). The level of serum cholesterol was decreased in Gp.NK compared with Gp.HCD (772.8 +/- 70.2 versus 1056.9 +/- 108.3 mg/d), whereas no significant alterations were observed in triglyceride and HDL-cholesterol. NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-l-arginine acetate were all improved by pitavastatin treatment. Pitavastatin treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits. In the aorta, the expression of eNOS mRNA was significantly up regulated and O(2)(-) production was slightly reduced in Gp.NK animals. Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp.NK compared with those from Gp.HCD ( 15.1 +/- 5.3 versus 41.9 +/- 10.2%, 3.1 +/- 1.1versus 7.9 +/- 1.2% in Gp.NK and Gp.HCD aortic arch and thoracic aorta). Anti-macrophage staining area, the MMP1 or 2 and the nitrotyrosine positive area were decreased in Gp.NK., Conclusion: Pitavastatin retards the progression of atherosclerosis formation and it improves NO bioavailability by eNOS up-regulation and decrease of O(2)(-).