ABSTRACT
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.
Subject(s)
Amidines/pharmacology , Atherosclerosis/prevention & control , Cholesterol, Dietary/pharmacology , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase Type II/antagonists & inhibitors , Animals , Aorta, Thoracic/enzymology , Aorta, Thoracic/pathology , Arginine/pharmacology , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Blotting, Western , Cholesterol, Dietary/blood , Cyclic GMP/metabolism , Endothelium, Vascular/enzymology , Endothelium, Vascular/pathology , Heterocyclic Compounds, 2-Ring/pharmacology , Immunohistochemistry , Macrophages/pathology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/genetics , Nitric Oxide Synthase Type III/metabolism , RNA, Messenger/metabolism , Rabbits , Reactive Oxygen Species/metabolism , Up-Regulation/drug effects , Vasodilation/drug effectsABSTRACT
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)(-).
Subject(s)
Arteriosclerosis/drug therapy , Arteriosclerosis/physiopathology , Enzyme Inhibitors/pharmacology , Quinolines/pharmacology , Administration, Oral , Animals , Arteriosclerosis/veterinary , Biological Availability , Cholesterol, HDL/blood , Disease Models, Animal , Disease Progression , Female , Nitric Oxide/pharmacology , Rabbits , Triglycerides/blood , Up-RegulationABSTRACT
The effect of L-carnitine on lipid peroxidation and enzymatic antioxidants, such as superoxide dismutase, catalase, and glutathione peroxidase, was evaluated in brain regions of young and old rats. In all brain regions except the hypothalamus, lipid peroxidation was higher for old rats than for young control rats. The activity of superoxide dismutase, glutathione peroxidase, and catalase was lower in the striatum, cerebral cortex, and hippocampus, but no difference was observed in the hypothalamus and cerebellum. L-Carnitine administration (intraperitoneally) prevented thiobarbituric acid-reactive substance formation in the cerebral cortex, cerebellum, hypothalamus, hippocampus, and striatum of 24-month-old rats. Administration of L-carnitine reversed the age-associated changes in a duration-dependent manner. Results suggest that the neuroprotective effect on the brains in old rats was achieved by the elevation of antioxidants with L-carnitine.
