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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.

Objective: We investigated the effect of apocynin, an NADPH oxidase inhibitor, in the impairment of vascular responses in Otsuka Long-Evans Tokushima Fatty (OLETF) rats (type 2 diabetic rat model) with or without (w/wo) N-nitro-l-arginine methyl ester treatment., Methods: Male OLETF and littermate Long-Evans Tokushima Otsuka (LETO) (28 weeks old) rats were separated as follows: LETO w/wo apocynin (Gp C, Gp C-apo), OLETF w/wo apocynin (Gp DM, Gp DM-apo) and OLETF plus l-nitro arginine acetate ester w/wo apocynin (Gp DMLN, Gp DMLN-apo). Five days after, peritoneal macrophages were stimulated with thioglycolate. Two days after, they were evaluated., Results: Plasma glucose and lipid levels remained unchanged. Acetylcholine-induced nitric oxide-dependent (NO-dependent) relaxation and nitroglycerin-induced NO-independent relaxation were improved in the Gp DMLN-apo, compared with that in Gp DMLN. Tone-related basal NO release and plasma NO(2) (-) and NO(3) (-) tended to be lower in Gp DM and Gp DMLN groups. The increased amount of superoxide anion released from macrophages in Gp DM and Gp DMLN was restored by apocynin. Intimal thickening was observed in aortae of Gp DM and Gp DMLN animals; however, there was little in aortae of Gp DM-apo and Gp DMLN(-) apo rats. Increased tumour necrosis factor-alpha (TNF-alpha) in the Gp DM and Gp DMLN was also restored by apocynin treatment., Conclusion: Apocynin restores the impairment of endothelial and non-endothelial function in diabetic angiopathy in OLETF without changing plasma glucose and lipid levels. NO and O(2) (-) may play a role in this process by decreasing TNF-alpha levels.

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)(-).