Selective iNOS inhibitor, ONO1714 successfully retards the development of high-cholesterol diet induced atherosclerosis by novel mechanism

ObjectiveWe 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 resultsSeven 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. O2− release was decreased in Gp2-O17 and Gp7-LN-O17.ConclusionONO1714 retards the progression of atherosclerosis in rabbits. Although the up-regulation of endothelial nitric oxide synthase (eNOS) and the decrease of O2− may play roles in this retardation, the inhibition of iNOS may be the principal factor, alone was not sufficient.