Endothelium-dependent relaxation of rabbit atherosclerotic aorta was not restored by control of hyperlipidemia: the possible role of peroxynitrite (ONOO^-)

We determined the role of ONOO^- in nitric oxide (NO) mediated vascular response in atherosclerosis and regression following removal of dietary cholesterol. The effect of ONOO^- on NO-mediated vascular responses was examined in vitro. Basal and stimulated NO release was estimated by an NO-selective electrode as well as vascular response and the plasma NO metabolites. An immunohistochemical study was also carried out. Responses were compared in normal controls, atherosclerotic rabbits fed 1% cholesterol diet for 6 or 9 weeks (atherosclerotic group) and animals fed a normal diet for 6-36 weeks after the high cholesterol diet for 6 or 9 weeks (regression group). ONOO^- impaired the basal and acetylcholine-stimulated NO release, but did not affect endothelium-independent relaxation. After 15 weeks on a normal diet, the acetylcholine-stimulated and basal NO-mediated relaxation, which was diminished in the aorta induced by 6 weeks high cholesterol diet, became restored. However, the vascular response in the 9 weeks high cholesterol diet group did not return to normal after 36 weeks on a normal diet. iNOS was observed in atherosclerotic plaques in atherosclerotic and regression groups along with ONOO^- in the 9 weeks high cholesterol diet group, but not in the 6 weeks group. Conclusively, ONOO^- can play a role in impairment of NO-mediated vascular response during the regression of dietary cholesterol-induced atherosclerosis, not in the initiation of atherosclerosis. Copyright (C) 1999 Elsevier Science Ireland Ltd.