P124	Potent novel peroxynitrite decomposition catalyst FP15 improves endothelial dysfunction associated with aging.
T.Radovits, L.Seres, C.J.Beller, S.Hagl, G.Szabó
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, DE.

Overproduction of reactive oxidants and free radicals by the mitochondrial electron-transport chain in aging tissues induce oxidative and nitrosative stress, which have recently been implicated in the pathogenesis of endothelial dysfunction associated with aging. Peroxynitrite, a strong oxidant formed from nitric oxide and superoxide, damages DNA causing tissue injury. In this study we investigated the effectiveness of the novel peroxynitrite decomposition catalyst, FP15 on endothelial dysfunction associated with advanced aging. Aging (20 month old) male rats were treated for 3 weeks with vehicle (aging control), or FP15 (0,1mg/kg/day intraperitoneal). Vehicle-treated young (3 month old) rats served as control. Thoracic aortic rings from the rats were immersed in isolated organ bath, superfused by oxygenated Krebs-Henseleit solution and precontracted by phenylephrine. The dose-dependent vasoresponse to acetylcholine (Ach) and to sodium-nitroprusside (SNP) was investigated in all groups. Our experiments demonstrated impaired endothelial function in aging control rats, indicated by the decreased maximal relaxation to Ach and the rightward shift of the dosis-response curve compared to young rats (52,1±1,27% vs. 80,8±1,49% p<0,05) (Fig. 1.). Pharmacological chelating peroxynitrite with FP15 resulted in a significantly higher vasorelaxation to Ach in aging animals (70,25±1,49% vs. 52,1±1,27% p<0,05). The endothelium-independent vascular smooth muscle function indicated by the vasorelaxation to SNP was not affected by FP15 treatment. In the rat aortic model we have shown an impaired endothelial function associated with advanced aging. Treatment with the peroxynitrite decomposition catalyst, FP15 effectively improved the Ach-induced endothelium-dependent relaxation of aortic rings. The current results demonstrate the important role of endogenous peroxynitrite generation in the pathogenesis of vascular dysfunction in the aging organism, and offer a possible therapeutic utility for the future.

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