A labile inorganic free radical, nitric oxide (.NO), is produced by nitric oxide synthase from the substrate L-arginine in various cells and tissues. It acts as an endothelium-derived relaxing factor (EDRF) or as a neurotransmitter in vivo. We investigated the reactivity of stable radical compounds, imidazolineoxyl N-oxides such as 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO), carboxy-PTIO, and carboxymethoxy-PTIO against .NO/EDRF in both chemical and biological systems. By using electron spin resonance (ESR) spectroscopy, imidazolineoxyl N-oxides were found to react with .NO in a stoichiometric manner (PTIO/.NO = 1.0) in a neutral solution (sodium phosphate buffer, pH 7.4) with rate constants of approximately 10(4) M-1 s-1, resulting in the generation of NO2-/NO3- and imidazolineoxyls such as 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl (PTI), carboxy-PTI, or carboxymethoxy-PTI. Furthermore, the effects of imidazolineoxyl N-oxides on acetylcholine- or ATP-induced relaxation of the smooth muscle of rabbit aorta were tested. The vasorelaxations were inhibited by all three imidazolineoxyl N-oxides markedly. The inhibitory effects of carboxy-PTIO was almost 2-fold stronger than those of .NO synthesis inhibitors, N omega-nitro-L-arginine and N omega-monomethyl-L-arginine. Generation of EDRF/.NO was identified by reacting the PTIO in aortic strips and quantitating the reaction product with ESR spectroscopy. Thus, it was clarified that imidazolineoxyl N-oxide antagonize EDRF/.NO via a unique radical-radical reaction with .NO.
Formation of senile plaques composed of amyloid beta peptide, a pathological hallmark of Alzheimer disease, in human brains precedes disease onset by many years. Noninvasive detection of such plaques could be critical in presymptomatic diagnosis and could contribute to early preventive treatment strategies. Using amyloid precursor protein (APP) transgenic mice as a model of amyloid beta amyloidosis, we demonstrate here that an intravenously administered (19)F-containing amyloidophilic compound labels brain plaques and allows them to be visualized in living mice by magnetic resonance imaging (MRI) using (19)F and (1)H. Our findings provide a new direction for specific noninvasive amyloid imaging without the danger of exposure to radiation. This approach could be used in longitudinal studies in mouse models of Alzheimer disease to search for biomarkers associated with amyloid beta pathology as well as to track disease course after treatment with candidate medications.
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