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Biological impact of cyclic nitroxide 4-OH-TEMPO and nitrogen dioxide interaction

Michał Woźniak 

Medical University of Gdańsk (MUG), Dębinki 1, Gdańsk 80-211, Poland

Abstract

Nitric oxide (nitrogen monoxide, NO) produced by constitutive nitric oxide synthase plays a fundamental physiological role in the regulation of vasomotor tone and mediating neurotransmission. In contrast the larger micromolar amounts of NO produced by inducible nitric oxide synthase are cytotoxic being biotransformed into reactive nitrogen species like peroxynitrite and nitrogen dioxide (NO2). NO2 (E=0.99V) belongs to oxidizing radical species displaying relatively low water solubility – a property creating limitations in studies of its reactivity in aqueous solutions. Consequently nitrogen dioxide has been less frequently studied in biological systems than peroxynitrite due to technical limitations of its detection. In order to overcome these limitations a number of analytical tools including antibodies against 3-nitrotyrosine as expected fingerprint of NO2 reactivity have been developed and utilized to explain chemical reactivity of NO2.

At sites of inflammation, myeloperoxidase has been found to produce both powerful oxidant NO2 and hypochlorous acid. Unfortunately under conditions of inflammation, i.e. concomitant NO2 and HOCl formation, there is a rapid loss of free and protein bound 3-nitrotyrosine observed which may have implications upon assessing the role of reactive nitrogen species in a pathological situation of disease.

Taking into account the above considerations, the primary purpose of the study was to design a convenient biosensor making it possible to directly assess NO2 in biological samples, in water solution as well as in the insoluble environment of biological membrane. Considering the highly protective effect of a cyclic nitroxide, namely 4-OH-TEMPO in acute pancreatitis model, however being poorly defined at the mechanistic level due to rather low SOD mimetic activity at physiological pH, we decided to inspect a direct scavenging activity of NO2 by the nitroxide. Coordination compounds of Cr(III) with aminodeoxysugar were synthesized as biosensors assessing NO2 level in experimental acute necrotizing pancreatitis induced by L-arginine. As much as 20 nmol of NO2 radical per mg of cytosolic protein was detected which had been found to correlate with severe deterioration of pancreatic acinar cell ultrastructure. 4-OH-TEMPO was found to be a good NO2 scavenger that proved to decrease NO2 level simultaneously preventing pancreatic amylase release into the bloodstream as well as preserving acinar cell ultrastructure. This study has revealed great impact of NO2 generation under inflammatory condition leading to necrotic cell death.
 

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Presentation: Wykład at Zjazd Polskiego Towarzystwa Biochemicznego, Sympozjum M, by Michał Woźniak
See On-line Journal of Zjazd Polskiego Towarzystwa Biochemicznego

Submitted: 2007-04-30 15:58
Revised:   2009-06-07 00:44