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On the Distinction Between Nitroxyl and Nitric Oxide Using Nitronyl Nitroxides

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On the Distinction Between Nitroxyl and Nitric Oxide Using Nitronyl Nitroxides Published on Web 05/26/2010 On the Distinction between Nitroxyl and Nitric Oxide Using Nitronyl Nitroxides Uri Samuni,† Yuval Samuni,‡ and Sara Goldstein*,§ Department of Chemistry and Biochemistry, Queens College, City UniVersity of New York, Flushing, New York 11367, and Department of Prosthodontics, School of Dental Medicine, and Institute of Chemistry, The Accelerator Laboratory, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel Received March 8, 2010; E-mail: [email protected] Abstract: A better understanding of the origins of NO and HNO and their activities and biological functions requires accurate methods for their detection and quantification. The unique reaction of NO with nitronyl nitroxides such as 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (C-PTIO), which yields the corresponding imino nitroxides, is widely used for NO detection (mainly by electron paramagnetic resonance spectroscopy) and for modulation of NO-induced physiological functions. The present study demonstrates that HNO readily reacts with nitronyl nitroxides, leading to the formation of the respective imino nitroxides and hydroxylamines via a complex mechanism. Through the use of the HNO donor Angeli’s salt (AS) with metmyoglobin as a competing agent, the rate constant for C-PTIO reduction by HNO has been determined to be (1.4 ( 0.2) × 105 M-1 s-1 at pH 7.0. This reaction yields the corresponding nitronyl • hydroxylamine C-PTIO-H and NO, which is trapped by C-PTIO to form NO2 and the corresponding imino • nitroxide, C-PTI. NO2 oxidizes the nitronyl and imino nitroxides to their respective oxoammonium cations, which decay mainly via comproportionation with the nitronyl and imino hydroxylamines. When [AS] > [C-PTIO], the reduction of C-PTI by HNO proceeds, eventually converting C-PTIO to the corresponding imino hydroxylamine, C-PTI-H. Similar results were obtained for 2-phenyl-4,4,5,5-tetramethylimidazoline- 1-oxyl 3-oxide (PTIO). It is concluded that nitronyl nitroxide is readily reduced by HNO to nitronyl hydroxylamine and is eventually converted into imino nitroxide and imino hydroxylamine. The yield of the imino hydroxylamine increases at the expense of the imino nitroxide as the ratio [AS]0/[nitronyl nitroxide]0 is increased. Since the reaction of NO with nitronyl nitroxide yields only the corresponding imino nitroxide, nitronyl nitroxide can discriminate NO from HNO only when present at a concentration much lower than the total production of HNO. 7-10 Introduction ides. It has been argued that iron N-methyl-D-glucamine dithiocarbamate can distinguish NO from HNO,11 although the Nitric oxide (NO) is an important mediator of both physi- specificity of this method has been questioned.12 ological and pathophysiological processes.1 HNO, the 1-electron- The most widely used nitronyl nitroxides are 2-phenyl-4,4,5,5- reduced and protonated product of NO, has been suggested to tetramethylimidazoline-l-oxyl 3-oxide (PTIO) and its water- be formed in cellular milieu via several routes.2 A better soluble analogue 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimi- understanding of the origins of NO and HNO and their activities dazoline-1-oxyl 3-oxide (C-PTIO). The unique reaction 1 of and biological functions requires accurate methods for their nitronyl nitroxides with NO yields the corresponding imino detection and quantification. Electron paramagnetic resonance nitroxides, which are detectable and distinguishable by EPR (EPR) methods have been developed that enable the stabilization spectrometry.7–10 of NO using endogenous and exogenous spin traps, such as iron 3-6 N-methyl-D-glucamine dithiocarbamate and nitronyl nitrox- (6) Pou, S.; Tsai, P.; Porasuphatana, S.; Halpern, H. J.; Chandramouli, G. V. R.; Barth, E. D.; Rosen, G. M. Biochim. Biophys. Acta 1999, † Queens College, City University of New York. 1427, 216–226. ‡ School of Dental Medicine, The Hebrew University of Jerusalem. (7) Akaike, T.; Yoshida, M.; Miyamoto, Y.; Sato, K.; Kohno, M.; § Institute of Chemistry, The Hebrew University of Jerusalem. Sasamoto, K.; Miyazaki, K.; Ueda, S.; Maeda, H. Biochemistry 1993, (1) Moncada, S.; Palmer, R. M. J.; Higgs, E. A. Pharmacol. ReV. 1991, 32, 827–832. 43, 109–142. (8) Hogg, N.; Singh, R. J.; Joseph, J.; Neese, F.; Kalyanaraman, B. Free (2) Fukuto, J. M.; Dutton, A. S.; Houk, K. N. ChemBioChem 2005, 6, Radical Res. 1995, 22, 47–56. 612–619. (9) Akaike, T.; Maeda, H. Methods Enzymol. 1996, 268, 211–221. (3) Rao, D. N. R.; Cederbaum, A. I. Arch. Biochem. Biophys. 1995, 321, (10) Rosen, G. M.; Porasuphatana, S.; Tsai, P.; Ambulos, N. P.; Galtsev, 363–371. V. E.; Ichikawa, K.; Halpern, H. J. Macromolecules 2003, 36, 1021– (4) Xia, Y.; Zweier, J. L. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 12705– 1027. 12710. (11) Xia, Y.; Cardounel, A. J.; Vanin, A. F.; Zweier, J. L. Free Radical (5) Tsuchiya, K.; Jiang, J. J.; Yoshizumi, M.; Tamaki, T.; Houchi, H.; Biol. Med. 2000, 29, 793–797. Minakuchi, K.; Fukuzawa, K.; Mason, R. P. Free Radical Biol. Med. (12) Komarov, A. M.; Wink, D. A.; Feelisch, M.; Schmidt, H. Free Radical 1999, 27, 347–355. Biol. Med. 2000, 28, 739–742. 8428 9 J. AM. CHEM. SOC. 2010, 132, 8428–8432 10.1021/ja101945j 2010 American Chemical Society On the Distinction between Nitroxyl and Nitric Oxide ARTICLES (Tempol),37 which at pH 7.0 has a lower reduction potential than that of PTIO/C-PTIO (i.e., E1/2 ) 130 compared with 270 mV vs NHE, respectively).38,39 We previously reported that the mechanism of the reaction of NO with C-PTIO and PTIO involves the oxidation of PTIO • and C-PTIO by NO2 to their respective oxoammonium cations, which can be reduced back to the parent nitroxides by NO.39 Here we demonstrate that C-PTIO and PTIO are readily reduced by HNO and eventually converted into their respective imino Nitronyl nitroxides have also been widely employed as nitroxides or imino hydroxylamines. specific NO scavengers in various experimental in vitro and in vivo models13-21 to attenuate17,22-31 or even, surprisingly, Materials and Methods 19,32 potentiate NO-induced physiological effects. Conversely, All of the chemicals were of analytical grade and used as the failure of C-PTIO to affect a system was taken as proof received. Water for preparation of the solutions was purified 33 excluding the intermediacy of NO. Several studies even using a Milli-Q purification system. Angeli’s salt (Na2N2O3, AS) proposed a therapeutic potential of nitronyl nitroxides against and C-PTIO were purchased from Cayman Chemical Co. and NO-induced neurotoxicity.15,34,35 However, some of the obser- PTIO from ALEXIS Biochemicals. A stock solution of AS was prepared in 10 mM NaOH, and the concentration was determined vations could not be readily settled with the reported selectivity by the absorbance at 248 nm (ε ) 8mM-1 cm-1). Metmyoglobin 25,32 III of nitronyl nitroxides toward NO. In cases where NO or (MbFe OH2) was prepared by addition of excess ferricyanide HNO donors induced similar biological effects, the use of to myoglobin in 10 mM phosphate buffer (PB) at pH 7.0 C-PTIO could not clearly distinguish NO from HNO.16,30 It was followed by chromatographic separation through a Sephadex III therefore suggested that HNO is oxidized to NO by C-PTIO, G-25 column. The concentration of MbFe OH2 was determined ) -1 -1 40 albeit slightly,16 but later that reaction was examined and spectrophotometrically using ε408 188 mM cm . NO was 36 purchased from Matheson Gas Products and purified by passing excluded. However, the feasibility of HNO oxidation by it through a series of scrubbing bottles containing deaerated 50% nitronyl nitroxides is supported by the observation that HNO NaOH and purified water in that order. NO solutions were readily reduces 4-hydroxyl-2,2,6,6 tetramethylpiperidine-N-oxyl prepared in gas-tight syringes containing 10 mM PB, and the concentration of NO (1.9 mM/atm at 22 °C) was accurately determined on the basis of its known temperature- and pressure- (13) Kaneda, K.; Yoshioka, Y.; Makita, K.; Toyooka, H.; Amaha, K. Crit. dependent solubility in aqueous systems. Care Med. 1997, 25, 1019–1029. C-PTI was prepared by mixing NO-saturated solution with a (14) Li, C. G.; Karagiannis, J.; Rand, M. J. Br. J. Pharmacol. 1999, 127, deaerated solution of C-PTIO in 10 mM PB at pH 7.0. Oxidized 826–834. and reduced nitronyl and imino nitroxides were prepared electro- (15) Miura, K.; Yamanaka, S.; Ebara, T.; Okumura, M.; Imanishi, M.; Kim, chemically. Briefly, the electrochemical cell consisted of a working S.; Nakatani, T.; Iwao, H. Jpn. J. Pharmacol. 2000, 82, 261–264. (16) Ellis, A.; Lu, H.; Li, C. G.; Rand, M. J. Br. J. Pharmacol. 2001, 134, electrode of graphite grains packed inside a porous Vycor glass 521–528 tube (5 mm i.d.) through which the solution of nitronyl or imino . - (17) Wanstall, J. C.; Jeffery, T. K.; Gambino, A.; Lovren, F.; Triggle, C. R. nitroxides in 10 mM PB (pH 7.0) was pumped (2-4mLmin 1). Br. J. Pharmacol. 2001, 134, 463–472. An outer glass cylinder contained 10 mM PB in which a Pt auxiliary (18) Costa, G.; Labadia, A.; Triguero, D.; Jimenez, E.; Garcia-Pascual, A. electrode and a Ag/AgCl (3.5 M) reference electrode were Naunyn-Schmiedeberg’s Arch. Pharmacol. 2001, 364, 516–523. immersed. A BAS100B Electrochemical Analyzer was used to (19) Cao, B. J.; Reith, M. E. A. Eur. J. Pharmacol. 2002, 448, 27–30. (20) Zeller, A.; Wenzl, M. V.; Beretta, M.; Stessel, H.; Russwurm, M.; control the voltage. Koesling, D.; Schmidt, K.; Mayer, B. Mol. Pharmacol. 2009, 76, 1115– Oxidation of imino hydroxylamines was achieved either elec- 1122.
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