Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 84, Issue -, Pages 154-160Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.03.025
Keywords
Inorganic nitrite; Nitric oxide; cGMP independent; Kidney; Renal vasculature; Interlobar artery; Xanthine oxidoreductase; Ischemia; Free radicals
Funding
- Swedish Research Council [521-2011-2639]
- Swedish Heart and Lung Foundation [20140448, 20110589]
- Jeanssons Foundation [JS2013-00064]
- Karolinska Institutet
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The kidney is vulnerable to hypoxia, and substantial efforts have been made to ameliorate renal ischemic injury secondary to pathological conditions. Stimulation of the nitrate-nitrite-nitric oxide pathway is associated with renal and cardiovascular protection in disease models, but less is known about the vascular effects during renal ischemia. This study was aimed at investigating the vascular effects of nitrite in the kidney during normoxic and ischemic conditions. Using a multiwire myograph system, we assessed nitrite-mediated relaxation (10(-9)-10(-4) mol/L) in isolated and preconstricted renal interlobar arteries from C57BL/6 mice under normal conditions (pO(2) 13 kPa; pH 7.4) and with low oxygen tension and low pH to mimic ischemia (pO(2) 3 kPa; pH 6.6). Xanthine oxidoreductase expression was analyzed by quantitative PCR, and production of reactive nitrogen species was measured by DAF-FM DA fluorescence. During normoxia significant vasodilatation (15 +/- 3%) was observed only at the highest concentration of nitrite, which was dependent on NO-sGC-cGMP signaling. The vasodilatory responses to nitrite were greatly sensitized and enhanced during hypoxia with low pH, demonstrating significant dilatation (11 +/- 1%) already in the physiological range (10(-8) mol/L), with a maximum response of 27 +/- 2% at 10(-4) mol/L. In contrast to normoxia, and to that observed with a classical NO donor (DEA NONOate), this sensitization was independent of sGC-cGMP signaling. Moreover, inhibition of various enzymatic systems reported to reduce nitrite in other vascular beds, i.e., aldehyde oxidase (raloxifene), aldehyde dehydrogenase (cyanamide), and NO synthase (L-NAME), had no effect on the nitrite response. However, inhibition of xanthine oxidoreductase (XOR; febuxostat or allopurinol)abolished the sensitized response to nitrite during hypoxia and acidosis. In conclusion, in contrast to normoxia, nitrite exerted potent vasorelaxation during ischemic conditions already at physiological concentrations. This effect was dependent on functional XOR but independent of classical downstream signaling by sGC-cGMP. (C) 2015 Elsevier Inc. All rights reserved.
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