A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis.
Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, SE-171 77 Stockholm, Sweden.
Emmelie A
EA
Jansson
Liyue
L
Huang
Ronny
R
Malkey
Mirco
M
Govoni
Carina
C
Nihlén
Annika
A
Olsson
Margareta
M
Stensdotter
Joel
J
Petersson
Lena
L
Holm
Eddie
E
Weitzberg
Jon O
JO
Lundberg
D000328:Adult; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D050901:Nitrate Reductase / Q000378:metabolism / Q000502:physiology*; D009566:Nitrates / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000097:blood / Q000378:metabolism*; D009928:Organ Specificity; D010084:Oxidation-Reduction; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D000493:Allopurinol; C031618:sodium nitrate; D019001:Nitric Oxide Synthase; D014968:Xanthine Dehydrogenase; D050901:Nitrate Reductase