title: Nitrite attenuates ischemia-reperfusion-induced microcirculatory alterations and mitochondrial dysfunction in the microvasculature of skeletal muscle.
abstract: BACKGROUND
  Recently, nitrite has been rediscovered as a physiologically relevant storage reservoir of nitric oxide in blood and it can readily be converted to nitric oxide under hypoxic and acidic conditions. In this study, the authors evaluated the therapeutic efficacy of nitrite on reperfusion-induced microcirculatory alterations and mitochondrial dysfunction in the microvasculature of skeletal muscle.
  
  
  METHODS
  The authors used a vascular pedicle isolated rat cremaster model that underwent 4 hours of warm ischemia followed by 2 hours or 17 hours of reperfusion. At 5 minutes before reperfusion, normal saline, sodium nitrite (0.20 μM/minute/kg), or nitrite mixed with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl (potassium salt) (0.2 mg/minute/kg) was infused into the microcirculation of ischemic cremaster by means of intraarterial infusion. Ischemia-reperfusion-induced microcirculatory alterations were measured after 2 hours of reperfusion. Microvasculature of the cremaster muscle including the vascular pedicle was harvested to determine the mitochondrial dysfunction. The blood concentration of methemoglobin was also measured to determine the toxicity of nitrite.
  
  
  RESULTS
  The authors found that nitrite significantly attenuated ischemia-reperfusion-induced vasoconstriction, arteriole stagnation, and capillary no-reflow in the early phase of reperfusion and the depolarization of mitochondrial membrane potential and cytochrome c release in the late phase of reperfusion. Nitrite-induced protection was significantly blocked by a nitric oxide scavenger (potassium salt). The methemoglobin results showed that the doses of nitrite we used in the present study were safe.
  
  
  CONCLUSIONS
  The supplementation of a low dose of nitrite, directly into the microcirculation of ischemic muscle through local intraarterial infusion, significantly attenuated ischemia-reperfusion-induced microcirculatory alterations in vivo and mitochondrial dysfunction in vitro in the microvasculature of skeletal muscle.
authors.affiliation: Las Vegas, Nev. From the Department of Surgery, Division of Plastic Surgery, University of Nevada School of Medicine.
authors.forename: Wei Z
authors.initials: WZ
authors.lastname: Wang
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Fang
authors.forename: Linda L
authors.initials: LL
authors.lastname: Stephenson
authors.forename: Xinlan
authors.initials: X
authors.lastname: Zhang
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Richard C
authors.initials: RC
authors.lastname: Baynosa
authors.forename: Kayvan T
authors.initials: KT
authors.lastname: Khiabani
authors.forename: William A
authors.initials: WA
authors.lastname: Zamboni
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D008564:Membrane Potentials; D008706:Methemoglobin / Q000187:drug effects / Q000378:metabolism; D008833:Microcirculation / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000503:physiopathology; D009573:Nitrites / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D009573:Nitrites; D045304:Cytochromes c; D008706:Methemoglobin