Nitrite reduces ischemia/reperfusion-induced muscle damage and improves survival rates in rat crush injury model.
BACKGROUND
Nitrite is an intrinsic signaling molecule with potential therapeutic implications in mammalian ischemia/reperfusion (I/R) injury of the heart, liver, and kidney. Although limb muscle compression and subsequent reperfusion are the causative factors in developing crush syndrome (CS), there has been no report evaluating the therapeutic effects of nitrite on CS. We therefore tested whether nitrite could be a therapeutic agent for the treatment of CS.


METHODS
To create a CS model, anesthetized rats were subjected to bilateral hind limb compression with rubber tourniquets for 5 hours, followed by reperfusion for 0 hour to 6 hours while monitoring blood pressure. Saline for the CS group or sodium nitrite (NaNO(2)-100, 200, and 500 μmol/kg) for the nitrite-treated CS groups was intravenously administered immediately before reperfusion. Blood and tissue samples were collected for biochemical analysis.


RESULTS
Tissue nitrite levels in injured muscles were significantly reduced in the CS group compared with the sham group during I/R injury. Nitrite administration to CS rats restored nitric oxide bioavailability by enhancing nitrite levels of the muscle, resulting in a reduction of rhabdomyolysis markers such as potassium, lactate dehydrogenase, and creatine phosphokinase. Nitrite treatment also reduced plasma levels of interleukin-6 and myeloperoxidase activities in muscle and lung tissues, finally resulting in a dose-dependent improvement of survival rate from 24% (CS group) to 36% (NaNO(2)-100 group) and 64% (NaNO(2)-200 and 500 groups).


CONCLUSIONS
These results indicate that nitrite reduces I/R-induced muscle damage through its cytoprotective action and contributes to improved survival rate in a rat CS model.
Laboratory of Drug Safety Management, Faculty of Pharmaceutical Science, Josai University, Saitama, Japan.
Isamu
I
Murata
Ryo
R
Nozaki
Kazuya
K
Ooi
Kazuo
K
Ohtake
Soichiro
S
Kimura
Hideo
H
Ueda
Genya
G
Nakano
Kunihiro
K
Sonoda
Yutaka
Y
Inoue
Hiroyuki
H
Uchida
Ikuo
I
Kanamoto
Yasunori
Y
Morimoto
Jun
J
Kobayashi
D000704:Analysis of Variance; D000818:Animals; D001795:Blood Pressure Determination; D003444:Crush Syndrome / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000293:injuries; D009573:Nitrites / Q000494:pharmacology*; D009195:Peroxidase / Q000097:blood / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D012206:Rhabdomyolysis / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
D015850:Interleukin-6; D009573:Nitrites; D009195:Peroxidase