Nitrite reduces ischemia/reperfusion-induced muscle damage and improves survival rates in rat crush injury model

Murata, Ikuo; Nozaki, Ryo; Ooi, Kazuya; Ohtake, Kazuo; Kimura, Soichiro; Ueda, Hideo; Nakano, Genya; Sonoda, Kunihiro; Inoue, Yutaka; Uchida, Hajime; Kanamoto, Ikuo; Morimoto, Yasunori; Kobayashi, Jun

doi:10.1097/ta.0b013e31824a76b5

Cited by 29 publications

(23 citation statements)

References 22 publications

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“…There is lack of data about putative interplay between NO-mediated signaling and myokines. However, sparse evidence suggests that such interplay can in fact exist (Takahashi et al, 1999 ; Figueras et al, 2004 ; Steensberg et al, 2007 ; Ouchi et al, 2008 ; Murata et al, 2012 ; Sandonà et al, 2012 ; Baum et al, 2013 ; Most et al, 2013 ; Chong et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Physical exercise associated with NO production: signaling pathways and significance in health and disease

Dyakova

Капилевич

Shylko

et al. 2015

Front. Cell Dev. Biol.

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Here we review available data on nitric oxide (NO)-mediated signaling in skeletal muscle during physical exercise. Nitric oxide modulates skeletal myocyte function, hormone regulation, and local microcirculation. Nitric oxide underlies the therapeutic effects of physical activity whereas the pharmacological modulators of NO-mediated signaling are the promising therapeutic agents in different diseases. Nitric oxide production increases in skeletal muscle in response to physical activity. This molecule can alter energy supply in skeletal muscle through hormonal modulation. Mitochondria in skeletal muscle tissue are highly abundant and play a pivotal role in metabolism. Considering NO a plausible regulator of mitochondrial biogenesis that directly affects cellular respiration, we discuss the mechanisms of NO-induced mitochondrial biogenesis in the skeletal muscle cells. We also review available data on myokines, the molecules that are expressed and released by the muscle fibers and exert autocrine, paracrine and/or endocrine effects. The article suggests the presence of putative interplay between NO-mediated signaling and myokines in skeletal muscle. Data demonstrate an important role of NO in various diseases and suggest that physical training may improve health of patients with diabetes, chronic heart failure, and even degenerative muscle diseases. We conclude that NO-associated signaling represents a promising target for the treatment of various diseases and for the achievement of better athletic performance.

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Section: Introductionmentioning

confidence: 99%

Physical exercise associated with NO production: signaling pathways and significance in health and disease

Dyakova

Капилевич

Shylko

et al. 2015

Front. Cell Dev. Biol.

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“…10,11) The most important mechanism causing CS-related mortality is ischemia/reperfusion (I/R)-induced rhabdomyolysis and the subsequent onset of reactive oxygen species (ROS)-mediated systemic inflammation. 12) In our previous study, 5.0 mg/kg dexamethasone (DEX) dramatically improved the survival of CS rats, suggesting that DEX treatment could protect against I/R injury followed by inflammation (nitric oxide protection mechanism) and reverse or prevent hyperkalemia and hypovolemic shock (i.e., rescue death). 13) Moreover, the pharmacokinetic (PK) parameters of CS rats administered DEX were significantly different from those of normal rats.…”

mentioning

confidence: 99%

Early Therapeutic Intervention for Crush Syndrome: Characterization of Intramuscular Administration of Dexamethasone by Pharmacokinetic and Biochemical Parameters in Rats

Murata

Goto

Komiya

et al. 2016

Biological & Pharmaceutical Bulletin

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Crush syndrome (CS) is the systemic manifestation of muscle cell damage resulting from pressure and crushing. It is associated with a high mortality rate, even when patients are treated with conventional therapy. We demonstrated the utility of intramuscular administration of dexamethasone (DEX) in disaster medical care by using a model of CS to characterize the pharmacokinetics and biochemical parameters. We compared intravenous (IV) and intramuscular (IM) injection. The IM sites were the right anterior limb (AL), bilateral hind limbs (bHL), and unilateral hind limb (uHL). DEX (5.0 mg/kg) was administered in sham-operated (sham, S-IV, S-AL, S-bHL, S-uHL groups) and CS rats (control, C-IV, C-AL, C-bHL, C-uHL groups). The survival rate in the IM groups was lower than that in the C-IV group. Survival was highest in the C-AL group, followed by the C-uHL and C-bHL groups. The blood DEX concentration of the C-AL group was similar to that in the C-IV group. The C-bHL and C-uHL groups had decreased blood DEX concentrations. Moreover, inhibition of inflammation was related to these changes. Administration of DEX to non-injured muscle, as well as IV administration, increased the survival rate by modulating shock and inflammatory mediators, consequently suppressing myeloperoxidase activity and subsequent systemic inflammation, resulting in a complete recovery of rats from lethal CS. These results demonstrate that injection DEX into the non-injured muscle is a potentially effective early therapeutic intervention for CS that could easily be used in transport to the hospital. Key words crush syndrome; dexamethasone; intramuscular injection; disaster medical careCrush syndrome (CS) is often reported as a traumatic disorder with high mortality and occurs after sudden catastrophes, such as the Hanshin-Awaji, Marmara, and Wenchan earthquakes.1-3) CS is defined as the systemic manifestation of muscle cell damage resulting from pressure and crushing. 4)The typical clinical and pathological features of CS result predominantly from traumatic rhabdomyolysis and subsequent release of muscle cell contents upon rescue.5-7) Systemic manifestations may include bleeding, hypovolemic shock, cardiac failure, arrhythmia, electrolyte disturbance, psychological trauma, acute kidney injury (AKI), sepsis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation (DIC). 8)After major earthquakes, up to 20% of deaths occur shortly after extrication. 9) Some of these deaths include victims who were relatively stable before extrication, but deteriorated suddenly thereafter, and this phenomenon is called rescue death. Consequently, for affected victims and patients, it is necessary to identify who should receive an intensive care strategy. Most victims survive upon volume replacement or massive fluid resuscitation at the disaster site. However, this treatment improves symptoms of the acute phase (e.g., hyperkalemia, hypovolemic shock...

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“…In rats subjected to bilateral hind limb compression for 5 h followed by reperfusion for 0 to 6 h, nitrite administration reduced the extent of rhabdomyolysis markers such as potassium, lactate dehydrogenase and creatine phosphokinase. Nitrite treatment also reduced the inflammatory activities in muscle and lung tissues, finally resulting in a dose‐dependent improvement of survival rate (Murata et al ., ). Similarly, in a mouse shock model induced by a lethal tumour necrosis factor challenge, nitrite treatment significantly attenuated hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction and mortality.…”

Section: Nitrite In Organ Protectionmentioning

confidence: 97%

Nitrite in organ protection

Rassaf

Ferdinándy

Schulz

2013

British J Pharmacology

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In the last decade, the nitrate-nitrite-nitric oxide pathway has emerged to therapeutical importance. Modulation of endogenous nitrate and nitrite levels with the subsequent S-nitros(yl)ation of the downstream signalling cascade open the way for novel cytoprotective strategies. In the following, we summarize the actual literature and give a short overview on the potential of nitrite in organ protection. AbbreviationsCypD, cyclophilin D; eNOS, NOS III, endothelial nitric oxide synthase; Hb, haemoglobin; iNOS, NOS II, inducible nitric oxide synthase; Mb, myoglobin; MPTP, mitochondrial permeability transition pore; Ng, neuroglobin; nNOS, NOS I, neuronal nitric oxide synthase; XOR, xanthine oxidoreductase Sources of nitriteThree sources of nitrite have been identified in mammalian physiology. The first, endogenous source is the oxidation of the nitric oxide (NO) radical to nitrite. NO is produced endogenously from the amino-acid L-arginine by the NO-synthases (NOSs). Three different NOSs exist: the endothelial NOS (eNOS, NOS III), the inducible NOS (iNOS, NOS II) and the neuronal NOS (nNOS, NOS I). The genes for the three different NOS-isoforms are located on different chromosomes. eNOS was first discovered in the vascular endothelium, nNOS in the brain and iNOS in macrophages. Whereas eNOS and nNOS are constitutively expressed in calcium and calmodulin-dependent, transcription of iNOS is induced by cytokines and lipopolysaccharides. The enzymatic production of NO contains a five-electron transfer and requires the presence of several substrates and cofactors, such as L-arginine, oxygen, tetrahydrobiopterin and reduced nicotinamide adenine dinucleotide phosphate (for review see: Moncada and Higgs, 1993). NO is a highly reactive gaseous molecule with one unpaired electron. NO acts mainly in auto/paracrine fashion, and signalling is limited by its rapid oxidation to nitrite and nitrate, and its rapid non-enzymatic reaction with superoxide to yield peroxynitrite (for review see: Ferdinandy and Schulz, 2003). NO rapidly reacts with oxyhaemoglobin to form methemoglobin and nitrate. Oxidation of NO to nitrite is enhanced by the multicopper oxidase ceruloplasmin, catalyzing the oxidation of NO to NO + which is rapidly hydrolyzed to nitrite (Shiva et al., 2006). The second major source is nitrite reduced from nitrate ( Figure 1). Green leafy vegetables, such as lettuce, spinach and beetroot all contain high concentrations of nitrate. One serving of such a vegetable contains more nitrate than what is endogenously formed by all three NOS isoforms during 1 day in humans (Lundberg et al., 2009). After ingestion of nitrate and effective absorption in the upper gastrointestinal tract, concentrations of nitrate in the saliva reach millimolar concentrations. In the oral cavity, commensal anaerobic bacteria reduce nitrate to nitrite by their nitrate reductase enzymes. When swallowed, due to the acidic gastric milieu, part of the nitrite is immediately protoned to nitrous acid, which then decomposes to NO and other nitrogen oxides. Mo...

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Nitrite reduces ischemia/reperfusion-induced muscle damage and improves survival rates in rat crush injury model

Abstract: 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.

Cited by 29 publications

References 22 publications

Physical exercise associated with NO production: signaling pathways and significance in health and disease

Physical exercise associated with NO production: signaling pathways and significance in health and disease

Early Therapeutic Intervention for Crush Syndrome: Characterization of Intramuscular Administration of Dexamethasone by Pharmacokinetic and Biochemical Parameters in Rats

Nitrite in organ protection

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