Efficacy and mechanism of hypoxic postconditioning in salvage of ex vivo human rectus abdominis muscle from hypoxia/reoxygenation injury

Naparus, Andreas; Ashrafpour, Homa; Hofer, Stefan O. P.; Zhong, Toni; Huang, Ning; Cahoon, Neil J.; McAllister, Sandra E.; Neligan, Peter C.; Roy, Trisha; Lipa, Joan E.; Pang, Cho Y.

doi:10.1016/j.ejphar.2012.04.045

Cited by 9 publications

(10 citation statements)

References 61 publications

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“…Our study demonstrated that NIM-811 was capable of reducing the serum levels of necroenzymes and ions, which could be attributed to the lower extent of fiber disintegration possibly as the result of the inhibitory effect of NIM-811 on the opening of mPTP. Our observations are consistent with previous data, namely that both LDH level and rhabdomyolysis could be significantly attenuated by different conditioning techniques (preconditioning, postconditioning), as well as by pretreatment with CsA and NIM-811 in an experimental model of skeletal muscle IR [26].…”

Section: Discussionsupporting

confidence: 93%

“…There are only two publications in the literature so far reporting that NIM-811 is effective during skeletal muscle IR after autogen transplantation and replantation [26], [38]. Our results support this finding concerning the skeletal muscle.…”

Section: Discussionsupporting

confidence: 89%

“…The favourable effects of CsA have been successfully demonstrated in previous IR models [32]–[35] as well as following lower limb IR [36]. Further investigations have confirmed that both CsA and NIM-811 are able to attenuate injuries of the skeletal muscle [26], [38]. NIM-811 has not yet been investigated in regard to its effects on the systemic and distant organ impacts of these vascular diseases.…”

Section: Discussionmentioning

confidence: 97%

“…The aim of the present study was to set up an experimental model and search for a therapeutic option suitable for treatment of the postoperative complications of this vascular disease. Several pharmacological interventions [25], [26] and surgical conditioning techniques [14], [27] may be suitable approaches to mitigate the IR injuries of the skeletal muscle [28].…”

Section: Discussionmentioning

confidence: 99%

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Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811

et al. 2014

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IntroductionOperation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP).ObjectivesOur aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.Materials and methodsWistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-α and IL-6 levels were measured.ResultsLess significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-α and IL-6 levels were significantly lower (TNF-α: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group.ConclusionNIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811

et al. 2014

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“…Since Zhao et al first demonstrated the cardioprotective effect of postconditioning, other investigators subsequently demonstrated similar protective effects in skin flaps, human endothelium, and both human and animal skeletal muscle models. [21][22][23][24][25][26][27][28][29] It is important to note, however, that even though pre-and postconditioning have both been found to be effective strategies to mitigate I/R injury, they have not shown additive effects when used together. 30,31 While recent studies have demonstrated a clear benefit of postconditioning in the setting of I/R injury, no definitive time window has been established within which this strategy is most effective.…”

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confidence: 99%

Defining the Salvage Time Window for the Use of Ischemic Postconditioning in Skeletal Muscle Ischemia Reperfusion Injury

Schmucker

Mendenhall

Reichensperger

et al. 2015

J reconstr Microsurg

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When ischemia occurs in skeletal muscle, intra and extracellular changes result in an influx of calcium, lactic acid metabolism, reduction of intracellular pH, and adenosine triphosphate (ATP) depletion. These processes ultimately result in cell death if they are not interrupted by reperfusion. While the return of blood flow is necessary for cellular survival, reperfusion brings with it the possibility of increasing the spectrum of injury. As the ischemic muscle is flushed with oxygenated blood, reactive oxygen species and other harmful free radicals are produced and distributed throughout the area. 1-4 Keywords AbstractBackground The aim of this study was to determine the optimal salvage time window within which ischemic postconditioning can be used to ameliorate ischemia/reperfusion (I/R) injury in skeletal muscle. Methods A total of 48 Sprague-Dawley rats were divided into two groups: I/R only (control) and I/R with postconditioning. Subgroups were divided by duration of ischemia (2, 4, 6, and 8 hours). A pedicled gracilis muscle model was used. The postconditioning protocol consisted of six cycles of 15 seconds of reperfusion followed by 15 seconds of ischemia (total time ¼ 3 minutes). Muscles were harvested 24 hours after I/R injury to examine tissue viability, histology, myeloperoxidase activity, and protective gene expression. Results Postconditioning groups showed improved muscle viability after 4 and 6 hours of ischemia time as compared with controls (p < 0.05). Higher expression of mitochondrial complexes I, II, III, endothelial nitric oxide synthase, inducible nitric oxide synthase, and Bcl-2 were observed in the postconditioning group after 4 and 6 hours of ischemia (p < 0.05). Lower expression of tumor necrosis factor-α and caspase 3 was observed in the postconditioning group at 4 hours (p < 0.05). Myeloperoxidase activity was similar in both groups at all-time points except 8 hours ischemia, where the control group had higher activity (p < 0.05). Conclusion Results of this study demonstrate that the effective time window within which postconditioning is most effective for the salvage of skeletal muscle is between 4 and 6 hours of ischemia. Postconditioning offered improved mitochondrial and vascular function with decreased inflammation and cell death. This may be clinically useful as a postinjury salvage technique to attenuate I/R injury after 4 to 6 hours of ischemia.

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Effects of Postconditioning on Skeletal Muscle Injury and Apoptosis Induced by Partial Ischemia and Reperfusion in Rats

Lintz

Dalio

Tirapelli

et al. 2017

Annals of Vascular Surgery

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Efficacy and mechanism of hypoxic postconditioning in salvage of ex vivo human rectus abdominis muscle from hypoxia/reoxygenation injury

Cited by 9 publications

References 61 publications

Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811

Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811

Defining the Salvage Time Window for the Use of Ischemic Postconditioning in Skeletal Muscle Ischemia Reperfusion Injury

Effects of Postconditioning on Skeletal Muscle Injury and Apoptosis Induced by Partial Ischemia and Reperfusion in Rats

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