title: Attenuation of skeletal muscle and renal injury to the lower limb following ischemia-reperfusion using mPTP inhibitor NIM-811.
abstract: BACKGROUND
  Operation 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).
  
  
  OBJECTIVE
  Our aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.
  
  
  METHODS
  Wistar 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.
  
  
  RESULTS
  Less 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.
  
  
  CONCLUSIONS
  NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: David
authors: D
authors: Garbaisz
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: Zsolt
authors: Z
authors: Turoczi
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: Peter
authors: P
authors: Aranyi
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: Andras
authors: A
authors: Fulop
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: Oliver
authors: O
authors: Rosero
authors: University of Szeged, Department of Biochemistry and Molecular Biology, Szeged, Hungary.
authors: Edit
authors: E
authors: Hermesz
authors: University of Szeged, Department of Biochemistry and Molecular Biology, Szeged, Hungary.
authors: Agnes
authors: A
authors: Ferencz
authors: Semmelweis University, 2nd Department of Pathology, Budapest, Hungary.
authors: Gabor
authors: G
authors: Lotz
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: Laszlo
authors: L
authors: Harsanyi
authors: Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
authors: Attila
authors: A
authors: Szijarto
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002470:Cell Survival; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006439:Hemodynamics; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007677:Kidney Function Tests; D035002:Lower Extremity / Q000601:surgery*; D008297:Male; D008833:Microcirculation; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D012206:Rhabdomyolysis / Q000150:complications* / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; C090438:(melle-4)cyclosporin