Protective mechanisms during ischemic tolerance in skeletal muscle

Amit Badhwar, Aurelia Bihari, Alison A. Dungey, Jeffrey R. Scott, Caroline D. Albion, Thomas L. Forbes, Kenneth A. Harris, Richard F. Potter

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


The purpose of this study was to test specific mechanisms of protection afforded the rat extensor digitorum longus (EDL) muscle during ischemic tolerance. Two days following five cycles of 10 min ischemia and 10 min reperfusion, heme oxygenase (HO) and calcium-dependent nitric oxide synthase (cNOS) activities were increased 2- and 2.5-fold (p < .05), respectively. Interestingly, calcium-independent NOS (iNOS) activity was completely downregulated (p < .05). The levels of superoxide dismutase (SOD) and catalase were increased 2-fold (p < .05), while glutathione peroxidase activity remained unchanged from non-preconditioned controls. Using intravital microscopy combined with chromium mesoporphyrin (CrMP), a selective HO inhibitor, and L-NAME, a NOS inhibitor, the roles of HO and cNOS were evaluated. Ischemic tolerance in the EDL muscle, 48 h after the preconditioning stimulus, was characterized by complete protection from both microvascular perfusion deficits and tissue injury after a 2-h period of ischemia. Removal of NOS activity completely removed the benefit afforded microvascular perfusion, while inhibition of HO activity prevented the parenchymal protection. These data suggest that ischemic tolerance within skeletal muscle is associated with the upregulation of specific cytoprotective proteins and that the benefits afforded by cNOS and HO activity are spatially discrete to the microvasculature and parenchyma, respectively.

Original languageEnglish
Pages (from-to)371-379
Number of pages9
JournalFree Radical Biology and Medicine
Issue number3
StatePublished - Feb 1 2004
Externally publishedYes


  • Catalase
  • Free radicals
  • Glutathione
  • Heme oxygenase
  • Ischemic tolerance
  • Nitric oxide synthase
  • Preconditioning
  • Rat
  • Skeletal muscle
  • Superoxide dismutase


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