Constitutive nitric oxide synthase activity is required to trigger ischemic tolerance in mouse retina

Yanli Zhu, Kevin K. Ohlemiller, Belinda K. McMahan, Tae Sung Park, Jeffrey M. Gidday

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Profound morphologic and functional protection against retinal ischemic injury can be achieved if the tissue is 'preconditioned' one day earlier with a brief, noninjurious ischemic challenge. To begin to address the mechanistic basis of this 'ischemic tolerance', we used genetic and pharmacologic approaches to test the hypothesis that nitric oxide (NO) derived from one of the three NO synthase (NOS) isoforms was responsible for triggering the adaptive response to brief preconditioning ischemia. Retinae of adult mice were preconditioned with 5-min preconditioning ischemia and subjected to 45-min injurious ischemia 24 hr later. Some animals were treated with the constitutive NOS inhibitor L-nitroarginine (5 mg/kg, i.p.) 1 hr before preconditioning. Retinal layer thicknesses and cell counts were determined one week postischemia in 5-μm thin sections, and flash electroretinograms were obtained at 1 and 7 days postischemia. We confirmed that ischemic preconditioning afforded morphologic and functional protection in the strains of wild-type mice studied. Histopathologic analyses of inducible NOS (iNOS) knockout mice revealed that ischemic preconditioning was completely effective, whereas ischemic tolerance was not achieved in the retinae of endothelial NOS (eNOS) and neuronal NOS (nNOS) knockout mice. The participation of the constitutive NOS enzymes in preconditioning-induced tolerance was confirmed by the finding that administration of the NOS inhibitor L-NA to wild-type mice prior to ischemic preconditioning blocked the development of ischemic tolerance. These cross-validating genetic and pharmacologic findings indicate that NO derived from both eNOS and nNOS is a required molecular signal in the adaptive response to ischemic preconditioning in the retina.

Original languageEnglish
Pages (from-to)153-163
Number of pages11
JournalExperimental eye research
Issue number1
StatePublished - Jan 2006


  • NOS
  • Preconditioning
  • Retinal ganglion cell
  • Signal transduction


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