Timing of administration of dexamethasone or the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester, is critical for effective treatment of ischaemia-reperfusion injury to rat skeletal muscle

Baimeng Zhang, Kenneth R. Knight, Bruce Dowsing, Elizabeth Guida, Long H. Phan, Michael J. Hickey, Wayne A. Morrison, Alastair G. Stewart

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1. The effects of the nitric oxide synthase (NOS) inhibitors, N(G)-nitro-L-arginine-methyl ester (L-NAME), nitroiminoethyl-L-ornithine and S-methylisothiourea on skeletal muscle survival following 2 h of tourniquet ischaemia and 24 h of reperfusion were compared with those of the anti-inflammatory steroid, dexamethasone. 2. Administration of each of the NOS inhibitors or dexamethasone 30 min before reperfusion reduced the degree of skeletal muscle necrosis 24 h after reperfusion. 3. The influence of timing of drug administration was investigated. L-NAME administered 30 min before reperfusion, at 3 h after reperfusion, but not thereafter, significantly improved muscle survival compared with saline-treated controls. Dexamethasone administered 30 min before, or at 3 or 8 h after reperfusion, but not at 16 h, significantly improved muscle survival, but neither agent had protective effects when administered before ischaemia. 4. After 8 h of reperfusion of ischaemic skeletal muscle, cell-free homogenates contained Ca2+-independent (inducible) NOS activity which was reduced in dexamethasone-treated (2.5 mg/kg) rats. Furthermore, inducible NOS mRNA levels, as detected by reverse transcriptase-PCR, were increased after 8 h of reperfusion in saline, but not in dexamethasone-treated rats. 5. These data suggest a significant deleterious effect of endogenous NO which may be restricted to the first 3 h of the reperfusion phase of ischaemia-reperfusion injury, and raise the possibility of effective treatment of incipient reperfusion injury, even after several hours of reperfusion.

Original languageEnglish
Pages (from-to)167-174
Number of pages8
JournalClinical Science
Issue number2
Publication statusPublished - 1 Jan 1997
Externally publishedYes


  • Glucocorticoid
  • Ischaemia-reperfusion
  • Nitric oxide
  • Nitric oxide synthase inhibitors
  • Skeletal muscle

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