Ischaemia/Reperfusion Injury of Skeletal Muscle: Mechanisms, Morphology, Treatment Strategies, and Clinical Applications

Summary: Background: Any surgical manoeuvre that involves cessation of blood supply to an organ with subsequent re-establishment of blood flow can result in ischaemia/reperfusion (I/R) injury. The consequences of such injury are local and remote tissue destruction. Methods: I/R is characterized by ‘no reflow phenomenon’ and interstitial oedema formation. Changes in the production of nitric oxide (NO) and superoxide play an important role in the development of I/R. Overproduction of reactive oxygen-derived free radicals (OFR) leads to a consumption and depletion of endogenous scavenging antioxidants. Results: Direct NO measurements showed a production of large concentrations of NO from cNOS at the beginning of ischaemia. Intracellular influx of Ca2+ after onset of ischaemia activates cNOS, leading to local depletion of L-arginine and subsequently to disarrangement of cNOS, which produces superoxide instead of NO. Microvascular constriction during ‘no reflow’ reflects deficiency in vasodilator NO due to its consumption by vasoconstrictor oxygen free radicals. Stimulated production of thromboxane A2 and endothelin release may also promote ‘no reflow’. Conclusions: At least two major strategies are viable for preventing I/R injury: (a) treatment with L-arginine and their analogues, or BH4, thus preventing L-arginine and H4B deficient conditions, so that cNOS will not produce excessive O2–; (b) scavenging O2– already produced by cNOS and other potential sources of O2– by using large concentrations of free radical scavengers. Further research on oxidant/antioxidant biochemistry and its clinical application is needed.