Arginine and Protective Ischemic Preconditioning

Article Title: Arginine and Protective Ischemic Preconditioning
Article Date: 9/1/2005
The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 3 • July 2005

Arginine and Protective Ischemic Preconditioning

Preconditioning is the term for the protective effect induced in tissues exposed to brief periods of reduced oxygen availability against later (within a certain time period) exposure to more severe reduced oxygen availability. It is believed to be due to the induced expression of protective substances, such as antioxidant enzymes and heat-shock proteins. An example of preconditioning is that the brief periods of ischemia followed by reperfusion that occur during angina provide protection to the heart against damage from ischemia-reperfusion events during the following day or so.

A recent study1 reports that the amino acid L-arginine induces a protective effect like preconditioning in the liver by stimulating the production of nitric oxide, which, the authors suggest, might inhibit the downregulation of eNOS (endothelial nitric oxide synthase, which makes nitric oxide in the lining of blood vessel walls) during reperfusion following ischemia (reduced oxygen availability).

Ischemia-reperfusion is a source of considerable damage during a heart attack. While the reduced oxygen availability of ischemia causes damage (for example, by reducing the ability of heart cells to produce ATP, for which oxygen is required), the reperfusion following ischemia also causes damage via increased free radical activity. The liver suffers similar damage in response to ischemia-reperfusion (IR). In this study of preconditioning in the rat liver, IR was associated with a decline in L-arginine levels and decreased eNOS activity in the affected tissue. (An excessively low level of L-arginine is associated with decreased production of nitric oxide and also with “uncoupling” of nitric oxide synthase, where the enzyme produces superoxide radicals rather than nitric oxide, with resulting increased production of the potent oxidant peroxynitrite.) The researchers also found increased ornithine levels in the IR group, which suggests that there was an increase in liver arginase activity. Arginase is an enzyme that metabolizes L-arginine to ornithine, which is then converted to polyamines. Many cancers are associated with upregulated arginase, which reduces the availability of L-arginine for conversion to nitric oxide by nitric oxide synthase.

The authors induced preconditioning in the rat livers by causing 5 minutes of lobar ischemia and 10 minutes of reperfusion; this was followed by the more severe treatment of 45 minutes of ischemia and 2 hours of reperfusion. The authors report, “The major finding of the study is that cytoprotective nitric oxide is produced by eNOS during ischemic preconditioning of the liver … The results also demonstrate that IPC [ischemic preconditioning] was associated with an increased availability of the L-arginine substrate. … Arginine is degraded by arginase to ornithine, and sufficient quantities of arginase can limit the availability of arginine for NO synthesis, and hepatic [liver] ischemia reperfusion has been shown to be associated with an increased arginase-1 activity. The low ornithine levels in the preconditioned [by exposure to short-term ischemia followed by reperfusion] livers could suggest the possibility that the effect of IPC may involve modulation of arginase to increase substrate availability for NO biosynthesis.

“The effects of L-arginine administration were similar to those evident following IPC. … L-Arginine supplementation modulates the NO-dependent vascular functions, and clinical studies have reported that L-arginine administration reduces the symptoms of coronary heart disease in patients.” However, “… the administration of exogenous L-arginine not only significantly increased plasma level but also led to increased ornithine levels. The higher production of ornithine would indicate arginase activity. This raises the possibility that some of the NO generation after L-arginine administration may be independent of the L-arginine/NOS pathway.”

In conclusion, arginine may provide protection similar to preconditioning in tissues subject to ischemia and reperfusion. This is one reason that both of us take L-arginine supplements in the form of our Muscle Memory  formulation, which contains L-arginine plus choline and B5 and other nutrients.


  1. Koti et al. Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver. FASEB J 19:1155-7 (2005).