The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 12 No. 6 • October 2009

L-Arginine Supplementation Protects Against
Ischemia/Reperfusion Injury as Occurs in Heart
Attacks and Strokes

A new paper1 reports finding that the data developed in their experiments “strongly implicate reduced L-arginine availability as a key factor in the pathogenesis of I-R [ischemia/reperfusion] injury.” I-R occurs when oxygen supply is reduced (hypoxia) and then restored (reperfusion), such as occurs in heart attacks, strokes, or in obstructive sleep apnea. Although restoration of blood flow protects against further injury resulting from reduced oxygen supply, additional injury occurs that is believed to be due to the production of reactive oxygen species (ROS) during reperfusion. The ROS during the early stages of myocardial reperfusion is thought to be involved in the arrythmias, ventricular fibrillation, tachycardia, premature beating, and contractile dysfunction that can occur at that time.1

In this very interesting paper, the authors tested the hypothesis that “the I-R process induces a state of insufficient L-arginine availability for NO [nitric oxide] biosynthesis, and that this is pivotal in the development of myocardial I-R damage.”1

It is known that insufficient amounts of arginine (the precursor to nitric oxide) can cause the enzyme eNOS (endothelial nitric oxide synthase) to become “decoupled” from the production of NO, and to generate superoxide radicals instead. This means not only that less nitric oxide is produced, but that excess superoxide radicals are produced and the latter chemically interact with the available nitric oxide to form the potent oxidant peroxynitrite. The authors1 cite two earlier studies in animal models in which researchers found improved post-ischemic myocardial function and smaller infarct sizes (fewer heart cells died) following the infusion of L-arginine during reperfusion. Their purpose in doing this new research was to investigate mechanisms to explain the L-arginine cardioprotection as well as the role of CAT1 (the L-arginine transporter) in I-R injury. The studies were done on Sprague-Dawley rat neonatal ventricular cardiomyocytes (NVCM heart muscle cells) and in isolated mouse hearts.

Several experiments were performed. In one, NVCMs that were infected with adenovirus expressing the CAT1 L-arginine transporter (and, thus, overexpressing the CAT1 gene) and NVCMs supplemented with 1 mmol/L L-arginine during hypoxia-reoxygenation had significantly reduced ROS generation, significantly improved mitochondrial membrane potentials and significantly increased NO production (all p<0.001), while L-arginine deprived NVCMs had significantly worsened responses to hypoxia-reoxygenation. In the isolated mouse hearts, the authors found that “infusion of 1 mmol/L L-arginine in hearts during reperfusion significantly improved recovery when compared to that of untreated hearts” for measures that indicated improved ventricular relaxation and reduced diastolic stiffness. Protein oxidation by peroxynitrite in the mouse hearts (as measured by nitrotyrosine) was significantly lower (P<0.001) in L-arginine infused hearts as compared to untreated controls. The researchers found that there was reduced L-arginine transport during both hypoxia and in reoxygenation.

One of the possible mechanisms to explain these beneficial effects of L-arginine infusion was the observation that the extent of phosphorylation (activation) of Akt was increased significantly in L-arginine infused hearts after I-R. Akt has important anti-apoptotic (prevents a form of programmed cell death) properties and has been found when overexpressed to prolong survival, prevent cardiac remodeling (pathogenic changes) and improved contractile performance in infarcted hearts.1 Moreover, other studies have reported increased Akt signalling as a result of ischemic preconditioning (in which exposure to a small ischemic stress can protect against a larger ischemic stress later during a specific period of time).

The authors conclude that “[r]estoration of L-arginine availability may therefore be a valuable strategy to ameliorate I-R injury.”

Obstructive Sleep Apnea

As we mentioned above, obstructive sleep apnea is a significant cause of ischemia-reperfusion injury because of repeated episodes of discontinued breathing following by restoration of breathing during sleep. At present, there are no really satisfactory treatments except for uncomfortable masks that deliver compressed air to the sufferer’s airways during sleep. The use of arginine supplements could be a way to help reduce or prevent I-R damage that would otherwise occur during sleep apnea. We hope to see published research on this, but human studies are expensive to do and are governed by many rules and regulations. We do not know if there are good animal models for obstructive sleep apnea.

Citrulline May Increase Arginine Supply Even Better Than Arginine3

As we have reported before, studies have shown that the amino acid citrulline is part of a salvaging cycle in which arginine is used by nitric oxide synthase to make NO, with citrulline as a byproduct. Citrulline is then recycled to arginine.2 It is for this reason that we include small catalytic amounts of citrulline in our InnerPower Plus™ arginine supplement.

  1. Venardos et al. Reduced L-arginine transport contributes to the pathogenesis of myocardial ischemia-reperfusion injury. J Cell Biochem 108:156-168 (2009).
  2. Hecker et al. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci USA 87:8612-6 (1990).
  3. Kuhn et al. Oral citrulline effectively elevates plasma arginine levels for 24 hours in normal volunteers. Circulation 206(Suppl II):11-339 (2002).

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