Assessing The Potential Of Nitric Oxide In The Diabetic Foot

By Paul J. Kim, DPM

   Researchers have studied nitric oxide (NO) extensively for the past 40 years. However, there has been an increased interest within the past 15 years. In 1998, the Nobel Prize in Physiology and Medicine was awarded to scientists who worked out the signaling mechanisms for NO in the human body.

   Nitric oxide is an endogenous gas produced by cells with many diverse physiological effects. The substrate arginine is converted by the enzyme nitric oxide synthase (NOS) to citrulline with the liberation of NO (see “A Closer Look At Nitric Oxide Production” below).1 After NO is released, it has a half-life of seconds with subsequent binding to receptors on or within the cell that causes a second messenger cascade. The result of this cascade depends on the type of NOS. There are many subtypes of NOS including: nNOS, which are found in neurons; iNOS, which are inducible forms found throughout the body; and eNOS, which are found in blood vessel cells. The iNOS and eNOS subtypes are particularly interesting with their implications in the lower extremity, especially when it comes to wound healing.

   There are two relevant components of NO on wound healing. The first is the vascular component. Endogenous NO acts upon endothelial cells to cause dilatation of vessels (both arterial and venous). Contrarily, inhibition of NO synthesis causes vasoconstriction and subsequent hypertension.1 Evidence also suggests there is decreased NO activity with an increase in activity levels by vasoconstrictors in the diabetic rat model.2 Studies of humans have also demonstrated decreased NO production in diabetic patients with peripheral neuropathy.3 Further, the vessels of insulin dependent diabetic patients demonstrate less responsiveness to NO and potentially a decrease in availability of NO.4,5 Researchers have also shown that NO increases blood flow to the microcirculation adjacent to wound sites.6

   The second component of NO on wound healing is in the inflammatory process. Researchers have measured NO at higher levels in proximity to wound sites.7 Cytokines stimulate macrophages and fibroblasts to produce NO.8,9 Nitric oxide appears to have cytotoxic properties and this suggests some level of antimicrobial activity.10 Also keep in mind that inhibition of NO synthesis retards collagen synthesis and deposition which we know are key components in providing principal strength characteristics of wounds.11

   There is growing interest in the clinical use of NO in the lower extremity. Clinically, we know that NO can play a role in two key pathologic components in the diabetic foot: vascular compromise and peripheral neuropathy.

   There have been promising results for the use of NO in treating painful peripheral neuropathy. Researchers have demonstrated that monochromatic near-infrared photoenergy (MIRE®, Anodyne® Therapy System) increases sensation and decreases pain.12-14 The proposed principle behind MIRE is that photon energy induces the release of NO, thereby increasing blood flow to vascularly compromised peripheral nerves. Clinicians have also utilized topical NO, in the form of a spray, for the treatment of painful peripheral neuopathy with good success.15

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