Just say NO: An exciting possibility for wound care takes the Nobel prize

Knowledge has been around for years; now researchers are putting it together

The role nitric oxide plays in keeping our bodies healthy is one of the hottest topics in healing circles — and may be the most exciting news in wound care today.

Though known for decades mainly as an atmospheric pollutant, nitric oxide (NO) is also produced by cells in several tissues of the body.1 Last October, the Nobel Assembly announced three Americans had won the 1998 Nobel Prize in Physiology or Medicine for discovering that NO acts as a signal for the cardiovascular system by telling blood vessels to relax and widen. Thanks to the work of these scientists, NO is now known to stimulate the body’s wound-healing response, defend against infections, and act as a regulator of blood pressure and a "gatekeeper" of blood flow to different organs.

Ronald G. Scott, MD, medical director of the Wound Care Clinic of North Texas at Presbyterian Hospital in Dallas, says nitric oxide deficiency is a "possible explanation as to why some wounds with apparently the same causation or diagnosis do not respond to the same treatments in the same way or at the same rate." It seems astounding that this common air pollutant, formed when nitrogen burns, could beneficially influence human health—especially when you consider that NO is so unstable, it is converted to nitrate and nitrite within 10 seconds.

NO stimulates collagen production, appears to enhance macrophage and white cell activities, and is key in matrix remodeling and fibroplasia of the wound, according to Joseph V. Boykin Jr., MD, medical director of Retreat Hospital Wound Healing Center and assistant professor of plastic surgery at the Medical College of Virginia in Richmond. "We’re still testing this as a hypothesis," Boykin says, "and so far it does appear that nitric oxide is an extremely important regulator of the wound healing process."

Boykin says hyperbaric oxygen (HBO) therapy recently has been discovered to be an important source of nitric oxide production. "All diabetics are deficient in nitric oxide, so their wounds are deficient in NO. We are fairly certain that the poor wound healing diabetics demonstrate is linked to a nitric oxide deficiency as much as to any other thing. What this now allows us to do is to look at the experience that people have had with hyperbaric oxygen therapy and diabetic wounds. For a long time, we’ve looked at the oxygen side of HBO, and felt very comfortable that this could explain a lot of what HBO did for wounds. But now that we know that HBO significantly increases the amount of nitric oxide in wounds that are probably deficient in it, we can go back and redesign that whole schema, and things really begin to make a lot more sense.

"Suddenly you begin to look at this diabetic patient," he says, "and you see that all of these things are in some way related to the unhinging of the physiology of these organs because of the absence of sufficient amounts of nitric oxide. This is why we got really excited about the wound healing part of it. The information we glean about nitric oxide’s role in wound healing will do two things right off the bat: open up a whole new perspective on wound healing, and firmly establish HBO’s credibility because we will be able to look at HBO as a delivery system, not only for high oxygenation but also for nitric oxide. That combination makes for a very exciting future for wound research.

"I just really became aware of the relationship between nitric oxide deficiency and diabetics in the last few years," Boykin says. "I talk about this with clinicians who’ve been working with diabetes for a long time, and they frown and look at me and ask, What do you mean?’ And then we start reviewing it, and they say, My gosh, I didn’t realize this.’ This kind of information has been at a laboratory level, and now it’s just beginning to come to the surface. It’s the kind of news that’s going to keep a lot of us busy looking at new ways of treating things."

Understanding the relationship between NO deficiency and diabetics means understanding how NO is produced in our bodies. There are two substrates for nitric oxide: One is oxygen, and the other is the semiessential amino acid L-arginine, commonly called arginine. Woodson Merrell, MD, executive director of Beth Israel Center for Health and Healing in New York and assistant clinical professor in medicine at Columbia College of Physicians and Surgeons at Columbia University in New York, details the arginine-nitric oxide connection in his book, The Arginine Solution.2

"L-arginine is primarily a nitrogen donor, the primary nutrient the body uses to make almost all the nitric oxide that’s in the body for virtually every physiologic process that uses it," Merrell says. "Arginine enhances the immune system in general. Part of wound healing, obviously, is having a strong immune system, so that’s where arginine would be of particular benefit."

Merrell points out that arginine also stimulates the release of growth hormones from the brain and that one of its mechanisms for wound healing may be making more growth hormone available for tissue regrowth. Arginine may have effects reaching far beyond just providing a nutrient to the tissue to make protein.

Studies have shown that arginine speeds wound healing via several different mechanisms. In a clinical study reported in the August 1990 issue of Surgery, scientists recruited 36 healthy volunteers from medical and nonmedical hospital personnel. None of the subjects suffered from diabetes, smoked, or took drugs known to impair wound healing. The 36 subjects were randomly placed into three groups of equal size. Group 1 received 100 ml/day of an aromatic syrup as a placebo. Group 2 received 30 gm of arginine aspartate in 100 ml, while Group 3 received 30 gm of hydrochloride in 100 ml of aromatic syrup (the equivalent of 24.8 gm/day of free arginine). All supplements were taken throughout the day for two weeks.

Immediately prior to the study, and on days seven and 14, peripheral blood was drawn for analysis after an overnight fast. On the first day of the study, all the subjects underwent the creation of a "standard wound" (5 cm long, 1 mm in diameter) after receiving a local anesthetic. A catheter was inserted into the wound with one end sutured and left protruding from the skin. The wound then was covered with an occlusive, transparent dressing that was changed during the study as needed.

The primary finding of the study was that in both arginine groups, there was a significant increase in the amount of reparative collagen synthesized at the site of the wound. The scientists concluded, "To our knowledge, this is the first instance in which collagen synthesis has been shown to be enhanced to supranormal’ levels." In the same study, there also was marked enhancement in the activity and effectiveness of peripheral T-lymphocytes in the bloodstream.3

How much arginine supplementation is safe?

Scott says arginine, which is present primarily in protein-rich foods, can be an important tool in helping stubborn wounds heal. "Some of the more expensive formulas for tube feeding that are necessary when the regular formulas aren’t working are L-arginine-supplemented," Scott notes. "For a patient with bedsores that are failing to heal, even after they’ve been on good nutritional supplementation for a while, switching to a formulation with higher levels of L-arginine can result in improved healing. Some of the supplemental formulas provide 15-25 gm of arginine per day." Scott also notes that it’s difficult to get levels of arginine high enough to boost healing through diet alone, especially in the American Diabetes Association 1,800-2,000 calorie diet. He uses formula supplementation for older, debilitated, diabetic patients in skilled nursing facilities.

Patients not living in skilled nursing facilities can benefit from taking arginine supplements. Merrell says most studies have shown that 9,000 mg/day of arginine supplementation is statistically significant in helping reverse some of the damage in the small blood vessels in the body, including the coronary arteries. "A number of other studies have used anywhere from 3,000 to 6,000 mg," he says. "The intravenous studies were originally around 30,000 to 50,000. We say, start with 3,000 [mg arginine supplement/day] and move up to 6,000 if you need to. The average amount in the American diet is about 5,600."

Arginine can cause a drop in blood pressure

Merrell warns that arginine supplementation is not a "magic bullet." Dietary supplementation with arginine has been demonstrated to shorten wound healing times and rates, but wound care providers must be certain their patients do not have any conditions for which arginine supplementation is contraindicated. Boykin says most people can safely tolerate fairly hefty supplements of arginine, but cautions at the same time that a patient who has hypertension, heart disease, or thromboembolic problems could have serious problems from increasing the amount of this amino acid because it can cause blood pressure to drop.

"It’s a very good substance for wound healing, but if given to the wrong person at the wrong time, it could lead to complications; however, I think looking at arginine-based therapy for diabetics will be the main entree on our plate for the new millennium," he says. "The news for the clinician at large is that nitric oxide-related deficiency in wound healing is something we’re very keen on now, and we’re beginning to look at how we can use this new information to better predict the patients that are at risk and help treat those that are already demonstrating problems related to wound healing."

References

    1. Bruch-Gerharz D, et al. Nitric oxide in human skin: Current status and future prospects. J Invest Dermatol 1998; 110:1-7.

    2. Freid R, Merrell W. The Arginine Solution: First Guide to America’s New Cardio-Enhancing Supplement. New York: Warner Books; 1999.

    3. Faloon W, ed. Disease Prevention and Treatment Protocols. 2nd ed. Hollywood, FL: Life Extension Foundation; 1998.