Not to worry[horizontal ellipsis]this is not spam, junk mail, or an annoying television commercial. Now that I have your attention, we can explore the linkage of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil (Viagra), to the potential for chronic wound healing and the enhancement of nitric oxide (NO). Cyclic GMP is a common regulator of ion-channel conductance, glycogenolysis, and cellular apoptosis (cell senescence). It also facilitates relaxation of smooth muscle tissue, resulting in vasodilation and subsequent increased blood flow to the tissues. These attributes make cyclic GMP an important player in enhancement of wound healing.
Cyclic GMP is a second messenger, that regulates the NO pathway, and NO is synthesized from the amino acid L-arginine. Thus, cyclic GMP, the PDE-5 antagonist, and NO are the "Gordian knot" of the ideal biochemical balance to promote wound healing through increased blood flow, oxygenation, neovascularization, and wound healing. On the route to discovery, the formulation of hypothesis-driven interrogatives is paramount. In the case of PDE-5 inhibitors, NO, and L-arginine, singularly and in combination, we want to know how they work, when they work, and what are the alternative uses for PDE-5 inhibitors in wound healing. A survey of the literature unfolds a wealth of scientific investigations relating to the potential clinical uses of NO in wound healing.
The Viagra Connection
The basic science discovery that made the formulation of Viagra possible resulted in the awarding of the 1998 Nobel Prize for Physiology or Medicine to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad for their discoveries concerning "nitric oxide as a signaling molecule in the cardiovascular system." They discovered that the body uses NO to regulate blood vessels, a fundamental concept used in the development of the venerable drug, Viagra. Their prizewinning work, while important for science and medicine, was "a small piece of information" that researchers used in creating Viagra, noted Mariann Caprino, spokeswoman for Viagra maker, Pfizer Inc (New York, NY).
PDE-5 inhibitors regulate the balance of NO at the cellular and endovascular level. Thus, the upregulation of NO, to a point, has a positive influence on wound healing. However, NO levels are like all other homeostatic mechanisms-a harmonic balance is essential. If there is not enough NO, wound healing is inhibited due to decreased blood supply. In contrast, too much NO may be responsible for apoptosis of the cells in conditions such as stroke, heart failure, and other ischemic conditions, associated with free-radical damage, including chronic wounds. High levels of NO are thought to be a significant factor in toxic shock and are associated with increasing levels of tumor necrosis factor.
The NO Connection
NO is a natural occurring gas in the body. NO should not be confused with nitrous oxide (N2O [also called dinitrogen oxide, dinitrogen monoxide, or commonly known as laughing gas]), an anesthetic agent. At a scientific conference in 1986, Furchgott and Ignarro presented their seminal discovery that a gas can act as a signal molecule facilitating intra- and intercellular communication in the organism. In 1977, Murad discovered that nitroglycerin and similar substances release NO, which relaxes smooth muscle cells.
Our knowledge base about the function of NO and its role in the circulation of the blood and regulating activities of the brain, lungs, liver, kidneys, stomach, genitals, and other organs is becoming the basis of new and improved uses of drugs that stimulate or down-regulate the production of NO. Apparently, the immune system uses NO in fighting viral, bacterial, and parasitic infections, as well as tumors, certainly a constructive attribute for the wound healing environment. NO is also a broad-spectrum antimicrobial agent with apparent effectiveness against numerous pathogens that ravage wound healing, including Clostridium difficile, Staphylococcus, Streptococcus, Candida albicans, and Pseudomonas aeruginosa. NO has been shown to be effective against diverse burn wound pathogens, as well.
NO transmits messages between nerve cells and is associated with the processes of learning, memory, sleeping, feeling pain, and, probably, depression. It is also a mediator in inflammation and rheumatologic conditions, as well.
Drugs that liberate or enhance the action of NO may be useful in the treatment of pulmonary hypertension and could prevent the formation of blood clots. Drugs that alter the amount or activity of NO help protect the brain in stroke and Alzheimer and Parkinson disease. Now that time and experience have established the role of Viagra in the treatment of erectile dysfunction (ED), researchers are studying how the drug may improve outcomes for other problems, such as wound healing, Raynaud phenomena, and sickle cell disease, as well as its safety and efficacy when combined with other therapies. Beyond the use of PDE-5 inhibitors to treat ED, investigators are now proposing novel and off-label uses for these agents such as pulmonary hypertension and ulcerations of the skin. Approval from the Food and Drug Administration has now been granted to use PDE-5 for the treatment of pulmonary hypertension. Moreover, ongoing studies have indicated the potential of PDE-5 inhibition for an expanded number of indications, including cardioprotection, enhanced memory, diabetes, and others.
The Wound Connection
In wound healing, our focus is on how PDE-5 inhibitors stimulate the release of NO, which relaxes the arterial walls and increases blood flow. Managing the NO pathway to effect maximal advantage for the subcellular and cellular environment is our goal. The NO pathway starts with NO inactivating the enzyme, guanylate cyclase, resulting in increased levels of cGMP and leading to smooth muscle relaxation in blood vessels. This increases oxygenation to the tissues at risk. Hypothesis-driven studies in both animal and human subjects indicate that NO influences wound repair at multiple levels, including angiogenesis, inflammation, cell proliferation, matrix deposition, and remodeling. In addition, the PDE-5 antagonist reduces inflammation and fights infection. It can increase the levels of the NO processes that are central to wound healing, such as angiogenesis and endothelial and epithelial cell proliferation and migration. Numerous trials are studying whether the delivery of NO enhances wound healing though special drug delivery systems.
The use of NO in wound healing commands a delicate balance-too much NO delivered in the wrong dose or through the wrong delivery system will impede healing. Likewise, too little NO decreases wound tensile strength and collagen deposition, as observed in acute incisional wound models. Underproduction of NO in wounds is seen in patients with malnutrition, diabetes, and steroid use; patients with these conditions also experience impaired wound healing. In malnutrition, wound repair is impaired by associated decreases in NO levels in wound fluid, resulting in deficient collagen formation. Abnormally high levels of NO in the chronic wound environment have detrimental effects as well. Wound infections and inflammatory states are associated with the overproduction of NO in the wound environment and, unless treated, usually result in prolonged recovery.
However, NO does have wound care-specific attributes. For example, it regulates the recruitment and proliferation of keratinocytes at the wound edges, leading to accelerated wound closure. In fact, the overproduction of NO in chronic wounds raises interest in the use of NO inhibitors, which may be an effective treatment option to normalize NO levels in the chronic wound environment, increase wound collagen content, and potentially enhance wound healing.
Conclusions
Obviously, when it comes to the novel uses of current drugs for off-labeled uses described in this editorial, we must proceed with caution. However, I think that the model of enhancing the wound environment by understanding basic synergistic mechanisms that could potentially accelerate wound healing is important. I believe that now, and in the future, we will be using intelligent combination therapeutic regimens to treat chronic wounds.
When the PDE-5 antagonist hit the market about a decade ago, I wrote an article titled "New Remedies for an Old Problem?" In 2008, the principles may be the same, but the theme should change: We should use old remedies for an old problem. That is, we should further investigate the healing of chronic wounds through combination therapy with PDE-5 inhibitors, l-arginine, and NO delivery systems from bench to bedside.
Richard "Sal" Salcido, MD
Selected References