Nitric Oxide (NO)

NITRIC OXIDE (NO) A small, potentially toxic, compound of oxygen and nitrogen that is also a free radical. Nitric Oxide is different from laughing gas, nitrous oxide, N20. Nitric Oxide serves multiple functions in the body as a freely diffusible messenger molecule. Nitric oxide is synthesized by specific enzymes, nitric oxide synthases, from the amino acid ARGININE.

Nitric Oxide serves as a neurotransmitter in the brain and other parts of the nervous system and perhaps plays a key role in memory. Neurotransmitters are chemicals that transmit nerve impulses between the gaps that exist between cells. When macrophages, phagocytic cells of the immune system, are stimulated to respond to foreign invaders and immune activators, they produce large amounts of Nitric Oxide to wage chemical warfare against viruses and bacteria.

Nitric Oxide is produced by endothelial cells lining blood vessels where it relaxes blood vessels and helps maintain blood pressure. Too little Nitric Oxide may play a role in hypertension and angina. It also is involved in penile erection and may be a factor in impotence. Nitric Oxide also interacts with blood platelets to decrease platelet aggregation, thus lowing the risk of blood clots. Red blood cells rapidly inactivate nitric oxide by converting it to nitrate for excretion.

Excesses of Nitric Oxide may be a factor in strokes and inflammatory bowel disease. In stroke, too much calcium can enter cells, causing nitric oxide overproduction to toxic levels when oxygen supply is restored. Nitric Oxide combines with superoxide, another free radical produced in the body, to form peroxynitrite. This powerful oxidizing agent may account for some of the cellular damage that occurs with prolonged inflammation and could contribute to tissue damage in colitis and other conditions.

NO as a gas molecule can act as a chemical messenger for numerous functions in the body. It signals the release of important hormones and acts as a neurotransmitter in the brain. It is used by the immune system to kill marauding bacteria and cancer cells. Thus, adequate levels of NO in the body normalize blood pressure, prevent heart disease, and maintain good circulation.

For years no one could explain the diversity of the amino acid, Arginine’s action. Then in 1988 it was discovered that this amino acid is the precursor of Nitric Oxide. Arginine works by increasing the level of Nitric Oxide in the body.

Protects Against Heart Disease

NO staves off heart disease in several ways. It protects the endothelial cells lining the arteries from the initial adherence of plaque. It is a potent antioxidant (more powerful than vitamin E according to some studies), guarding LDL cholesterol from the free radical damage that transforms it from a benign blood fat to an aggressive artery toxin. It also prevents platelets in the blood from sticking together, decreasing the formation of clots that might initiate a heart attack. In addition, NO relaxes the arteries and prevents arterial spasms. (This is how nitroglycerin works to relieve chest pain in heart patients-it is converted to NO in the body.)

Diseased arteries produce significantly less NO than healthy arteries. Therefore, once the atherosclerotic process is set into motion, it gains a momentum of its own. Damaged arteries make less NO, and inadequate production of NO increases arterial damage. Supplemental Arginine interrupts this destructive cycle by providing the remaining healthy endothelial cells with the raw materials to boost production of NO.

Arginine has been shown to actually restore normal function in arteries damaged by LDL cholesterol. A study published in the journal Circulation showed that long-term Arginine supplementation in patients with high cholesterol was associated with a reduction in the thickness of plaque. Other studies have demonstrated improvements in exercise capacity, peripheral artery disease, and angina with Arginine.

Reduces Blood Pressure

When NO was first discovered in the arteries, it was named endothelium-derived relaxing factor (EDRF) because it was found to be such a powerful vasodilator. Released by the endothelial cells, it signals the smooth muscle cells of the arteries to relax, thus increasing their diameter. By allowing blood to flow more freely, with less pressure against arterial walls, NO is a primary regulator of blood pressure.

When the synthesis of NO is inhibited, blood pressure soars. Boosting NO levels with supplemental Arginine is a potential powerful therapy for hypertension. A 1997 study presented at the American Heart Association’s 70th Scientific Session showed that patients with mild to moderate hypertension taking two grams of Arginine daily experienced significant reductions in blood pressure. An Italian study of patients with newly diagnosed mild hypertension demonstrated that two grams of oral Arginine lowered systolic blood pressure by 20 mm Hg after only a week of supplementation.

Enhances Sexual Function

Given the widespread actions of NO in the blood vessels, it’s hardly surprising that Arginine is an excellent therapy for many circulatory disorders. You might not think of impotence, or erectile dysfunction, as a circulatory disease, but in most cases that is exactly what it is. The greatest risk factors for erectile dysfunction are age, atherosclerosis, smoking, diabetes, hypertension, and high cholesterol-and every single one of these factors is associated with impairments in blood flow and artery health.

But there is an even more direct relationship between NO and erections. Erections occur when NO, produced in response to arousal messages relayed from the brain, triggers the release of a compound that causes the smooth muscles of the spongy tissues inside the penis to relax, allowing these tissues to engorge with blood. Inadequate NO, inadequate erection-it’s as simple as that.

Although it has been ignored in the clamor over Viagra, Arginine is for some men an equally effective, far less expensive option for erectile dysfunction. Patients who are taking Arginine for cardiovascular conditions often report improvements in erectile function also. Even those who don’t have problems with impotence note increased duration and firmness of erections. Women likewise notice heightened sexual function. Although NO’s role in female sexuality has not been as intensely studied, it is known to improve blood flow to the genital area, which increases sensitivity and lubrication. It also stimulates the release of hormones that may enhance the female sexual response.

Recommendations for Arginine

The recommended starting dose of Arginine is one gram three times a day, although some people require double that dose (two grams three times a day) to notice benefits. Doses up to 20 grams are sometimes used for maximum benefit.

Consult your physician before taking Arginine if you are taking Viagra, nitroglycerin or a related drug, or if you have any of the following: pregnancy, migraines, autoimmune disorders, AIDS, cirrhosis, depression, or breast cancer (although Arginine fights many types of cancer, very high doses may increase breast tumor growth). While there are no firm contraindications to Arginine in these conditions, it may be prudent to wait until further research clarifies its effects.

For more information on this highly effective amino acid, we suggest you read The Arginine Solution by Drs. Robert Fried and Woodson Merrell (Warner Books, 1999), available in bookstores and on the Internet.

Life Sci 1999;65(21):2167-74

New insights into nitric oxide and coronary circulation.Gattullo D, Pagliaro P, Marsh NA, Losano G

Dipartimento di Scienze Cliniche e Biologische, Universita di Torino, Ospedale S. Luigi, Orbassano, Italy.

Since its discovery over 20 years ago as an intercellular messenger, nitric oxide (NO), has been extensively studied with regard to its involvement in the control of the circulation and, more recently, in the prevention of atherosclerosis. The importance of NO in coronary blood flow control has also been recognized. NO-independent vasodilation causes increased shear stress within the blood vessel which, in turn, stimulates endothelial NO synthase activation, NO release and prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and vasodilator effects of acetylcholine and bradykinin are all mediated by NO. Ischemic preconditioning, which protects the myocardium from cellular damage and arrhythmias, is itself linked with NO and both the first and second windows of protection may be due to NO release. Exercise increases NO synthesis via increases in shear stress and pulse pressure and so it is likely that NO is an important blood flow regulatory mechanism in exercise. This phenomenon may account for the beneficial effects of exercise seen in atherosclerotic individuals. Whilst NO plays a protective role in preventing atherosclerosis via superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO release leading the way for endothelial dysfunction and atherosclerotic lesions. Exercise reverses this process by stimulating NO synthesis and release. Other factors impacting on the activity of NO include estrogens, endothelins, adrenomedullin and adenosine, the last appearing to be a compensatory pathway for coronary control in the presence of NO inhibition. These studies reinforce the pivotal role played by the substance in the control of coronary circulation.

Hepatogastroenterology 1999 Sep-Oct;46(29):2999-3003

The role of nitric oxide (NO) in the human pyloric sphincter.
Tomita R, Tanjoh K, Fujisaki S, Fukuzawa M

First Department of Surgery, Nihon University School of Medicine, Japan.

BACKGROUND/AIMS: Nitric oxide (NO) has recently been shown to be a neurotransmitter in non-adrenergic non-cholinergic (NANC) inhibitory nerves in the gastrointestinal tract. To clarify the role of NO in the human pyloric sphincter, enteric nerve responses in pyloric tissue specimens obtained from patients with gastric cancer were investigated. METHODOLOGY: Fresh specimens of normal pylorus obtained from 18 patients with gastric cancer were used. The subjects consisted of 12 men and 6 women, aged from 45-74 years (average: 60.1 years). A mechanograph was used to evaluate in vitro pyloric sphincter muscle responses to electrical field stimulation (EFS) of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, and N(G)-nitro-L-arginine (L-NNA) and L-arginine. RESULTS: Cholinergic nerves were mainly involved in the regulation of enteric nerve responses to EFS in the basal condition of the study, and NANC inhibitory nerves acted on human pylorus. L-NNA concentration dependently inhibited the relaxation in response to EFS in the human pylorus, and this inhibitory effect in the pylorus was reversed by L-arginine. CONCLUSIONS: These findings suggest that the cholinergic/adrenergic and NANC inhibitory nerves play important roles in regulating contraction and relaxation of the human pylorus, and that NO plays an important role as a neurotransmitter in NANC inhibitory nerves of the human pylorus.