The Silent Epidemic of Nitric Oxide Insufficiency

by Nathan S. Bryan, PhD

It is nearing the end of 2011, and there have been more than 120,000 published papers on nitric oxide (NO). It is now well established and appreciated that it is one of the most important molecules produced within our body. Medical research has shown that NO signaling is involved in practically every organ system, and perturbations in NO signaling are associated with numerous aspects of health. During the first three parts of this four part series, we have described the importance of NO in multiple health conditions, explained the effects of aging on NO production and provided evidence that L-arginine is not a viable solution or effective strategy for restoring NO production in patients, especially patients with endothelial dysfunction. We have also introduced the latest technology for diagnosing and testing for NO insufficiency through the salivary test strips.

In this last part of the series, we hope to raise awareness on the long term effects of NO by providing population based reports on the two extremes: populations that can sustain and maintain normal NO production and populations that are chronically NO insufficient. Fortunately, these two extremes are well studied and documented. The first example of NO sufficiency and the ability to maintain and sustain NO production is in natives of Tibet that use NO as a means to adapt to the high altitude and low oxygen environment of living at 12,000 feet above sea level. The other extreme is two examples of chronic NO insufficiency; the first in African Americans and a second in hemodialysis patients that are subjected to sub-chronic depletion of NO. Although these examples of population based reports are two extremes, most of the general population likely fall somewhere in between. Recognizing and implementing strategies to restore and replete NO homeostasis is paramount to affecting patient outcome and well-being as well as affecting the current health care system.

High Altitude Natives as an Example of NO Producers

The low barometric pressure at high altitude causes lower arterial oxygen content among Tibetan highlanders, who maintain normal levels of oxygen use as indicated by basal and maximal oxygen consumption levels that are consistent with sea level predictions. Hypothetically, the unavoidably low supply of oxygen in the air and the blood could be offset by increasing blood flow to improve oxygen delivery. Blood flow is determined by numbers, length, and diameter of blood vessels that in turn are largely determined directly or indirectly by levels of NO, a potent vasodilator synthesized in the endothelial cells lining the vessels. Tibetans have high levels of NO synthesis in the lungs,¹ and pulmonary blood flow correlated with NO in a sample studied at 4,200 meters above sea level.¹ This suggests the hypothesis that Tibetan highlanders offset hypoxia with higher systemic blood flow and higher levels of circulating, biologically active metabolites of NO.

After synthesis by the endothelium, NO rapidly undergoes reaction in the blood to form products that have circulatory and metabolic effects, including nitrite and nitrate. A recent study affirmed the hypothesis that Tibetans living at 4,200 meters offset physiological hypoxia and achieve normal oxygen delivery by means of higher blood flow enabled by higher levels of bioactive forms of NO, the main endothelial factor regulating blood flow and vascular resistance. The natural experimental study design compared Tibetans at 4,200 meters and U.S. residents at 206 meters. The study found that forearm blood flow, an indicator of systemic blood flow, as measured noninvasively by using plethysmography at rest, after breathing supplemental oxygen, and after exercise found that Tibetans had more than double the forearm blood flow of low-altitude residents, resulting in greater than sea level oxygen delivery to tissues. In comparison to sea level controls, Tibetans had greater than 10-fold-higher circulating concentrations of bioactive NO products, including plasma and red blood cell nitrite and nitrate.² This suggests that the need to enhance NO production is a fundamental physiological response to low oxygen or hypoxia. People who have healthy endothelial function are able to accommodate this increased NO formation; however, if one is unable to enhance NO production, then this level of protection and adaptation is not possible. This was further corroborated recently by studies showing that even healthy people living at sea level that are able to increase NO production upon need are able to adapt to high altitude and low oxygen conditions if they are given time to adapt.³ These findings demonstrate that the ability to enhance NO production is an adaptive physiological response to low oxygen, which becomes an issue in patients with cardiovascular health concerns and poor circulation. This may also explain why some people living at sea level get altitude sickness when ascending to high altitude and why others do not. The ability to generate NO may be the difference.

Health Disparities of African Americans is Due to NO Insufficiency

Despite considerable overall improvements in the clinical prevalence and outcome of patients with poor cardiovascular health in the US population over the past 50 years, striking disparities in these conditions impact specific racial/ethnic subgroups. Specifically, African Americans bear a higher burden of cardiovascular health-related issues such as excess weight gain, poor blood sugar control, and blood pressure imbalances when compared with whites. Black patients who have blood pressure imbalances are disproportionately burdened with a higher risk of poor kidney health and suboptimal cardiovascular function as compared with whites. Collectively, African Americans are at a disadvantage when it comes to cardiovascular risk; however, the mechanisms for these disparities remain poorly understood, but likely include a combination of genetic, environmental, and socioeconomic factors.⁴ Moreover, differences in vascular endothelial function, especially the decrease in NO bioavailability observed in blacks, has been proposed as a mechanism to account for these ethnic disparities in CVD outcomes.

Several groups have reported impaired vascular endothelial function in blacks as compared with whites.^5-7 This impairment is likely to be important in that it may reflect a deficiency of bioactive endothelial NO that compromises its actions as a mediator of vascular homeostasis, including vasodilatation, platelet function, smooth muscle cell growth inhibition, and anti-inflammatory function. It should be recognized that decreased NO bioactivity can not only arise from impaired NO production, but also enhanced oxidative inactivation, or perhaps a combination of the two. Polymorphisms in the endothelial nitric oxide synthase (NOS) gene have been identified that alter NO production. One of these polymorphisms is more common among blacks than it is among whites and is associated with a decrease in the expression of endothelial NOS and a resulting decrease in NO production.^8-9 A recent study showed that homozygosity for the 4a polymorphism conferred a significantly increased risk of heart health issues before age 45 in blacks.¹⁰ Another important genetic determinant of NO synthesis and its oxidative inactivation is glucose-6-phosphate dehydrogenase (G6PD). A deficiency of G6PD is the most common enzymopathy globally, and it is particularly common in the US black population (11 to 15 percent prevalence). Recent work has shown, however, that G6PD is a key determinant of vascular function and that its deficiency can lead to impaired NO production and enhanced vascular oxidant stress.¹¹

Leopold and coworkers^11-12 have demonstrated these principles in cultured endothelial cells, as well as in an animal model of G6PD deficiency. Of equal importance, these investigators recently showed that healthy black subjects with G6PD deficiency have impaired endothelium-dependent vasodilation and increased oxidant stress as compared with age-matched controls. Regardless of the cause it is apparent that African-Americans suffer from insufficient NO production, which may explain the health disparities.

Strategies to restore NO should be a first line of therapy or support for these patients but only recently have such strategies been implemented to address differences in pathophysiology and responses to drugs that are based on ethnicity. Novel approaches to address cardiovascular health issues in African Americans have included the use of therapeutics that act as NO donors combined with vasodilators, which may enhance endothelial function and improve NO levels in this population. Using this combination therapy in addition to standard therapies, a major clinical trial demonstrated significant improvements in heart health outcomes, and enhancements in quality of life and functional status.¹³ These data not only provide proof of concept, but emphasize that strategies to restore NO homeostasis in the African American population can provide enormous benefit. However, we must address this problem early to ensure optimal cardiovascular health in this population. This can be achieved by products such as Neo40® Daily.

Chronic NO Depletion in Hemodialysis Patients

Maintaining cardiovascular health in dialysis patients remains a serious challenge. Cardiovascular complications are a major contributor to poor health outcomes in patients with end stage renal disease (ESRD) undergoing hemodialysis.¹⁴ Cardiovascular health issues in patients undergoing hemodialysis remains poorly understood. Therapeutic approaches shown to be effective to maintain cardiovascular health in the general population have thus far demonstrated no benefit to patients undergoing hemodialysis.¹⁵ This may be because the prevalence of poor cardiovascular function in this population cannot solely be explained by the high prevalence of classical cardiovascular health factors, such as age, blood pressure imbalances, poor blood sugar metabolism, cholesterol levels and smoking.¹⁶

We recently investigated the effects of hemodialysis on NO availability and production. The objective of our study was to determine the extent of removal of plasma and salivary NO congeners nitrite and nitrate by hemodialysis, as this might disrupt physiological NO bioactivity and help explain the health disparity in dialysis patients. Blood and saliva were collected at baseline from patients on dialysis and as it exited the dialysis unit. There was a 57 percent reduction in blood levels of nitrite and an 84 percent reduction in nitrate after a single pass through the dialysis instrument. After a 4-5 hour session of dialysis, there was 80-90 percent less of these bioactive NO metabolites than before dialysis began. Dialysis also resulted in a significant reduction in salivary nitrite disrupting this important and critical enterosalivary circulation of nitrate, nitrite and NO.¹⁷ These results suggest that chronic and persistent depletion of plasma and salivary nitrite and nitrate likely reduces NO bioavailability and may be related to the poor cardiovascular health outcomes seen in the dialysis patient.

These population-based reports clearly show the effects of NO availability in specific groups of people. Whereas people with healthy endothelial function are able to produce more NO upon need, people with endothelial dysfunction are not able to sustain and maintain normal NO production, which therefore is likely the underlying cause of many of the health problems. The good news is that there is a way to correct and restore NO homeostasis naturally. We have defined the NO index of certain foods that when consumed contribute to NO production in the body. Green leafy vegetables and beets are highest on the NO index. This allows for custom tailored diets specifically for patients that may be NO deficient.

Furthermore, there is now a clinically demonstrated dietary supplement that has been shown to correct NO insufficiency and improve important cardiovascular health parameters in patients over the age of 40.¹⁸ Implementing diet and exercise lifestyle modifications combined with Neo40 Daily is an effective strategy for restoring and correcting NO insufficiency in a number of different patients, especially when L-arginine-based products are ineffective. Hopefully this four part series has brought awareness to the role of NO in health and provided the practitioner with practical information that can be immediately taken to the clinic where you can begin to diagnose, correct and monitor the NO status of your patients and begin to see the improvement in their health. The Nitric Oxide Salivary Test Strips and Neo40 Daily should be part of that regimen.

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