Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea

Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy - Schulz et al. (2000)

Key Points

Nitric oxide (NO) concentrations are significantly lower in patients with obstructive sleep apnea
NO concentrations can be increased both acutely and long-term through use of CPAP therapy

The Breathing Diabetic Summary

We learned in the Ip et al. (2000) study that nitric oxide (NO) concentrations are lower in patients with obstructive sleep apnea (OSA) than in healthy subjects. The current paper, which was published in the same year, also looked at NO levels in patients with OSA. Moreover, they also examined the effects of continuous positive airway pressure (CPAP) on NO, again similar to the Ip et al. study. Let’s see how their results compare.

The study had 21 patients with OSA, 13 healthy subjects (control group 1), and 18 patients that did not have OSA, but suffered from other ailments (e.g., pneumonia), as control group 2. They measured serum NO levels after a night of sleep in each of these groups, and then did a follow-up to see the impacts of CPAP therapy in the OSA group.

(NOTE: Direct measurements of NO cannot be made because of its short lifetime. Instead, they measure the stable derivatives of NO, nitrite and nitrate, which are collectively referred to NOx. For simplicity, I’m just calling it NO here. However, this does have important implications for their findings because they cannot tell what is causing the increased/decreased NO. Because this paper (and the Ip et al. study) was published in 2000, the general consensus was that NO was endothelial-derived. However, the PNAS study published in 2015 showed that bioactive NO can “ride” around on the hemoglobin and plays a critical role in whole-body oxygenation. Thus, any changes in NO seen here potentially could be related to the hemoglobin.)

The results showed that NO levels were significantly lower in the OSA group than in both of the control groups. Control group 1 (the healthy patients) had the highest NO levels, followed by control group 2, and finally by the OSA patients. These results suggest that low NO is due to sleep-disordered breathing itself because patients with other serious ailments (control group 2) still had higher NO than the OSA group.

After two nights of CPAP therapy, a majority of the OSA patients saw significant increases in NO concentrations. OSA patients with hypertension saw the greatest increases. Then, they followed up with 13 of the OSA patients after using CPAP for a longer duration (the average being ~5.5 months). They found that NO levels in 10 of the patients were still increased, while the other 3 patients still suffered from low NO.

Overall, this study showed that OSA patients have low levels of NO.They also found that CPAP therapy can reduce this issue, both acutely and long-term. This is important because NO plays a critical role in preventing many cardiovascular diseases. Unfortunately, they could not provide a direct mechanism for why CPAP increased NO in OSA patients. However, I suspect that CPAP increases nasal breathing during night, allowing the body to utilize the warehouse of NO that resides in the nasal passages. We’ll see if any studies support this hypothesis. In the meantime, I think these studies suggest that following Principle 2 and taping our mouth at night is a safe bet for increasing NO and decreasing the risk of cardiovascular disease.

Abstract from Paper

BACKGROUND: Reduced endothelium dependent vasodilation has been reported in patients with obstructive sleep apnoea (OSA) but direct measurements of the most potent naturally occurring vasodilator, nitric oxide (NO) or its derivatives (nitrate and nitrite, NO(x)), have not yet been performed in these patients.

METHODS: In 21 patients with OSA of mean (SE) age 54 (2) years, body mass index (BMI) 30.9 (1.1) kg/m(2), and apnoea-hypopnoea index (AHI) 37 (4)/h, NO(x) levels were measured in peripheral venous blood samples by chemiluminescence. Blood samples were obtained before and after two nights of continuous positive airway pressure (CPAP) and after 5.5 (1.5) months of follow up. Thirteen age matched, healthy volunteers and 18 patients without OSA but with a similar spectrum of comorbidity served as controls (control groups 1 and 2).

RESULTS: Before CPAP NO(x) levels were 21.7 (1.5) microM in patients with OSA compared with 42.6 (2.2) microM and 36.7 (1.7) microM in control groups 1 and 2, respectively (p<0.01 for each comparison). NO(x) concentrations increased to 32.1 (2.7) microM after two nights of CPAP and remained constant at 32.9 (2.3) microM at follow up (p<0.01 compared with levels before CPAP).

CONCLUSIONS: Plasma NO(x) levels are reduced in OSA and can be increased by short and long term CPAP therapy. Although the precise mechanism underlying this observation remains to be clarified, it may have important implications for the development of cardiovascular disease in patients with OSA and for the life saving effect of CPAP.

Journal Reference:

R Schulz, D Schmidt, A Blum, X Lopes-Ribeiro, C Lücke, K Mayer, H Olschewski, W Seeger, and F Grimminger, (2000) Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy, Thorax, 55, 1046 – 1051.