A Breakthrough in Respiratory Physiology: Inhaled Nitric Oxide Transported as SNO-Hb

Key Points

• Inhaled nitric oxide (NO) increases circulating levels of SNO-Hb, a bioactive form of NO

• Inhaled NO also increases circulating levels of nitrite, another NO metabolite

• The lungs might act as a reservoir of SNO-Hb, releasing it into circulation as needed

The Breathing Diabetic Summary

Inhaled nitric oxide (NO) has many systemic impacts.  An overview of these effects can be found here and here.  However, it has remained unclear how inhaled NO exerts these effects.  In general, inhaled NO is believed to react and become inactive after reaching the lungs.  Thus, conventional thinking is that the systemic effects of NO are due to improved gas exchange in the lungs, which then has positive downstream impacts.

Interestingly, despite its widespread clinical use, there have been very few studies testing this hypothesis to truly discover how inhaled NO exerts its systemic effects.  This paper sought to fill that gap.

To do this, they recruited 15 healthy volunteers.  They had them inhale NO at concentrations of 40 ppm (the maximum produced in the paranasal sinuses is on the order of ~20 ppm, but typically much less).  They inhaled the added NO for 15 minutes.  Blood samples were collected before inhalation, at the end of the 15 minutes of inhalation, and then at 5, 15, and 30 minutes post-inhalation. 

A Breakthrough in Cardio-Respiratory Physiology

The results were striking.  They found that NO inhalation significantly increased circulating levels of SNO-Hb and nitrite.  This is important because SNO-Hb plays a significant role in whole-body oxygenation.  A 2015 PNAS study discovered that SNO-Hb “senses” areas of low oxygen, and then releases bioactive NO to increase blood flow and oxygenation.  This discovery led to breathing be considered as a three-gas system involving oxygen, carbon dioxide, and NO.  Thus, if inhaling NO increases SNO-Hb, it could be playing a critical role in whole-body oxygenation.  This gets even more intriguing (see next two sections), but first, let’s cover their nitrite finding.

They also observed increases in circulating nitrite.  This is important because, like SNO-Hb, nitrite can also release bioactive NO in regions of hypoxia. However, nitrite can do this independent of the hemoglobin, thus providing a “back-up mechanism” for increasing blood flow in regions of low oxygen.

The Lungs as a Reservoir of SNO-Hb

An interesting finding from this study was that nitrite levels were most significant at the 5-min post inhalation mark.  In contrast, SNO-Hb continued rising throughout the 30 minutes.  This led the authors to believe that the lungs might be acting as an SNO-Hb reservoir, releasing it "as needed." 

Why These Findings Matter

When we breathe through our nose, we carry NO into the lungs (although not at concentrations as high as those studied here).  Based on these findings, we can now be reasonably confident this NO enters the bloodstream and is carried as SNO-Hb and nitrite.  Thus, breathing through your nose might not just improve gas exchange in the lungs.  It might also help make sure oxygen gets delivered where it is needed most throughout the body. 

Additionally, their finding that SNO-Hb levels continued increasing after NO inhalation is intriguing.  It might support the idea that nose breathing provides a baseline level of NO that keeps SNO-Hb in its normal range.  Then, when excess NO is inhaled, the body stores that "just in case."  This is speculative, but interesting to contemplate.

Finally, this is one study, and it’s relatively new.  We’ll need more to confirm/deny that NO inhalation consistently increases SNO-Hb and nitrite across different populations.  In the meantime, let’s keep breathing through our noses.  It may just be the key to whole-body oxygenation.

Abstract

Rationale: Inhaled nitric oxide (NO) exerts a variety of effects through metabolites and these play an important role in regulation of hemodynamics in the body. A detailed investigation into the generation of these metabolites has been overlooked. 

Objectives: We investigated the kinetics of nitrite and S-nitrosothiol-hemoglobin (SNO-Hb) in plasma derived from inhaled NO subjects and how this modifies the cutaneous microvascular response.

Findings: We enrolled 15 healthy volunteers. Plasma nitrite levels at baseline and during NO inhalation (15 minutes at 40 ppm) were 102 (86-118) and 114 (87-129) nM, respectively. The nitrite peak occurred at 5 minutes of discontinuing NO (131 (104-170) nM). Plasma nitrate levels were not significantly different during the study. SNO-Hb molar ratio levels at baseline and during NO inhalation were 4.7E-3 (2.5E-3-5.8E-3) and 7.8E-3 (4.1E-3-13.0E-3), respectively. Levels of SNO-Hb continued to climb up to the last study time point (30 min: 10.6E-3 (5.3E-3-15.5E-3)). The response to acetylcholine iontophoresis both before and during NO inhalation was inversely associated with the SNO-Hb level (r: -0.57, p = 0.03, and r: -0.54, p = 0.04, respectively).

Conclusions: Both nitrite and SNO-Hb increase during NO inhalation. Nitrite increases first, followed by a more sustained increase in Hb-SNO. Nitrite and Hb-SNO could be a mobile reservoir of NO with potential implications on the systemic microvasculature.

Journal Reference:

Tonelli AR, Aulak KS, Ahmed MK, Hausladen A, Abuhalimeh B, Casa CJ, Rogers SC, Timm D, Doctor A, Gaston B, Dweik RA. A pilot study on the kinetics of metabolites and microvascular cutaneous effects of nitric oxide inhalation in healthy volunteers. PLoS One. 2019 Aug 30;14(8):e0221777. doi: 10.1371/journal.pone.0221777. PMID: 31469867; PMCID: PMC6716644.

Meta-Analysis: Slow Breathing Reduces Systolic Blood Pressure by 5.62 mmHg

Key Points

• Diabetics are at an increased risk of hypertension and its negative cardiovascular outcomes

• Slow breathing reduces systolic blood pressure by 5.62 mmHg and diastolic blood pressure by 2.67 mmHg

• Slow breathing is a simple way to reduce blood pressure and potentially improve cardiovascular outcomes

The Breathing Diabetic Summary

Hypertension is a significant risk factor for cardiovascular disease, which is the leading cause of death in the U.S. For instance, if systolic blood pressure rises from 115 mmHg to 135 mmHg, your risk of cardiovascular disease doubles.

People with diabetes are also much more likely to develop hypertension. Anywhere from 40 to 80% of diabetics have hypertension, a somewhat somber statistic. Moreover, I am writing this in April 2020 during the COVID-19 pandemic. Studies are revealing that hypertension is correlated with more severe complications.

All of this is to say that reducing blood pressure is more important than ever. There are several medications and lifestyle changes available; however, compliance with these approaches are often low. Therefore, alternative therapies are needed. One such treatment is slow breathing.

Slow Breathing and Hypertension

Slow breathing has consistently been shown to reduce blood pressure. In particular, a device called RESPeRATE (which is FDA approved), which slowly reduces breathing rate down to below ten breaths per minute, has been examined extensively. The American Heart Association has even given device-guided slow breathing a “class IIA” rating for reducing blood pressure.  

This meta-analysis provides a concise yet comprehensive summary of studies that have examined slow breathing and hypertension. Their strict search criteria and thorough review of the available randomized controlled trials (RCTs) make this the most robust meta-analysis of slow breathing and blood pressure published to date. 

Study Inclusion and Strict Search Criteria

The authors searched several public databases (e.g., Web of Science, MEDLINE) since their inception until mid-2015. They used a combination of search terms like “hypertension OR prehypertension” and “slow breathing OR device-guided breathing” to identify papers relevant to the meta-analysis.

In the identified papers, slow breathing was defined as anything below ten breaths per minute. The subjects had to perform slow breathing at least three times a week for at least 5 minutes each session. They included studies of people with both hypertension and prehypertension. The follow-up period had to be at least 4 weeks and changes in blood pressure had to be reported. They excluded studies of healthy subjects without baseline hypertension or prehypertension

Selecting Relevant Studies and Publication Bias

The authors started with 1,984 studies, but only 17 met their criteria for inclusion in the meta-analysis. Although meta-analyses are some of my favorites, there are caveats that we need to mention for this one.

Of the 17 studies selected, five were abstracts only. Additionally, only two had slow breathing without a device. The other fifteen were device-guided slow breathing using the RESPeRATE, and the maker of the device sponsored six of these. Thus, there was a high risk of publication bias with these studies.

Slow Breathing Significantly Reduces Blood Pressure

Despite these limitations, the collective results were impressive. The average decrease in systolic blood pressure (SBP) across all seventeen studies was 5.62 mmHg. The two non-device slow breathing studies had an even more significant drop of 7.69 mmHg. For diastolic blood pressure, the mean decrease was 2.67 mmHg for the device-guided slow breathing.  

Longer Practice Leads to Better Results

They also examined how the intensity of the slow breathing practice affected results—the conclusion: the longer subjects practiced, the greater their reduction in blood pressure. For example, for slow breathing <100 min a week, the decrease in SBP was 3.01 mmHg, for 100-200 min, it was 6.44 mmHg, and for >200 min, it was 14.00 mmHg.  

Reduced Blood Pressure Reduces Risk of Death

The significance of these findings is that modest reductions in blood pressure lower the chances of strokes, coronary events, heart failure, cardiovascular deaths, and total deaths. This is especially important for diabetics who are at higher risk of developing hypertension and heart disease.

Moreover, the improvements from slow breathing were similar to those seen with antihypertensive medications. Those medications have been shown to improve long-term outcomes in hypertensive and prehypertensive patients. Therefore, slow breathing could potentially provide similar positive results if practiced consistently over a long period.

Slow Breathing is Free and Has No Side Effects

Finally, slow breathing is free, easy to perform, and does not have any side effects. Moreover, the blood-pressure-lowering effects of slow breathing are far-reaching. For example, slow breathing helps with stress, anxiety, and depression, all of which will also help reduce blood pressure.

A Recap of the Main Points 

In summary, slow breathing reduces systolic blood pressure by 5.62 mmHg and diastolic blood pressure by 2.67 mmHg. The more time you practice per week, the greater the blood pressure reductions.  Slow breathing also lowers blood pressure by helping with anxiety, stress, and depression. And by lowering your blood pressure, you reduce the risk of many cardiovascular problems, like stroke or heart disease.

To begin, try breathing at six breaths per minute (4 sec inhale, 6 sec exhale) for five minutes a day and see how you feel. 

Abstract

OBJECTIVES: Interest is increasing in nonpharmacological interventions to treat blood pressure in hypertensive and prehypertensive patients at low cardiac risk. This meta-analysis of randomized controlled trials assesses the impact of device-guided and non-device-guided (pranayama) slow breathing on blood pressure reduction in these patient populations.

METHODS: We searched PubMed, EMBASE, CINAHL, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Web of Science, BIOSIS (Biological Abstracts) Citation Index and Alt HealthWatch for studies meeting these inclusion criteria: randomized controlled trial or first phase of a randomized cross-over study; subjects with hypertension, prehypertension or on antihypertensive medication; intervention consisting of slow breathing at ≤10 breaths/minute for ≥5 min on ≥3 days/week; total intervention duration of ≥4 weeks; follow-up for ≥4 weeks; and a control group. Data were extracted by two authors independently, the Cochrane Risk of Bias Tool assessed bias risk, and data were pooled using the DerSimonian and Laird random effects model. Main outcomes included changes in systolic (SBP) and/or diastolic blood pressure (DBP), heart rate (HR), and/or decreased antihypertensive medication.

RESULTS: Of 103 citations eligible for full-text review, 17 studies were included in the meta-analysis. Overall, slow breathing decreased SBP by -5.62 mmHg [-7.86, -3.38] and DBP by -2.97 mmHg [-4.28, -1.66]. Heterogeneity was high for all analyses.

CONCLUSIONS: Slow breathing showed a modest reduction in blood pressure. It may be a reasonable first treatment for low-risk hypertensive and prehypertensive patients who are reluctant to start medication.

Journal Reference:

Chaddha A, Modaff D, Hooper-Lane C, Feldstein DA.  Device and non-device-guided slow breathing to reduce blood pressure: A systematic review and meta-analysis.  Complement Ther Med. 2019;45:179-184. doi: 10.1016/j.ctim.2019.03.005.