Evidence of Systemic Transport and Delivery of Inhaled Nitric Oxide

Key Points

• Inhaled nitric oxide (NO) is traditionally thought to only have local effects in the upper airways and lungs.

• However, this study found that inhaled NO can improve blood flow in distant regions when endothelial NO is suppressed. The measurements were consistent with systemic transport and delivery of inhaled NO.

• The effects of inhaled NO on systemic blood flow might be important in diseases that disrupt endothelial-derived NO (such as diabetes).

The Breathing Diabetic Summary

There are two primary sources of nitric oxide (NO) in the body: inhaled NO and endothelial-derived NO.

Inhaled NO is produced in the paranasal sinuses.  When you breathe through your nose, you bring this NO into your lungs, where it aids in blood flow redistribution and increases oxygen uptake.  However, it is traditionally thought that this NO only affects the airways and lungs; it is said to immediately react and lose its bioactivity.  Although there are many benefits of inhaled NO in the lungs, its journey ends there. 

Endothelial-derived NO, on the other hand, has systemic effects in the body, including improving whole-body blood flow and, especially, blood flow to the heart.  However, it is thought that there is a complete disconnect between these two sources of NO: Inhaled NO does not have systemic effects. 

But several studies suggest otherwise (see review here).  The reported systemic effects of inhaled NO imply it is somehow retaining its bioactivity and being transported throughout the body.  But, it’s now quite sure how. 

This study did something interesting to try to find out. They administered L-NMMA, which inhibits endothelial-derived NO from being produced. Then, they measured what happened to forearm blood flow under several conditions:

1. When participants breathed normal air.

2. During a handgrip exercise (which should increase blood flow).

3. During inhalation of extra NO (at 80 ppm) and repeat the two measurements (sitting still and the handgrip exercise). Note that 80 ppm is much higher than what is produced in the paranasal sinuses, which maxes out around 25 ppm.

4. Lastly, they had participants inhale the added NO without using L-NMMA, which, as we will see, turns out to be a critical measurement.

The results were quite fascinating.  First, when NO was inhaled without the L-NMMA administered, nothing happened to forearm blood flow.  Therefore, under normal conditions, inhaling extra NO doesn’t seem to impact blood flow.  But things got interesting when L-NMMA was administered.  Inhaling NO counteracted the blood flow reduction due to L-NMMA.

Thus, under normal conditions, inhaled NO doesn’t have much impact on systemic blood flow.  But, when endothelial-derived NO is suppressed (the L-NMMA case), the inhaled NO “takes over,” compensating for the missing NO.  This opens up the blood vessels and increases blood flow.  This effect was most marked during the handgrip exercise.

Moreover, by looking at arterial-to-venous gradients in different gases, which show how gases change from when the blood leaves the lungs versus when it returns to the heart, they found evidence of NO transport and delivery.  This led them to conclude:

“The most fundamental and important observation of this study is that NO gas introduced to the lungs can be stabilized and transported in blood and peripherally modulate blood flow.” 

This study was groundbreaking in that it showed, for the first time, evidence of inhaled NO being transported throughout the body while maintaining its bioactivity.  These results might be significant to diabetics because we suffer from reduced endothelial-derived NO and reduced blood flow.  Thus, the results might provide more support for nose-breathing (although again, NO concentrations in the nose are far less than what was administered here).

To conclude, I’ll borrow a line from the abstract, which succinctly states how the findings of this study could be particularly important to diabetics: 

“These results indicate that inhaled NO during blockade of regional NO synthesis can supply intravascular NO to maintain normal vascular function. This effect may have application for the treatment of diseases characterized by endothelial dysfunction.”

Abstract

Nitric oxide (NO) may be stabilized by binding to hemoglobin, by nitrosating thiol-containing plasma molecules, or by conversion to nitrite, all reactions potentially preserving its bioactivity in blood. Here we examined the contribution of blood-transported NO to regional vascular tone in humans before and during NO inhalation. While breathing room air and then room air with NO at 80 parts per million, forearm blood flow was measured in 16 subjects at rest and after blockade of forearm NO synthesis with NG-monomethyl-l-arginine (l-NMMA) followed by forearm exercise stress. l-NMMA reduced blood flow by 25% and increased resistance by 50%, an effect that was blocked by NO inhalation. With NO inhalation, resistance was significantly lower during l-NMMA infusion, both at rest and during repetitive hand-grip exercise. S-nitrosohemoglobin and plasma S-nitrosothiols did not change with NO inhalation. Arterial nitrite levels increased by 11% and arterial nitrosyl(heme)hemoglobin levels increased tenfold to the micromolar range, and both measures were consistently higher in the arterial than in venous blood. S-nitrosohemoglobin levels were in the nanomolar range, with no significant artery-to-vein gradients. These results indicate that inhaled NO during blockade of regional NO synthesis can supply intravascular NO to maintain normal vascular function. This effect may have application for the treatment of diseases characterized by endothelial dysfunction.

Journal Reference:

Cannon RO 3rd, Schechter AN, Panza JA, et al. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest. 2001;108(2):279-287. doi:10.1172/JCI12761

How Breathing Regulates the Cardiovascular System and Improves Chemosensitivity

Key Points

• Breathing modulates the cardiovascular system through respiratory sinus arrhythmia

• Slow breathing reduces chemosensitivity to high carbon dioxide and low oxygen

• Controlled breathing could be a beneficial intervention in different pathological states

The Breathing Diabetic Summary

How does breathing affect us physiologically?  Well, the answer to that is complex.  Breathing is felt by various receptors throughout the body, affecting cardiovascular and autonomic variability on many levels. This review study examined these different modulatory effects of breathing through a comprehensive analysis of the peer-reviewed literature.

Breathing and the Cardiovascular System

The cardiovascular system is sensitive to external stimuli. Just picture something scary (like giving a presentation), and your heart rate will likely increase. Consequently, your breathing will also change to match your metabolic needs.

But this is a two-way street. Controlled, rather than reactive, breathing also has profound impacts on the cardiovascular system. This can be temporary, for example, breathing rapidly for one minute, or permanent, for example, developing the behavior/habit of chronic over-breathing.

Knowing that breathing has "direct access" to the cardiovascular system, let's look at how this occurs and how controlled breathing might be beneficial in different pathological states.

Respiratory Sinus Arrhythmia

One way in which breathing permeates the cardiovascular system is through respiratory sinus arrhythmia (RSA). RSA is a measurement of how breathing, heart rate, and blood pressure all interact. In simple terms, RSA refers to the increase in heart rate as you inhale and decrease in your heart rate as you exhale. RSA is thought to be an index of vagal activity and direct measurement of heart rate variability.  

When we breathe so that the length of our inhale matches seamlessly with our heart rate increase and our exhale with our heart rate decrease, we maximize RSA. Typically, this occurs when breathing at around 6 breaths per minute. This coherence among respiration and heart rate leads to the maximization of heart rate variability, improving cardiovascular efficiency.

Breathing and Chemoreflexes

Slow breathing can reduce breathlessness and improve exercise performance in patients with chronic heart failure. These results suggest that slow breathing could be modifying the chemoreflexes, allowing one to tolerate higher concentrations of carbon dioxide and lower concentrations of oxygen.

To test this hypothesis, a study was conducted with yoga trainees and non-yoga trained participants. Both groups performed different breathing protocols to test their response to high carbon dioxide (hypercapnia) and low oxygen (hypoxia). Although none of these participants had heart problems, the goal was to see if slow breathing could reduce chemoreflexes in the controls to the levels seen in yoga practitioners.

As we might expect, the chemoreflexes of the yoga practitioners at baseline were much lower than the non-trained participants.  This means their breathing did not increase as much when exposed to hypercapnia or hypoxia. Interestingly, the chemoreflexes of the controls decreased to levels similar to the yogis when breathing at 6 breaths per minute.  Therefore, the simple act of slow breathing reduced chemosensitivity to carbon dioxide and hypoxia, regardless of previous training.

These results indicate that breathing could represent another way to better coordinate the breathing muscles, improve chemoreflexes, and improve exercise performance in patients with cardiovascular problems. Slow breathing could, therefore, be a practical alternative when other rehabilitation programs are not available.

Breathing Modulates Cardiovascular and Autonomic Control

To summarize, breathing is a potent modulator of cardiovascular and autonomic systems.  Deliberate practice of different breathing patterns (for example, slow breathing) could be beneficial for increasing heart rate variability, improving breathing efficiency, improving chemosensitivity, and enhancing cardio-autonomic control.

Abstract

Respiration is a powerful modulator of heart rate variability, and of baro- and chemoreflex sensitivity. Abnormal respiratory modulation of heart rate is often an early sign of autonomic dysfunction in a number of diseases. In addition, increase in venous return due to respiration may help in maintaining blood pressure during standing in critical situations. This review examines the possibility that manipulation of breathing pattern may provide beneficial effects in terms not only of ventilatory efficiency, but also of cardiovascular and respiratory control in physiologic and pathologic conditions, such as chronic heart failure. This opens a new area of future research in the better management of patients with cardiovascular autonomic dysfunction.

Journal Reference:

L Bernardi, C Porta, A Gabutti, L Spicuzza, P Sleight.  Modulatory Effects of Respiration.  Auton Neurosci. 2001;90(1-2):47-56. doi: 10.1016/S1566-0702(01)00267-3.