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:
When participants breathed normal air.
During a handgrip exercise (which should increase blood flow).
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.
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