New findings on how red blood cells deliver oxygen from the lungs to tissue in may mean it is time to rewrite the text books on how the respiratory cycle works.

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Researchers say the respiratory cycle is a three-gas system that involves oxygen, carbon dioxide and nitric oxide.

In the Proceedings of the National Academy of Sciences, cardiologist Jonathan Stamler, a professor of medicine at Case Western Reserve University School of Medicine in Cleveland, OH, and colleagues describe how they conducted a study that shows the respiratory cycle involves three gases and not just two.

The current convention describes the respiratory cycle as using blood to transport two gases – oxygen and carbon dioxide. Red blood cells pick up freshly inhaled oxygen from the lungs and carry it to cells in the tissues of the body, and bring back carbon dioxide – a waste product of metabolism – to be exhaled from the lungs.

But because of what they have found, Prof. Stamler and colleagues argue that the respiratory cycle also involves a third gas – nitric oxide – that controls the release of oxygen from red blood cells into the tissues that need it.

In their study they show that hemoglobin – the protein in red blood cells that picks up oxygen from the lungs – also needs to carry nitric oxide to enable blood vessels to open and supply the oxygen to tissues.

Prof. Stamler says “blood flow to tissues is actually more important in most circumstances than how much oxygen is carried by hemoglobin. So the respiratory cycle is actually a three-gas system.”

He and his colleagues say their findings will transform our understanding of the respiratory cycle and could save lives.

For some time doctors have known there is an imbalance between the amount of oxygen transported in the blood and the amount that is delivered to tissues – but not why.

Prof. Stamler says their study shows they have discovered the molecular basis of what controls blood flow in the respiratory cycle. The team believes nitric oxide is the key to oxygen delivery – and without it the respiratory cycle cannot run. Prof. Stamler explains:

“It’s in the hemoglobin protein itself, which has the ability to deliver the nitric oxide together with oxygen.”

In previous work, the team showed the cycle was more than just an exchange of carbon dioxide and oxygen. They discovered red blood cells carried and also released nitric oxide, but the underlying biology was not clear.

In this new study, the researchers show how nitric oxide controls the blood flow in small blood vessels inside tissue in a process known as “blood flow autoregulation.”

For their investigation, they used mice engineered to lack the ability to carry nitric oxide in their red blood vessels.

They found the mice could not oxygenate their muscle tissue – their blood flow autoregulation just did not work in the absence of nitric oxide. Even though their red blood cells were able to carry a full load of oxygen – they just could not unload it.

And when the researchers induced slight oxygen deprivation (hypoxia) in the mice, the blood flow to their organs dropped sharply, triggering heart attacks and heart failure.

In normal mice, the lack of oxygen prompts a spike in blood flow, so more oxygenated blood reaches tissues and cells. This did not happen in the mice whose red blood cells lacked nitric oxide.

Prof. Stamler explains how the mice had red blood cells “that by all traditional measures are completely normal in carrying oxygen and releasing it and then in picking up carbon dioxide, yet these animals cannot oxygenate their tissues. Lacking nitric oxide in red cells, oxygen deficiency could not induce vasodilation, which is essential for sustaining life as we know it.”

The study shows that when the mechanism that releases nitric oxide from the amino acid binding site in the hemoglobin is working, the blood vessels dilate and allow oxygen-rich red blood cells to flow into the tissue.

The findings also provide evidence that blood flow is not just under the control of blood vessels – red blood cells are also involved. This has not been appreciated before, with some scientists hypothesizing instead that the lack of blood flow that causes heart attacks and strokes is nothing to do with red blood cells – it is all about what happens in blood vessels. The authors suggest this view needs to be revised, as Prof. Stamler explains:

“Within the tissues, the tiny vessels and the red blood cells together make up the critical entity controlling blood flow. Red blood cell dysfunction is likely a hidden contributor to diseases of the heart, lung and blood such as heart attack, heart failure, stroke and ischemic injury to kidneys.”

The study also has implications for blood transfusions. Recent evidence shows blood transfusions lacking nitric oxide are linked to higher risk of heart attacks, disease and death.

Prof. Stamler says the effects being reported in these cases are similar to what they observed in the mice – the common factor is lack of nitric oxide.

“It’s not enough to increase to oxygen content of blood by transfusion; if the nitric oxide mechanism is shot, oxygen cannot make it to its destination. We know that blood in a blood bank is deficient in nitric oxide, so infusing that blood may cause plugging of blood vessels in tissues, making things worse,” he notes, and concludes:

Essentially, blood flow cannot autoregulate (increase) without nitric oxide. In terms of developing future therapies, the goal must be restoring red blood cell function, complete with nitric oxide delivery capability. As for the nation’s blood supply, the blood should be replenished with nitric oxide.”

Funds for the research came from the National Institutes of Health, Defense Advanced Research Projects Agency, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center.

In 2013, Medical News Today learned of another small study that suggested the shelf life of blood is nearer 3 than 6 weeks. In blood banks, the standard shelf life of blood for transfusion is 6 weeks, but research led by an expert from the Johns Hopkins University School of Medicine found that after 3 weeks, red blood cells are no longer flexible enough to squeeze through the tiny blood vessels to deliver oxygen where it is most needed.