Nitric oxide is essential for red blood cells to deliver oxygen
The tiny molecule nitric oxide is already known to be critical for blood vessel health and a multitude of functions throughout the body. Groundbreaking research published in PNAS (Proceedings of the National Academy of Sciences) reveals that nitric oxide is the third member of a three gas system (with oxygen and carbon dioxide) is carried by red blood cells and essential for oxygen delivery to tissues. The authors describe the critical role of hemoglobin βCys93, one of three amino acids found in the hemoglobin of all mammals and birds:
"...only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the β-chain (βCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO [nitric oxide] bioactivity by Hb [hemoglobin] redefines the respiratory cycle as a triune system (NO/O2/CO2)."
In other words, the nitric oxide built into hemoglobin as βCys93 is required for RBC-mediated vasodilation. Without sufficient nitric oxide, vasodilation and thus oxygen delivery to tissues is impaired. Hypoxia in tissues is supposed to stimulate a vasodilatory reaction in blood vessel, but this fails to occur normally in RBCs that are deficient in nitric oxide:
"Here we report that mice with a βCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia."
βCys93 nitric oxide in cardiovascular and fetal health
Too little oxygen gets to tissue under normal conditions, and it's even worse with heart disease and fetal stress:
"In addition, βCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, βCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia."
The authors summarize the the huge importance of their study:
"These findings support a new view of the respiratory cycle wherein, remarkably, RBCs regulate blood flow and (βCys93NO)-Hb is necessary for adequate tissue oxygenation and normal cardiovascular function."
Transforms understanding of the respiratory cycle
An excellent review of this research in Medical News Today states:
"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."
Quoting lead author cardiologist Jonathan Stamler, professor of medicine at Case Western Reserve University School of Medicine...
"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."
Furthermore:
"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."
Implications for blood transfusion
There are dire consequences when transfused blood is not replete with nitric oxide:
"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."
Clinical Note
Recently for the first time practitioners can directly test nitric oxide sufficiency and replete NO resources when deficient (see Neogenis Medical Practitioner Resources). The clinical importance of nitric oxide regulation can hardly be overstated. This approximately 3 minute video explains the unique properties of their product for NO levels and production.[embed]https://youtu.be/0vfMa7QxHmw[/embed]