Vasorelaxation by red blood cells and impairment in diabetes.  Reduced nitric oxide and oxygen delivery by glycated hemoglobin - James et al. (2004)

Key Points

  • Diabetics suffer from a lack of bioavailable nitric oxide (NO), which contributes to diabetic complications

  • High HbA1c increases the amount of NO that is bound inside red blood cells (RBCs) in a non-bioavailable form

  • High HbA1c impairs the blood flow autoregulation function of NO bound to RBCs in areas of tissue hypoxia

The Breathing Diabetic Summary

We learned the importance of the nitric oxide (NO) that “rides” on the red blood cells (RBCs) in a PNAS paper from Zhang et al. (2015).   Quick recap: NO is bound to RBCs (in its bioactive form) and can be released to increase blood flow and oxygenation in areas of tissue hypoxia. Although this paper was written over a decade prior to that one, it shows the same mechanism at play, but as it relates to high blood sugars (i.e., glycated hemoglobin).  High HbA1c can change the configuration and binding properties of blood proteins, so these authors wanted to investigate how that might affect NO metabolism in diabetics.

Some things to note before getting into the results are that this was a rabbit study and that their control HbA1c was 5.4% and their diabetic HbA1c was ~10.7%, which is fairly high, but not unrealistic for uncontrolled type 1 or type 2 diabetes.  Another thing to note is that NO bound to Hb in the form of HbNO is not bioactive, whereas NO bound as HbSNO is bioactive.  See Zhang et al. (2015) for a description of how HbSNO retains NO bioactivity.

The most important result for us was that a high HbA1c increased the affinity of the Hb for NO, but in the form of HbNO, and reduced the amount of bioavailable HbSNO. Thus, they vasodilator function of NO is impaired with high HbA1c.  Overall, this means that a high HbA1c would ultimately lead to a reduction of oxygen delivery to cells and tissues.

Not that any of us need another reminder, but this paper really highlights the importance of keeping our blood sugars in good range.By lowering our HbA1c, we can capitalize on the vasodilator function of NO bound to RBCs, increase blood flow and tissue oxygenation, and help reduce long-term complications of diabetes related to impaired blood flow.So, as we use our breathing to help control our blood sugars, we’ll see a snowball effect of better blood sugars leading to better blood flow, leading to better blood sugars, leading to even better blood flow, etc. etc

Abstract from Paper

Vascular dysfunction in diabetes is attributed to lack of bioavailable nitric oxide (NO) and is postulated as a primary cause of small vessel complications as a result of poor glycemic control. Although it has been proposed that NO is bound by red blood cells (RBCs) and can induce relaxation of blood vessels distal to its site of production in the normal circulation, the effect of RBC glycation on NO binding and relaxation of hypoxic vessels is unknown. We confirm RBC-induced vessel relaxation is inversely related to tissue oxygenation and is proportional to RBC S-nitrosohemoglobin (HbSNO) content (but not nitrosylhemoglobin content). We show more total NO bound inside highly glycated RBCs (0.0134 versus 0.0119 NO/Hb, respectively; P<0.05) although proportionally less HbSNO (0.0053 versus 0.0088 NO/Hb, respectively; P<0.05). We also show glycosylation impairs the vasodilator function of RBCs within a physiological range of tissue oxygenation. These findings may represent an important contribution to reduced NO bioavailability in the microvasculature in diabetes.

Journal Reference:

Philip E. James, Derek Lang, Timothy Tufnell-Barret, Alex B. Milsom, and Michael P. Frenneaux, (2004) Vasorelaxation by red blood cells and impairment in diabetes.  Reduced nitric oxide and oxygen delivery by glycated hemoglobin, Circulation Research, 94, 976 – 983, doi:10.1161/01.RES.0000122044.21787.01.