July 16, 2004 | David F. Coppedge

Haemoglobin More Complex than Thought: Regulates Blood Flow

Physiologists have long known that haemoglobin, the molecule that adds the redness to red blood cells and carries oxygen to the tissues, releases its oxygen as the blood vessels constrict.  Now, increasing evidence shows that haemoglobin (composed of four complex proteins that surround a central iron atom) is not just a passive oxygen carrier.  It actually works with other substances, including nitric oxide (NO), to regulate the flow of blood by adjusting the dilation of blood vessels, and NO in response can adjust how efficiently haemoglobin can carry oxygen.  This process, still not fully understood, is presented in a Concepts piece by David J. Singel and Jonathan S. Stamler in the July 15 issue of Nature,1 who speak of the “emergent complexity of haemoglobin.”
    Nitric oxide produces dilation of blood vessels.  Apparently it will hitch onto the alpha or beta subunits of haemoglobin depending on the concentrations of oxygen or carbon dioxide present in the blood, acting as a regulator of NO’s activity in dilating the vessels according to need.  For the chemists in the audience,

The disposition and reactivity of NO bound to haemoglobin is thus a function of multiple variables, including the other allosteric effectors of haemoglobin (pH; partial pressure of carbon dioxide, pCO2; partial pressure of O2, pO2) and the ratio of their concentrations to haem.  Changes in conditions can give rise to stark, rather than subtle, linear changes in the distribution of NO reaction products.  This complexity emerges both from the cooperative, nonlinear behaviour of the haemoglobin tetramer and from the branched network of coupled kinetic equations underlying this rich chemistry.

So when you are walking casually in the woods, oxygen outnumbers NO, which binds to the beta subunits, generating production of NO-downstream products, and your blood vessels relax.  When you see the bear and take off running, the binding of NO changes and “contributes to the matching of blood flow to demand under physiological conditions.”  What happens when the bear has you pinned to the ground and is licking your face?

In contrast, when micromolar concentrations of NO arise, as in septic shock, the potential problem of excess S-nitroso-haemoglobin and consequent excessive vasodilation is avoided by sequestering NO on the alpha-haems, which additionally lowers the overall oxygen affinity of the protein.  This chemistry restricts NO bioavailability while enhancing oxygen delivery.

NO works with haemoglobin, therefore, in response to physiological conditions to adjust its ability to carry oxygen, without going berserk under stress.  The authors encourage an “appreciation of the complexity” of this process, because “Emerging evidence [shows] that vasodilation by red blood cells is altered in disease, including heart failure, pulmonary hypertension and diabetes….”  Knowledge of this self-regulating activity “should open a new field of investigation and could potentially change the practice of medicine.”
    A related paper in PNAS2 explores additional biologic activities of NO and its reaction products in blood plasma, and suggests that “high-affinity, metal-based reactions in plasma with the haptoglobin-hemoglobin complex modulate plasmatic NO reaction products and limit S-nitrosation at low NO flux.”  These products coordinate with hormones, endocrine vasomotor function, and NO transport in the blood vessels.


1David J. Stingel and Jonathan S. Stamler, “Blood traffic control,” Nature 430, 297 (15 July 2004); doi:10.1038/430297a.
2Wang et al., “Biological activity of nitric oxide in the plasmatic compartment,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0402201101, online preprint July 16, 2004.

This wonderful story speaks for itself.  We need to be reminded of how many things have to work exactly right for us to do something as simple as taking a walk in the woods.  Things are not getting any easier for those who believe a long series of mistakes produced the human body, to say nothing of bears and forests.

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Categories: Human Body

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