Making blood share more of its oxygen.

Making Blood Share More of Its Oxygen

Chemical modification of hemoglobin -- the oxygen carrier in blood -- shows promise for treating a range of conditions, including heart attacks and stroke, that can be caused by the reduced flow of blood to tissues. Two experimental approaches were reported last week in New York City at the spring national meeting of the American Chemical Society.

"There's a site on the hemoglobin molecule that can either weaken or tighten the bond with oxygen," explains Murray Weiner, acting director of clinical pharmacology at the University of Cincinnati Medical Center. Normally, the body fills that crucial site with a substance called 2,3-diphosphoglycerate (DPG). Weiner and Robert S. Franco have found a way to instead bind onto hemoglobin a natural analog of DPG -- phytic acid -- that keeps the oxygen more loosely bound than does DPG.

The analog permits delivery of roughly twice as much oxygen per unit of blood to tissues. Weiner says, and with less work by the heart. That could prove especially useful in the treatment of ischemic disease -- conditions caused by reduced or obstructed blood flow -- because normal hemoglobin often cannot provide sufficient oxygen to prevent the death of affected tissues.

To incorporate phytic acid into red blood cells, the researchers bathe the cells in dimethylsulfoxide (DMSO), a small molecule that rushes into cells. Once the DMSO is inside, they rapidly dilute the bath, causing the cells to swell. The new bath also contains the phytic acid, a compound that can pass through the blood cell's membrane only when the cell is swollen. But as phytic acid enters the cells, the DMSO begins to leave. With DMSO's departure, the cells shrink back, trapping the phytic acid inside.

Weiner envisions that this process, in addition to modifying the blood of patients with ischemic disease, could help transfusion patients with sickle cell disease, because their painful sickling occurs only when affected blood cells give up their oxygen. Since the modified hemoglobin gives up its oxygen more readily than a sickle cell's does, he believes its presence could reduce the oxygen demand on cells with sickle cell hemoglobin. Weiner says he will soon begin human trials to establish the life span of blood cells with this modified hemoglobin.

In a second approach to the problem, at Columbia University's College of Physicians and Surgeons in New York City, Reinhold and Ruth Benesch, a husband-wife team of chemists, are incorporating an analog of vitamin B.sub.6 into hemoglobin stripped from red blood cells. The compound, which permanently links one of the hemoglobin molecule's two pairs of subunits, works "akin to a built-in super DPG -- one that is roughly 10 times more effective than DPG is at making oxygen available," according to Reinhold Benesch. Moreover, it keeps the hemoglobin from splitting in half and subsequently exiting through the kidneys -- the normal fate of hemoglobin outside of blood cells.

The Benesches envision their modified, out-of-blood-cell hemoglobin, which has already been tested on rats and rabbits, as a potential oxygen carrier that could be added to blood of trauma patients or persons with ischemic emergencies. And because, unlike other hemoglobins, it can still unload oxygen at low temperatures, they believe it could be used to oxygenate organ transplants during shipment or hearts during surgery.