New Blood Substitute Prototypes Engineered Without Blood Pressure Effect

first_imgAddThis Share CONTACT: Mike Cinelli PHONE: (713)831-4794E-MAIL: [email protected] NEW BLOOD SUBSTITUTE PROTOTYPES ENGINEERED WITHOUT BLOODPRESSURE EFFECTFor most people in an emergency room,having blood available–and disease-free–is of utmost concern. To guard againstshortages and potential disease transmission, blood substitutes are beingdeveloped to deliver oxygen to the brain and heart. Most of the protein-based blood substitutes now in clinicaltrials have a side effect that may not be desireable for some patientpopulations–increases in blood pressure. Researchers from Baxter Healthcare Corporation’s HemoglobinTherapeutic Division in Boulder, Colo., (formerly Somatogen, Inc.) and Ricebiochemist John Olson have determined why blood pressure increases whenhemoglobin-based blood substitutes are given to animals, and they haveengineered new prototype molecules without this side effect. “Researchers have known that hemoglobin, the carrier of oxygeninside a red blood cell, also reacts with nitric oxide, a compound that isrequired for maintaining normal blood pressure,” Olson says. “When the tworeact, the nitric oxide is depleted and blood pressure tends to goup.”Hemoglobins designed to steer clear of nitric oxide may be moresuitable for certain blood replacement uses than those which cause significantloss of nitric oxide (NO).Using genetic engineering methods to alter the hemoglobinreaction with NO, the Baxter team, led by Douglas Lemon, who received a Ph.D.from Rice in 1989, and Olson found that the rate of reaction with NO determinesthe magnitude of the blood pressure effect. The faster the cell-free hemoglobinreacts with the NO, depleting the resevoir of NO in the system, the greater theincreases in blood pressure. Their research appears in the July issue of Nature Biotechnology.Nitric oxide is found in the endothelial and smooth musclecells lining the outer walls of blood vessels. It is thought that because simplecell-free hemoglobins are small, they slip through the blood vessel walls toreact with NO. Researchers first designed interconnected hemoglobins to increasetheir size and discourage passage through the walls.Olson, the Dorothy and Ralph Looney Professor of Biochemistryand Cell Biology, said he adopted an alternative strategy to this problem:figure out the chemical mechanism of the reaction with nitric oxide and thengenetically engineer the hemoglobin to inhibit the process.“We needed a way to keep the bound oxygen molecule fromreacting with nitric oxide and the iron atom from rusting,” Olson says, “so weplaced a protective film of large oily amino acids around them.”Says Lemon: “When the engineered hemoglobin molecules weretested in rats, the blood pressure increase was proportional to the rate ofreaction with nitric oxide. At the lowest reaction rate, the blood pressureeffect was nearly eliminated.”It is possible that other side effects sometimes seen inclinical trials with blood substitutes, such as gastrointestinal dysfunction,are also based on nitric oxide depletion and inhibition of smooth musclerelaxation, making the new prototype molecules attractive choices for a secondgeneration blood substitute. ###Contact information:John Olson, Ph.D., Dorothy and Ralph Looney Professor ofBiochemistry and Cell BiologyRice University(713) 527-4762For more information about John Olson’s researchsee:” alt=”last_img” />