X-Message-Number: 5973 Date: Thu, 21 Mar 1996 17:46:37 MST From: "Richard Schroeppel" <> Subject: Hemoglobin transports NO Study finds major new task of hemoglobin in blood Copyright © 1996 Nando.net Copyright © 1996 N.Y. Times News Service (Mar 21, 1996 1:09 p.m. EST) -- With almost the surprise that might greet discovery of a new bone in the human body, scientists have detected a major new task performed by hemoglobin, the blood's red pigment and transporter of gases. Besides ferrying oxygen from lungs to tissues and carting back carbon dioxide on the return journey, hemoglobin has now been found to distribute a third gas on its rounds, according to research published Thursday in the journal Nature. The gas is nitric oxide, and hemoglobin seems to be able to make the blood vessels expand or contract by regulating the amount of nitric oxide to which they are exposed. The finding is likely to have significant implications for the treatment of blood pressure and the development of artificial blood. The atom of iron cradled by each subunit of hemoglobin is known to have a strong affinity for nitric oxide after it has released its oxygen, behavior hitherto regarded as something of a curiosity. The new discovery is that another part of the hemoglobin, a segment of its protein chain known as a cysteine residue, can also hold and release nitric oxide, giving the blood pigment the ability to regulate local levels of nitric oxide in the circulatory system according to need. Nitric oxide -- long known as a noxious gas in the atmosphere -- is turning out to be as important as oxygen in keeping cells and tissues alive, said Dr. Jonathan Stamler of Duke University Medical Center in Durham, N.C., and senior author of the new report. The invisible, odorless gas was first discovered to have a physiological role in the body in 1987. It is now known to be a messenger that acts on many different cells, changing their shape and function. And it plays a ubiquitous role in human health, Stamler said, including the maintenance of learning and memory, blood pressure and sexual erections. The finding that hemoglobin carries nitric oxide to all parts of the body will come as a complete surprise to most scientists and physicians, Stamler said in a telephone interview. "People thought they knew everything there was to know about hemoglobin," Stamler said. It is perhaps the most studied protein in all of biology and its intricate workings have been examined for more than 60 years. That it has another basic function is a stunning revelation, he said. "This is a seminal discovery about a new function for hemoglobin," said Dr. Steven Gross, an associate professor of pharmacology at Cornell University Medical College in New York and expert on nitric oxide. "It is exceedingly important -- a third arm for respiration." Dr. Max Perutz, a pioneer in hemoglobin research at the MRC Laboratory of Molecular Biology in Cambridge, said the research "provides a deeper insight into the structure of hemoglobin" and solves "a mystery that we couldn't understand." Stamler and his colleagues discovered the new role of hemoglobin through considering a paradox about the supply of nitric oxide in the tissues. The cells lining the blood vessels are known to release nitric oxide, and the gas has a powerful relaxing effect on the muscle cells that surround the arteries, thus increasing blood flow. Yet the iron molecules in hemoglobin scarf up nitric oxide so efficiently it seems there would be none left to relax the muscle cells. How were the muscle cells getting their necessary fix of nitric oxide, without which they would constrict and raise blood pressure? The Duke scientists started looking for other sources of nitric oxide in the blood stream. They noted that when nitric oxide acquires an extra electron, a form they call super nitric oxide, it takes on a different chemistry. In this form it is not mopped up by the iron atoms in hemoglobin. But it can bind to another part of the blood pigment, to the tail of an amino acid called cysteine, which is present in each of the two beta units of a hemoglobin molecule. Stamler, along with Duke colleagues Dr. Li Jia, Dr. Celia Bonaventura and Dr. Joseph Bonaventura found that super nitric oxide is indeed present in red blood cells as they leave the lungs, though not in the blood returning to the lungs from the tissues. This implies that super nitric oxide is made in the cells of the lungs and transferred to the cysteine residues in hemoglobin, but the details remain to be nailed down. According to Stamler, the revised textbook picture of the respiratory cycle now goes like this: When a red blood cell enters the lung, its hemoglobin molecules release carbon dioxide and pick up both oxygen and super nitric oxide. The red blood cell travels through the arteries and into the tiny capillary blood vessels where oxygen is released. Free of oxygen, the iron atoms of hemoglobin can then trap any local excess of ordinary nitric oxide, making blood vessels contract. But the hemoglobin changes shape as the oxygen leaves and can also release super nitric oxide, making blood vessels relax if necessary. When the red blood cell returns to the lungs, it dumps carbon dioxide and the ordinary kind of nitric oxide bound to the iron atoms. It then picks up more oxygen and super nitric oxide and the cycle continues, Stamler said. Confirming this thesis is the fact that the cysteine unit in hemoglobin has remained unchanged in mammals and birds, though all the other amino acids except the one that holds the haem-cradled iron have changed in the course of evolution. This constancy indicates that the cysteine must perform an essential function, though one not guessed until now. Stamler said he was delighted by a commentary in Nature on his paper by Dr. Max Perutz, who won a Nobel prize for discovering the crystal structure of hemoglobin. In an interview Wednesday, Perutz endorsed the paper but was more guarded than Stamler about its possible medical implications. The Duke experiments were performed in rats but Stamler feels certain the same results will be found in humans because of the basic similarity between rat and human physiology. The new finding suggests solutions to several medical mysteries. Most blood substitutes tend to raise blood pressure. The reason may be that they lack super nitric oxide, Stamler said. When the heart is deprived of oxygen for any reason, it is also lacks super nitric oxide. A dose of nitric oxide-laden hemoglobin might help heart attack patients to restore the natural balance. Shock results from the over production of ordinary nitric oxide. An infusion of nitric oxide-laden hemoglobin might help restore the system into balance. Finally, the research may lead to new ways to control blood pressure. The lungs and red blood cells play a more important role than previously thought, Stamler said. Copyright © 1996 Nando.net Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=5973