X-Message-Number: 27198 Date: Wed, 12 Oct 2005 12:45:49 +0200 From: Eugen Leitl <> Subject: [[ccm-l] Mystery of arteriolar O2 release solved] [forwards snipped] Nitric Oxide Found To Control Oxygen Delivery To Tissues; Findings Could Lead To Therapies For Diseases Of Heart, Lung, Blood DURHAM, N.C. -- Dr. Jonathan Stamler and his colleagues at Duke University Medical Center shook up conventional views of how blood delivers oxygen last year when they discovered hemoglobin also distributes nitric oxide. Now they have put the pieces of the oxygen-delivery puzzle back together by solving three apparent paradoxes that have left scientists perplexed for years. The researchers report in the June 27 issue of the journal Science that hemoglobin is an exquisitely tuned biosensor that adjusts blood flow to provide exactly the right amount of oxygen to tissues and organs. The research was funded by grants from the National Institutes of Health and the Pew Charitable Trust. Working with Stamler were Duke researchers Li Jia, Jerry Eu, Timothy McMahon, Ivan Demchenko, Kim Gernert, Joseph Bonaventura and Dr. Claude Piantadosi. "Most doctors believe blood flow is regulated by the expansion or contraction of the blood vessels themselves," said Stamler, the study's lead investigator. "But we've shown that hemoglobin in the blood itself can sense how much oxygen a tissue needs and change blood flow to meet that need." The findings may open up a whole new avenue of treatment for diseases such as stroke and heart attacks, in which blocked blood vessels are deprived of oxygen, or tissue injury after balloon angioplasty, in which reopened arteries can get too much oxygen too quickly, Stamler said. In addition, the findings have implications for treatment of sickle cell disease, lung injury and development of effective blood substitutes, the researchers say. For example, the current generation of blood substitutes behave as though the tissue is getting too much oxygen, and actually decrease oxygen delivery to tissues to compensate. A thorough understanding of how blood senses oxygen content in tissues could help researchers design more effective substitutes. "We are beginning to understand that hemoglobin is designed to deliver precisely the right amount of life-sustaining oxygen where it's needed," said Piantadosi, a circulatory physiologist. Mechanically, the body regulates blood flow by changing the width of blood vessels; rings of muscle in the vessel wall can expand or contract to increase or decrease blood flow. Scientists thought this process was controlled by hormones and other factors in the lining of the blood vessel wall, said Stamler. And they are right -- hormones such as adrenaline can cause vessels to dilate or constrict in response to stress or excitement, he says. But over the past several years scientists have further refined their understanding to show that hormones and other factors work by using nitric oxide (NO), long known as a noxious gas in the atmosphere. They believe that NO is released by cells on the inside of vessel walls, where it migrates to nearby muscle cells and relaxes them, opening the vessel. Now Stamler and his colleagues found that hemoglobin in red blood cells -- not the vessel wall -- actually plays the major role in regulating blood flow. It does so by changing shape and releasing a souped-up molecule of nitric oxide called s-nitrosothiol (SNO), which it carries along with oxygen, through the blood stream. Thus, hemoglobin simultaneously releases SNO to dilate blood vessels and delivers oxygen to nourish tissue. When oxygen levels are high, hemoglobin scavenges excess oxygen and NO, constricting blood vessels and reducing blood flow. The findings also provide an explanation for a long-standing paradox. In 1959, Dr. Max Perutz and his colleagues solved the three-dimensional structure of hemoglobin, showing each hemoglobin molecule carries four oxygen molecules when it leaves the lung. In the tissue, hemoglobin changes shape, allowing it to release the oxygen. But, on average, it returns to the lung still carrying three oxygen molecules. Thus, hemoglobin did not seem to be efficiently releasing oxygen. Other studies show hemoglobin paradoxically loses most of its oxygen before it reaches the capillaries. It has always been a mystery why most of the oxygen is lost in flow controlling arteries and is shunted back to the lung before hemoglobin completes its trip through the tissues, Stamler said. Textbooks gloss over the paradox entirely, he said, and teach that oxygen release happens in capillaries. "I'm a cardiologist and pulmonologist, and neither I, nor my colleagues had any idea when we embarked on this project last year that most oxygen is not released in the capillaries," Stamler said. "Our studies explain why hemoglobin releases much of its oxygen in the small flow-controlling arteries that feed capillary beds, not in the capillaries themselves." The loss of oxygen is a switch that releases nitric oxide in the arteries to dilate blood vessels and increase blood flow so that the remaining oxygen can be delivered to tissue. Then, on the return trip to the lungs, the oxygen that was lost in the arteries is recaptured in the veins, giving the appearance of inefficient oxygen delivery. "This makes complete sense," Stamler added, "if one appreciates that blood flow is the major determinant of oxygen delivery." The researchers measured blood flow and oxygen concentration in several regions of rat brain while the rats breathed air with varying oxygen levels. They showed that hemoglobin releases SNO in the small arteries that regulate blood flow, thus promoting oxygen delivery. When the animals breathed oxygen under higher air pressure, oxygen levels increased in tissue, and hemoglobin compensated by halting SNO release and contracting blood vessels. The finding also clears up another puzzle. In test tube experiments, hemoglobin scavenges NO and constricts blood vessels. Yet in the body, hemoglobin does not have this effect under normal conditions. "This tendency to constrict blood vessels seems to oppose hemoglobin's job of delivering oxygen," Stamler said. "Our findings explain why hemoglobin doesn't constrict blood vessels in the body. It releases NO in the arteries to counteract the NO it scavenges." The findings build on previous research, published in the March 21, 1996, issue of the British journal Nature, by Stamler and colleagues, which showed for the first time that nitric oxide, combined with hemoglobin, is a major regulator of gas exchange in the circulatory system. The research should help pharmaceutical companies design more effective blood substitutes and NO-based therapeutics, Stamler said. Specifically, an understanding of hemoglobin's relationship with NO could help in designing a new generation of oxygen and NO delivery molecules for treating the damage caused when tissue is deprived of oxygen, as in heart disease and stroke, and the many diseases, such as sickle cell anemia, in which ineffective oxygen delivery or NO delivery underlies the disease, he said. ----- End forwarded message ----- -- Eugen* Leitl <a href="http://leitl.org">leitl</a> ______________________________________________________________ ICBM: 48.07100, 11.36820 http://www.leitl.org 8B29F6BE: 099D 78BA 2FD3 B014 B08A 7779 75B0 2443 8B29 F6BE Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=27198