Hemoglobin molecule's secret revealed.

Intrigued by a paradox, Duke University researchers recently revisited one of life's deepest mysteries: how red blood cells carry oxygen to tissues and cart off carbon dioxide waste.

Now, the scientists report in the March 21 Nature, they have solved both the paradox-how blood vessels dilate even though red blood cells are filled with a potent vasoconstrictor, hemoglobin-and the larger mystery.

They have discovered an elusive component of hemoglobin's dynamic respiratory cycle that enables the substance not only to exchange oxygen for carbon dioxide but also to control blood pressure.

The component is what a member of the Duke team, biochemist Joseph Bonaventura, calls a near "mirror image" of the well-known oxygen-carbon dioxide cycle. The process relies on nitric oxide, a chemical synthesized in the lungs and blood vessel walls, to dilate blood vessels and ensure that oxygen-rich hemoglobin can penetrate even the narrowest capillaries to nourish tissues.

"We have discoveries here that I know will hold true and change the way that people think," says Jonathan S. Stamler of Duke University Medical Center in Durham, N.C. "This has major implications for diseases of every organ." Scientists say the discoveries could lead quickly to an effective blood substitute and new ways of treating ailments that involve blood and tissue oxygenation, including heart attack, stroke, and sickle-cell anemia. Researchers have long known that nitric oxide from blood vessel walls relaxes and dilates the vessels. Oxygenated hemoglobin was thought to act as a scavenger, rapidly eliminating nitric oxide from the blood. Yet somehow, enough nitric oxide remains to dilate the vessels, helping hemoglobin to make its vital rounds.

There was another loose end as well-literally. A single amino acid, cysteine, dangles from the hemoglobin molecule, and for 50 years researchers have wondered why. They have suspected that this cysteine must be useful because it is present in mammals and many birds.

The Duke team believes it has the explanation. Bonaventura says that the cysteine residue enables nitric oxide to ride safely on the hemoglobin molecule.

"In essence, it means that hemoglobin is carrying its own vasodilator," asserts Austen Riggs of the University of Texas at Austin.

Robert Furchgott of the State University of New York Health Science Center at Brooklyn, called the Duke insight "a new idea, surprising and interesting to those of us who have been using hemoglobin as a scavenger."

In essence, the Duke researchers say, the complete hemoglobin respiratory cycle-now recognized as the interplay of oxygen, carbon dioxide, and nitric oxide-works like this: In the lungs, nitric oxide latches onto hemoglobin's cysteine residue when the oxygen binds to hemoglobin's iron. The nitric oxide on the hemoglobin is part of a chemical group called a thiol. Blood with the enriched hemoglobin then circulates through the body.

Because the nitric oxide is sheltered as part of a thiol, circulating hemoglobin cannot degrade it. As the hemoglobin transfers its oxygen to tissues, it also sheds small amounts of nitric oxide, which dilates the blood vessels and helps get the oxygen into tissues.

Next, depleted hemoglobin picks up carbon dioxide and any circulating nitric oxide and carries both to the lungs, where they are exhaled.

"They have made a case for a very different behavior of hemoglobin," Furchgott says. "Now it will have to be looked at more carefully."

"It is inevitable in science that when you have a discovery like this it will be challenged," Stamler says. "But we can make buckets of [hemoglobin] with nitric oxide on the thiol and oxygen on the heme [iron group]. The dogma says that's impossible."