The Nitric Oxide Nobel Prize: A Breakthrough Discovery

The 1998 Nobel Prize in Physiology or Medicine, awarded jointly to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad, recognized their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system. What made the award remarkable was the molecule itself: nitric oxide is a toxic gas found in car exhaust and cigarette smoke, and the idea that human cells deliberately produce it to regulate blood pressure, fight infection, and transmit nerve signals struck most biologists as absurd until the evidence became overwhelming. The story behind the prize stretches from a laboratory accident in the 1970s to drugs that have changed millions of lives.

A Happy Accident With Rabbit Arteries

The discovery that earned the Nobel began with Robert Furchgott studying how drugs relax blood vessels. Working with strips of rabbit aorta in the late 1970s and early 1980s, Furchgott noticed something puzzling: acetylcholine, a well-known chemical messenger, sometimes relaxed the blood vessel and sometimes did not. The difference turned out to be accidental damage. Air bubbles in the perfusion line had mechanically stripped away the thin inner lining of the artery, called the endothelium.¹ When that lining was intact, acetylcholine triggered relaxation. When it was scraped off, the same drug had no effect or even caused the vessel to contract.

Furchgott realized the endothelial cells were releasing some short-lived substance that drifted into the surrounding muscle and made it relax. He called it endothelium-derived relaxing factor, or EDRF. The substance was extremely unstable, lasting only seconds in solution, and it was not a prostaglandin or any other known signaling molecule.² For years, researchers tried to figure out what EDRF actually was.

Identifying the Mystery Molecule

The answer came from converging lines of work. Ferid Murad had been studying nitroglycerin, the explosive compound that doctors had prescribed for chest pain since the 1800s without knowing how it worked. Murad showed in the late 1970s that nitroglycerin and related drugs released nitric oxide, and that this gas activated an enzyme in smooth muscle cells, ultimately causing them to relax. The idea that a simple gas could be a signaling molecule was radical, and most researchers were skeptical.

Louis Ignarro, working independently, set out to test whether EDRF and nitric oxide were the same thing. In a landmark 1987 paper, his group showed that EDRF released from arteries and veins was chemically indistinguishable from nitric oxide. Both had the same half-life of just three to five seconds. Both were destroyed by the same chemicals and stabilized by the same protective enzymes. Both produced the same increases in cyclic GMP, the downstream signal that tells smooth muscle to relax. Two independent chemical tests confirmed the match: EDRF reacted with hemoglobin to form the same compound nitric oxide did, and both promoted the same chemical reaction used to detect nitrogen-containing compounds.³

Meanwhile, separate work confirmed that vascular tissue released nitric oxide in quantities large enough to account for the biological effects of EDRF.⁴ The case was closed: the mysterious relaxing factor was a gas previously known mainly as an air pollutant.

The Scientist Left Out

The Nobel committee’s decision to honor Furchgott, Ignarro, and Murad was not without controversy. Salvador Moncada, a Honduran-born scientist working in Britain, had made contributions that many considered equal to or greater than some of the laureates’. More than 90 universities, academies, and scientific societies had recognized Moncada’s priority in discovering that endothelial cells release nitric oxide and in mapping out the metabolic pathway that produces it. Even Furchgott himself publicly stated that the committee could have made an exception and chosen a fourth person to share the prize.⁵ Nobel rules limit each prize to three recipients, and this constraint has generated similar debates in other fields. In the nitric oxide story, the exclusion of Moncada remains one of the most discussed omissions in Nobel history.

How the Body Makes and Uses Nitric Oxide

Cells produce nitric oxide using a family of enzymes called nitric oxide synthases, or NOS. There are three main forms. The endothelial form (eNOS) sits in the cells lining blood vessels. The neuronal form (nNOS) operates in the brain and nervous system. The inducible form (iNOS) ramps up in immune cells during infection and inflammation. Traditionally, eNOS and nNOS were called “constitutive” because they were thought to run at a steady low level, while iNOS was considered the on-demand version. That distinction has turned out to be oversimplified: all three forms can be both constitutive and inducible depending on conditions.⁶

All three enzymes convert the amino acid L-arginine into nitric oxide and a byproduct called citrulline. The process requires several helpers, including calcium, NADPH, and a cofactor called tetrahydrobiopterin. Once produced, nitric oxide is tiny enough to pass freely through cell membranes without needing a receptor or a channel. It simply diffuses from the cell that made it into neighboring cells, where it activates an enzyme called soluble guanylate cyclase. That enzyme then produces cyclic GMP, which is the actual workhorse that triggers effects like muscle relaxation or reduced platelet stickiness.⁷

Blood Pressure and Everyday Cardiovascular Health

The most immediate practical implication of the Nobel Prize work is in blood pressure regulation. Every time your heart beats, blood flows through your arteries and exerts a dragging force on the endothelial lining. That physical force, called shear stress, is one of the strongest triggers for nitric oxide production. When shear stress increases, endothelial cells ramp up nitric oxide release, and nearby smooth muscle relaxes, widening the vessel and lowering resistance to blood flow.⁸ This is one reason exercise helps keep blood pressure healthy: regular physical activity creates the shear stress that trains the endothelium to produce nitric oxide efficiently.

The mechanics of this response are more sophisticated than a simple on-off switch. Shear stress triggers a biphasic burst of nitric oxide that is far more potent than chemical stimulation alone. In laboratory experiments, flow-driven nitric oxide production outpaced calcium-driven production by roughly twofold, and the enzyme itself became phosphorylated within a minute of flow onset, a modification that could boost its activity even without a rise in calcium inside the cell.⁹

Besides relaxing arteries, nitric oxide also makes blood platelets less sticky. Human platelets contain their own nitric oxide-producing machinery, and when platelets are activated, the nitric oxide they generate raises cyclic GMP levels internally, which dials back their tendency to clump together.¹⁰ This is a built-in braking system that prevents excessive clotting during normal circulation.

When Nitric Oxide Fails and Atherosclerosis Takes Hold

When the endothelium stops making enough nitric oxide, the consequences are serious. Impaired nitric oxide production is now recognized as one of the earliest detectable steps in the development of atherosclerosis, the buildup of fatty plaques in arteries. The decline can be picked up before any structural damage is visible on imaging.¹¹

All the major cardiovascular risk factors converge on this pathway. High cholesterol, high blood pressure, diabetes, and smoking each increase the production of reactive oxygen species in blood vessel walls while simultaneously reducing nitric oxide output.¹² The reactive oxygen species, especially superoxide, do not just reduce nitric oxide levels indirectly by damaging the enzyme that makes it. Superoxide also reacts directly with whatever nitric oxide is present to form peroxynitrite, a far more destructive molecule that damages lipids, DNA, and proteins, pushing cells toward injury and death.¹³ This means that in a diseased vessel, the body loses its protective nitric oxide and simultaneously gains a toxic byproduct. It is a double hit that accelerates plaque formation.¹⁴

Nitric Oxide and the Immune System

Outside the blood vessels, nitric oxide plays a very different role as a weapon of the immune system. When the body detects a bacterial or parasitic infection, immune cells like macrophages switch on the inducible form of the enzyme and begin producing nitric oxide in large quantities. At these concentrations, nitric oxide is directly toxic to invading microbes.

The tradeoff is that the same high-output production can also harm the host. During severe infections like septic shock, widespread iNOS activation contributes to the dangerous drop in blood pressure that makes the condition life-threatening. Studies of iNOS activity in patients with septic shock found that the enzyme was concentrated at the site of infection, paralleling the expression of inflammatory signaling molecules.¹⁵ Experiments with mice lacking the iNOS gene showed that these animals were partially protected from septic shock, with less severe blood pressure drops and delayed death. But they also could not control the growth of bacteria like Listeria, confirming that nitric oxide is genuinely needed for infection defense.¹⁶ The immune system, in essence, accepts collateral damage as the price of deploying a powerful antimicrobial weapon.

A Retrograde Messenger in the Brain

One of the more surprising discoveries that followed the Nobel work was nitric oxide’s role in the brain. Most chemical messengers in the nervous system travel in one direction: from the sending neuron to the receiving neuron. Nitric oxide can do the reverse. In the hippocampus, the brain region crucial for forming memories, nitric oxide appears to act as a retrograde messenger during long-term potentiation, the process by which synaptic connections are strengthened and which is believed to underlie learning.¹⁷

The evidence is striking. Blocking nitric oxide production in hippocampal slices prevented long-term potentiation from forming. Injecting a nitric oxide synthase inhibitor directly into the receiving neuron also blocked it, indicating that the gas is produced on the receiving side. And applying hemoglobin to the extracellular space, which binds and neutralizes nitric oxide once it has left a cell, similarly prevented the strengthening of synaptic connections.¹⁸ Complementary experiments showed that nitric oxide enhanced the spontaneous release of neurotransmitter from the presynaptic side, completing the picture of a molecule that travels “backwards” to boost signaling at the synapse.¹⁹

Medical Applications Born From the Discovery

Perhaps the most famous drug to emerge from nitric oxide research is sildenafil, better known as Viagra. The nitric oxide/cyclic GMP pathway controls blood flow to the penis, and an erection depends on nitric oxide signaling working properly. Sildenafil does not produce nitric oxide itself; instead, it blocks the enzyme (PDE5) that breaks down cyclic GMP, effectively amplifying and prolonging whatever nitric oxide signal the body generates. Since its introduction, PDE5 inhibitors have been the standard first-line treatment for erectile dysfunction.²⁰

Another life-saving application is inhaled nitric oxide for newborns with persistent pulmonary hypertension, a condition in which the blood vessels in the lungs fail to open properly after birth, starving the infant of oxygen. Delivering nitric oxide gas directly into the lungs selectively dilates the pulmonary vessels without lowering blood pressure elsewhere in the body. In a pivotal trial, inhaled nitric oxide doubled blood oxygen levels in more than half of treated infants, compared with only about 7 percent of those on conventional therapy. The treatment also cut in half the proportion of newborns who needed to be placed on an invasive heart-lung bypass machine.²¹ Today, inhaled nitric oxide remains the only approved pulmonary vasodilator for this condition in newborns.²²

More recently, a newer class of drugs has emerged that bypasses nitric oxide entirely and stimulates soluble guanylate cyclase directly. Riociguat, the first of these to reach patients, was developed for pulmonary hypertension. In a clinical trial, patients taking riociguat walked an average of 36 meters farther in six minutes than those on placebo, and showed significant improvements in pulmonary vascular resistance, exercise tolerance, and clinical deterioration rates.²³ By acting downstream of nitric oxide production, these drugs can work even when the body’s own nitric oxide supply is depleted, opening a therapeutic window for patients who do not respond well to existing treatments.²⁴

Dosing Matters Even for a Natural Molecule

The therapeutic use of inhaled nitric oxide in newborns illustrates a broader principle about nitric oxide: context and dose are everything. A recent study of 118 infants treated with inhaled nitric oxide found that mortality followed a U-shaped curve. Babies whose oxygenation remained too low after treatment had a mortality rate of about 23 percent. But those who were over-oxygenated fared even worse, with a mortality rate of about 30 percent in the most severely hyperoxic group. In contrast, no deaths occurred among infants who landed in the normal oxygenation range.²⁵ The finding underscores that even a naturally occurring signaling molecule can cause harm when its effects overshoot the target.

Your Mouth Bacteria and Blood Pressure

One of the more surprising corners of nitric oxide research involves the bacteria living in your mouth. The body has a backup route for producing nitric oxide that does not rely on the NOS enzymes at all. When you eat nitrate-rich foods like beets or leafy greens, the nitrate enters your bloodstream, gets concentrated in your saliva, and is then converted to nitrite by bacteria on your tongue. That nitrite is swallowed and can be further reduced to nitric oxide in the acidic environment of the stomach and in tissues throughout the body.

This pathway is not trivial. Research showed that killing off these oral bacteria with chlorhexidine mouthwash led to a 90 percent drop in nitrite levels in the mouth, a 25 percent drop in plasma nitrite, and a small but measurable rise in blood pressure of about two to three and a half millimeters of mercury.²⁶ The implication is that antibacterial mouthwash, used routinely by millions of people, could be quietly undermining one of the body’s nitric oxide supply lines. The finding has also fueled interest in dietary nitrate supplementation for athletes: beetroot juice became a popular performance aid after studies showed that nitrate supplementation reduced the oxygen cost of exercise and improved time to exhaustion during high-intensity effort.²⁷

Tibetans and the Altitude Advantage

Perhaps the most dramatic illustration of nitric oxide’s importance comes from high-altitude populations. Tibetans, who have lived above 4,000 meters for thousands of years, show circulating levels of bioactive nitric oxide products more than tenfold higher than people living at sea level.²⁸ In some measurements, their red blood cell nitrogen oxide levels were more than two hundred times higher than lowlanders’.²⁹

These extraordinary nitric oxide levels appear to be a key part of how Tibetans thrive with less oxygen. Higher nitric oxide meant lower pressure in the lung’s blood vessels, more blood flow through the lungs, and better oxygen delivery to tissues. In the forearm, Tibetans showed more than double the blood flow of lowlanders, compensating for the thinner air by simply moving more blood past their tissues. Genetic studies have identified variants in a gene called EP300 that correlate with blood nitric oxide concentration in Tibetans, suggesting that natural selection has shaped their nitric oxide system over millennia.³⁰ Bolivian Aymara, another highland population, show a smaller but similar elevation, hinting that different human lineages have independently converged on nitric oxide as a solution to thin air.

Nitric Oxide in Plants

The molecule’s reach extends well beyond animals. In plants, nitric oxide regulates growth, flowering, senescence, and the opening and closing of stomata, the tiny pores on leaf surfaces that control gas exchange and water loss.³¹ When plants face drought or salt stress, they produce nitric oxide as part of a defense cascade triggered by the stress hormone abscisic acid. The nitric oxide drives stomatal closure, reducing water loss through transpiration, and also activates antioxidant defenses against the oxidative damage that accompanies drought.³²

In wheat, treating leaves with a nitric oxide donor before drought exposure allowed them to retain about 15 percent more water and reduced the transpiration rate by roughly 20 percent. Across three different plant species, nitric oxide-treated leaves showed stomatal closure ranging from about 30 to 65 percent. Cell damage after recovery from drought was about 25 percent lower in treated wheat leaves compared with untreated ones.³³ As climate change intensifies drought conditions in agricultural regions, this line of research has obvious practical appeal, even though commercial applications remain in early stages.

The breadth of nitric oxide’s influence, from human blood vessels to wheat fields to Tibetan highlands, is itself the legacy of the 1998 Nobel Prize. A molecule once dismissed as a toxic byproduct turned out to be woven into the most fundamental processes of life. Researchers in the 1980s could not have predicted that their work on rabbit arteries would eventually connect exercise physiology, neonatal medicine, immune defense, brain plasticity, high-altitude genetics, and crop science. That it did so is a reminder that basic research, even when it starts with an accident, can reshape entire fields in ways nobody sees coming.