1998 Nobel Prize in Physiology or Medicine — Furchgott, Murad, and Ignarro: Gaseous Molecules Transmit Cardiovascular Signals

What You Will Learn from This Article

This article explains how the completely new concept that gases can act as signaling molecules between cells was discovered. Robert Furchgott's 1980 experiment revealed that endothelial cells in blood vessels produce an unknown signaling molecule (EDRF). Ferid Murad's research on nitroglycerin showed that this drug releases nitric oxide (NO). Louis Ignarro's experiments confirmed that EDRF and NO are the same substance. This discovery solved the mystery of why nitroglycerin works as a heart medication after 100 years and led to the development and approval of Viagra (sildenafil) in 1998.

A Story Different from Common Knowledge: Gases Transmit Signals

The common understanding of intercellular signaling molecules was as follows: Hormones, neurotransmitters, and growth factors are molecules that bind to specific receptors. They dock onto cell membranes or intracellular receptors and transmit signals. From this perspective, gas molecules were not considered as signal transmitters—gases were thought to simply diffuse without recognizing any specific targets.

The answer revealed by these three individuals is dramatic. Nitric oxide (NO)—a simple gas molecule also found in car exhaust—is produced in endothelial cells of blood vessels and immediately diffuses to neighboring smooth muscle cells, causing vasodilation. It acts as an intercellular signaling molecule.

Murad's 1977 discovery: Nitroglycerin, which had been used for a long time in cardiovascular therapy, releases nitric oxide in the body, causing vasodilation. Nitroglycerin is the raw material for Alfred Nobel's dynamite and has been used as a treatment for angina since the late 1860s. However, its mechanism of action remained unknown for 100 years.

Furchgott's 1980 experiment: He discovered that endothelial cells, which make up the inner lining of blood vessels, produce an unknown signaling molecule, and this molecule acts on vascular smooth muscle cells to cause vasodilation. He named this molecule endothelium-derived relaxing factor (EDRF). Its identity remained a mystery.

Ignarro's 1986 confirmation: Through various experiments, he demonstrated that EDRF is identical to nitric oxide. The discoveries of these three individuals came together, completing the picture.

The complete picture of vasodilation:

1. A specific signal (acetylcholine, bradykinin, etc.) stimulates endothelial cells.
2. eNOS (endothelial nitric oxide synthase) in endothelial cells produces NO from arginine.
3. NO immediately passes through the cell membrane and diffuses to neighboring vascular smooth muscle cells.
4. It activates guanylyl cyclase (GC) in smooth muscle cells → increased cGMP → muscle relaxation → vasodilation.

This system solved the 100-year-old mystery of nitroglycerin → NO → cGMP → vasodilation. Nitroglycerin was a precursor that released NO in the body.

In the language of computer science, NO is like a diffusion broadcast signal. It is not a directed signal that binds to a specific target but rather, like UDP broadcast, it diffuses immediately and reaches all neighboring cells. Furthermore, this signal has a very short half-life (a few seconds), causing it to disappear quickly. It has the characteristics of being immediate, powerful, and short-lived.

The Zeitgeist: The Internet Revolution and Korea's IMF Overcoming

1998 was a year of the decisive popularization of the Internet age and the beginning of Korea's efforts to overcome the IMF crisis.

In world history, on March 27, sildenafil (Viagra) was approved by the FDA—a revolution in the erectile dysfunction treatment market. On September 4, Google was founded—Sergey Brin and Larry Page formally established the company at Stanford. It became the future champion of search, advertising, and AI. On June 25, Windows 98 was released, and on August 15, Apple iMac was released—the beginning of Steve Jobs's revival of Apple. On November 20, the construction of the International Space Station (ISS) began—with the launch of the Russian Zarya module.

Politically, the Clinton-Lewinsky scandal was exposed in January, and the House of Representatives voted for impeachment in December. In May, India and Pakistan conducted nuclear tests.

In Korean history, on February 25, Kim Dae-jung was inaugurated as President—marking the beginning of the People's Government. From January, the gold-collecting campaign began—with citizens voluntarily donating gold to help secure foreign exchange, collecting more than 350 tons. This symbolized the Korean people's will to overcome the crisis. Efforts began to repay the IMF loans early. Discussions began on a North-South summit.

In this year of great transition, the Nobel Committee recognized the three individuals who ushered in the age of gaseous signal transduction.

The Three Laureates: A 30-Year Lineage in Cardiovascular Pharmacology

Robert F. Furchgott (1916–2009) was an American pharmacologist. He received his Ph.D. from Northwestern University in 1939 and was head of the Department of Pharmacology at the State University of New York Health Science Center from 1956 to 1989. He was a long-standing authority in cardiovascular pharmacology.

Ferid Murad (1936–) is an American pharmacologist. He is an alumnus of Indiana Whiting. He received his M.D. from Case Western Reserve University in 1965. He served as director of the Clinical Research Institute at the University of Virginia from 1971 to 1981, where he elucidated the link between nitroglycerin and NO. He was a professor at Stanford University from 1981 to 1988 and has been a professor at the University of Texas Medical School since 1997—during which he received the Nobel Prize.

Louis J. Ignarro (1941–) is an American pharmacologist. He received his Ph.D. from the University of Minnesota in 1966 and has been a professor of medicine at the University of California, Los Angeles (UCLA) since 1985. He was instrumental in identifying the identity of EDRF.

Sildenafil (Viagra): The Commercial Culmination of the Nobel Prize-Winning Discovery

Sildenafil is a symbol of how significant the impact of this award has been.

Originally, sildenafil was a compound being developed by Pfizer as a treatment for angina. In clinical trials, an unexpected side effect (actually a unique effect) was observed—induction of male erection. After confirming the mechanism, it was found that sildenafil inhibits PDE5, an enzyme that degrades cGMP in the corpus cavernosum of the penis, leading to cGMP accumulation and erection.

Approved by the FDA in March 1998—the same year as the Nobel Prize announcement in October. This marked the beginning of the era of oral erectile dysfunction treatments. Subsequently, tadalafil (Cialis, 2003), vardenafil (Levitra, 2003), and avanafil (Stendra, 2012) were approved sequentially.

Social and cultural transformation: Open discussions about sexual function and quality of life in old age began. Previously hidden problems were redefined as pathologies that could be treated. Viagra became the most significant commercial application of the Nobel Prize-winning discovery.

Other clinical applications:

• Pulmonary hypertension—sildenafil (Revatio) and tadalafil are used to dilate pulmonary blood vessels.
• Nitroglycerin and sildenafil should not be used together—amplifying the NO signal in both directions can cause severe hypotension. This is a clinical safety standard based on the understanding of the Nobel Prize.

CS Framework: Diffusion Broadcast Signal

If we reconstruct nitric oxide signal transduction using the language of computer science, we get the following picture.

NO = Immediate Diffusion Broadcast Signal: It does not bind to a specific receptor but freely passes through the cell membrane and diffuses immediately to neighboring cells. Similar to a UDP broadcast packet.

eNOS = Signal Emission Service: The eNOS enzyme in endothelial cells produces NO from arginine. This is a service that emits a signal in response to a stimulus.

GC = Listener: Guanylyl cyclase in smooth muscle cells recognizes NO and produces cGMP. The way NO is recognized is that NO binds to the heme group in GC, in a unique way.

cGMP = Downstream Payload: cGMP activates a protein phosphorylation cascade, leading to muscle relaxation.

PDE5 = Payload Cleaner: The PDE5 enzyme degrades cGMP, terminating the signal.

Sildenafil = Payload Cleaner Blocker: Sildenafil inhibits PDE5, allowing cGMP to accumulate and maintain the signal, leading to vasodilation.

Nitroglycerin = NO Precursor Injector: Nitroglycerin releases NO in the body, causing vasodilation. This finally revealed the mechanism of action of a drug that had been used for 100 years without knowing why it worked.

Immediate Termination = Short Half-Life: The half-life of NO is only a few seconds. This allows for precise temporal control of the signal.

Limitations of this analogy: NO also acts on several other targets (e.g., nitrosylation of cysteine residues in proteins), and local and systemic effects are complexly intertwined.

Academic Impact: The Age of Gaseous Signal Transduction

Discovery of other gaseous signaling molecules:

• Carbon monoxide (CO)—produced by heme oxygenase (HO-1), causing vasodilation and anti-inflammation.
• Hydrogen sulfide (H2S)—produced by CBS and CSE enzymes, causing vasodilation and nerve regulation.
• Ammonia and oxygen—regulate signals in other ways.

Clinical applications:

• Pulmonary hypertension—sildenafil, tadalafil, and riociguat (direct GC activator).
• Angina—nitroglycerin, administered continuously (sublingual, patch, IV).
• Heart failure—sacubitril/valsartan (Entresto) utilizes GC activation.
• Erectile dysfunction—sildenafil, tadalafil, vardenafil.

Expanding research:

• NO signal transduction and tumors—NO influences tumor growth and metastasis.
• NO and immunity—macrophages produce NO for defense purposes.
• NO and the nervous system—NO is involved in synaptic plasticity and memory formation in the brain.

The Korean Connection and Today

In Korea, the impact of this lineage has been widespread. Since the late 1990s, NO signal transduction research has been actively conducted in cardiovascular and pharmacology laboratories at Seoul National University, Yonsei University, and KAIST.

Clinical: The prescription of sildenafil and tadalafil has exploded in Korea. Domestic generic and similar drugs, such as Hanmi Pharmaceutical's Palpal (2012) and Dong-A ST's Zaidena (2005), have been sold in large quantities. Sublingual nitroglycerin for angina is a standard in domestic emergency rooms.

Sildenafil, macitentan, and riociguat are used to treat pulmonary hypertension, and related treatments are provided at Severance Hospital, Seoul National University Hospital, and Samsung Medical Center in Korea.

Why is it important?

What the three scientists established is that "gas molecules can also be key players in intercellular signaling."

Expansion of the concept of signaling. Added a category to signaling molecules that was previously unimaginable.

Solving the 100-year-old mystery of nitroglycerin. A symbolic cycle in which the mechanism of a drug used since the time of Alfred Nobel was revealed through the Nobel Prize.

Viagra and quality of life – One of the most impactful examples of how a Nobel Prize discovery has directly affected the public's life. It opened up social discussions about sexual health and quality of life in old age.

Flow of expansion of signaling after this award:

• 2000, Carlsson, Greengard, and Kandel – Signaling in the nervous system
• 2014, O'Keefe and the Moser couple – Spatial cognition in the brain

Clinical applications of this discovery:

• Sildenafil (Viagra) – Erectile dysfunction, pulmonary hypertension
• Tadalafil (Cialis) – Long-acting treatment for erectile dysfunction, benign prostatic hyperplasia
• Nitroglycerin – Standard emergency treatment for angina
• Riociguat – GC activator for pulmonary hypertension

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