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For decades scientists have tried to understand how cells work together in tis- sues, as well as in whole organisms. By the 1980s, the identity of many signal- ing molecules, the cellular responses they evoked, and many aspects of intracellu- lar signaling pathways were understood. All the known signaling molecules — the familiar hormones and neurotransmitters — were nongaseous substances, primari- ly peptides and amino acid derivatives. However, studies on the dilation of blood vessels showed that the gas nitric oxide (NO) could indeed function as a signaling Background
the blood vessel to constrict, just the opposite of the nor-mal in vivo response. However, when he tried to repeat The discovery of nitric oxide as a signaling molecule began and expand these studies with another aorta preparation, with studies on the mechanism by which blood vessels a different response occurred. Now, adding acetylcholine relax and constrict, processes known as vasodilation and to the aorta caused it to dilate, or relax. Trying to un- vasoconstriction. In addition to their desire to understand cover why the effect of acetylcholine was inconsistent, the basic biology of these processes, scientists recognized Furchgott discovered significant differences in the aorta its medical importance, as drugs that promote vasodilation preparations used in the two experiments.
could aid in the treatment of cardiovascular diseases.
In the body, blood vessels are made up of two types of Nitroglycerin, long used to treat angina pectoris, was cells: smooth muscle cells that form the vessel wall, and known to promote vasodilation. When applied to isolated endothelial cells, which line the inside wall facing the vessel blood vessels, nitroglycerin and other nitrogen-containing lumen. Furchgott found that when an isolated aorta prepa- compounds had been found to activate a signaling ration contained endothelial cells as well as smooth muscle pathway that began by stimulating the production of cyclic cells, the vessel responded to acetylcholine by relaxing. But guanosine monophosphate (cGMP), and eventually when the endothelial cells were removed, vasoconstriction resulted in dilation. There was much interest in discovering was once again seen with acetylcholine treatment. To the natural signal for this process.
explain these results, Furchgott proposed that acetylcholine In vivo, vasodilation was known to occur after stimu- causes the endothelial cells to release a signaling molecule lation of vessels by the neurotransmitter acetylcholine.
that in turn causes smooth muscles to relax. Dubbing this However, uncovering the mechanism of this response was proposed molecule endothelium-derived relaxation factor, hindered by a puzzling finding by Robert Furchgott. In his or EDRF, he set out to determine its nature and identity.
research on the constriction and relaxation of blood ves- Subsequent work by Furchgott and two other scientists sels, Furchgott was using isolated rabbit aorta as a model would reveal that nitric oxide is behind the drug-induced system. He found that adding the neurotransmitter acetyl- dilation of blood vessels but also the natural physiological choline to section of isolated rabbit aorta in vitro caused process of vasodilation stimulated by acetlycholine.
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enzyme catalyzes the conversion of oxygen free radicals,which would normally react with nitric oxide yielding In his search to identify EDRF, Furchgott initial tested the and oxygen. Based on their identical biological ability of numerous classical signaling molecules to induce responses and susceptibilities to the same inactivating dilation of isolated aorta sections stripped of endothelial agents, Moncada concluded that EDRF is nitric oxide.
cells, his in vitro assay for EDRF activity. None of the var- The final proof that EDRF is indeed nitric oxide came ious hormones, prostaglandins, and cyclic nucleotides he in a paper published by Ignarro late in 1987. He had ear- tested exhibited EDRF activity. In 1986, Furchgott real- lier reported biological and inhibitor data similar to those ized that the only molecule known to elicit vasodilation of of Furchgott and Moncada (see Figure). However, he went isolated blood vessels was nitroglycerin. It had been pos- a step further, realizing that the only way to prove EDRF tulated that the pharmacological action of nitroglycerin is and nitric oxide were one and the same molecule would be due to release of the gas nitric oxide (NO). Could the elu- through chemical identification. To do this, Ignarro treated sive EDRF actually be nitric oxide? To test this idea, isolated blood vessels with acetylcholine, then collected Furchgott treated isolated blood vessels, stripped of and chemically analyzed the surrounding medium. He endothelial cells, with nitric oxide produced from acidified found nitric oxide in the medium from vessels that NaNO2. He found that the response of these stripped ves- retained their endothelial cells, whereas no nitric oxide sels to nitric oxide was similar to the dilation of isolated was detectable in the medium surrounding stripped ves- vessels with their endothelium intact caused by the pro- sels. This evidence served as undeniable proof that posed EDRF release following acetylcholine treatment.
endothelial cells signaled vasodilation through the release This observation suggested he was on the right track. He then reasoned that if EDRF is nitric oxide, the same com-pounds should inhibit NO activity and EDRF activity.
Subsequently, he showed that hemogloblin and other com- Discussion
pounds that bind nitric oxide do indeed inhibit both NO-mediated dilation of stripped vessels and EDRF-mediated While initially a startling and improbable hypothesis, the dilation of intact vessels. These findings led Furchgott to role of nitric oxide as a signaling molecule rapidly became hypothesize that EDRF was nitric oxide. This hypothesis an exciting field of research. Soon after these critical was echoed by a second scientist, Louis Ignarro, who experiments, Moncada went on to identify the enzyme through similar reasoning and experimentation was led to that produces nitric oxide. In just a few short years, this unusual signal was implicated in many other biological Meanwhile, a third scientist, Salvador Moncada, inde- processes including neurotransmitter release and immunity.
pendently conducted a critical set of experiments clearly These exciting advances were predicated on the will- demonstrating that EDRF and nitric oxide elicit the identi- ingness of Furchgott and Ignarro’s to stretch the concept cal biological response and are inhibited by the same com- of signaling molecules to include a gas that is unstable in pounds. Moncada went on to show that the short half-life solution. For this foresight, and the experiments resulting of both nitric oxide and EDRF is extended by adding the in the identification of EDRF as nitric oxide, they shared enzyme superoxide dismutase to the in vitro system. This the Nobel Prize for Physiology and Medicine in 1998.
Some of the evidence supportimg the identity of EDRF and nitric oxide*
*EDRF ϭ endothelial-derived relaxation factor, which is released from endothelial cells in response to acetylcholine.
SOURCE: M. T. Kahn and R. Furchgott, 1987, in M. J. Rand and C. Raper, eds., Pharmacology, Elsevier Science Publisher, pp. 341–344; R. M. J.
Palmer et al., 1987, Nature 327: 524; and L. J. Ignarro et al., Proc. Nat’l. Acad. Sci. USA 84: 9265.
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