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As the saying goes, unexpected scientific discoveries are often the most important. The “principle of limited sloppiness,” a term coined to describe fortuitous or accidental discoveries, hit in the 1970s, when Zawadski, a technician in the laboratories of Robert F. Furchgott, failed to follow his superior’s directions correctly and did not remove the endothelium in a rabbit aorta preparation. In this preparation, acetylcholine caused potent relaxation whereas contraction was expected. Shortly thereafter, it was established that acetylcholine was acting on endothelial cell receptors to produce a substance that could diffuse to the vascular smooth muscle and initiate its relaxation.1 This substance was called endothelium-derived relaxing factor. It took another 8 years for independent working groups to confirm that the chemical structure of endothelium-derived relaxing factor was identical to that of nitric oxide (NO).2,3

The scientific and global community honored the substance itself and its discovery by naming NO “Molecule of the Year” in 1992.4 The Nobel Prize in Physiology or Medicine for 1998 was awarded jointly to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad, for their breakthroughs concerning “nitric oxide as a signaling molecule in the cardiovascular system.”

NO is a colorless and odorless gas. It is a toxic air pollutant, present in motor vehicle exhaust and power plant effluent. The gas is found in the atmosphere in the range of 10 to 500 parts per billion (ppb), and locations with heavy vehicular traffic can exceed 1.5 parts per million (ppm). In the hot cone of a glowing cigarette, concentrations of 1000 ppm were measured in a 40-mL puff. NO is a free radical; it quickly reacts with oxygen (O2) to form poisonous nitrogen dioxide.

In the 1980s it became evident that NO is an essential molecule that regulates a wide range of human physiologic processes. Early studies revealed that NO is produced in endothelial cells and diffuses to vascular smooth muscle cells, where it mediates relaxation. Further studies demonstrated that the substance controls several other physiologic systems, including the immune system, platelet aggregation, and neurotransmission. The focus of this chapter is the prominent role of NO in respiratory physiology and its therapeutic application by inhalation.

Endogenous Nitric Oxide Synthesis

Endogenous NO is produced by the enzyme system, nitric oxide synthase (NOS). In human subjects, NOS activity can be found in the epithelium of nasal and paranasal mucosa, the bronchial epithelium, type II alveolar epithelial cells, airway nerves, inflammatory cells, airway and vascular smooth muscle cells, and endothelial cells. Three isoforms of the enzyme have been identified: the constitutive neuronal NOS, the inducible NOS (iNOS) that is incited by cytokines, and the constitutive endothelial NOS. There is evidence that a fourth isoform, mitochondrial NOS exists, which has important functions in cellular metabolism.

NO generated by neuronal NOS in the peripheral nervous system acts as a neurotransmitter that modulates ...

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