Academic journal article Proceedings of the American Philosophical Society

Serendipity in Discovery: From Nitric Oxide to Viagra 1

Academic journal article Proceedings of the American Philosophical Society

Serendipity in Discovery: From Nitric Oxide to Viagra 1

Article excerpt

Introduction

A fitting opening to a discussion centered on the biological effects of nitric oxide (NO) is Charles Sheeler's 1930 painting entitled American Landscape (Figure 1). In this painting, Sheeler depicts the Ford Motor Company's River Rouge manufacturing plant; a smokestack billowing smoke dominates the center of the painting. Why is this a fitting beginning? NO is a highly toxic gas, and oxides of nitrogen are common constituents of environmental pollutants that could easily have been part of the effluent smoke in Sheeler's painting. In fact, prior to the 1980s, published works on the biological effects of NO largely appeared in journals with a focus on environmental chemistry and toxicology. So it was a great surprise about 30 years ago when NO was found to be an important metabolite made endogenously in humans by an enzyme (nitric oxide synthase). NO is a diatomic gas and is chemically similar to oxygen (O2) and carbon monoxide (CO), the former being a requirement for aerobic life and the latter a well-known toxin. Compared to CO, NO is even more toxic, and one challenge for nature is to discern the subtle chemical differences among these three diatomic gases.

Two main functions for NO emerged in humans and other animals. The first function turned out to be a role in the immune system, and this perhaps is not a surprise. Studies over many years have established that cells of the immune system, such as macrophages, produce toxins to kill bacterial pathogens and tumor cells. To add NO to this chemical armamentarium of the immune system where high concentrations of toxins are generated locally to kill pathogens does make some sense. A good analogy is when firefighters dig a ditch around a forest fire to prevent it from spreading; NO and other immune system-derived toxins effectively do the same thing by creating a chemical wall that is difficult to cross.

The second function for NO is as a signaling molecule (a way for one cell to talk to another cell and elicit a specific response from this second cell). In this signaling role, NO controls some very important physiological processes such as blood vessel dilation. So in short, NO plays a vital role in controlling blood pressure, and, given the toxicity of NO, this is puzzling. This indeed was a surprise to the scientific world. Nature's roll of the evolutionary dice has led to some seemingly irrational choices, and this one certainly falls into that category. Regardless, we were not there when the dice settled so it is up to us to figure out how it is that NO functions in this important capacity without poisoning our own cells. Paracelsus had perhaps the best view of this dialectic when he said, "Poison is in everything, and no thing is without poison. The dosage alone makes it so a thing is not a poison." Clearly nature has evolved the means to handle NO for important tasks and yet keep the dose below the level where NO would be toxic, without question a very difficult challenge.

Why is NO so toxic? Recall the periodic table of the elements and the fact that the periodicity means that elements have increasing numbers of protons moving from left to right. In the periodic table you will find -C-N-O- in that order; therefore, combinations of these three elements in different ratios will be unique yet show some close similarities to one another. Thus, it is not so surprising that CO can act as an inactive surrogate for O2 and, in so doing, interfere in the vital life functions of O2. NO is capable of the same interference with O2 with the added issue that it is much more chemically reactive compared to O2 and CO, and consequently creates trouble.

In brief, here is the problem: humans are aerobic organisms, meaning we require O2 to live, and yet we have evolved to make and use NO to control vital cellular processes. However, NO is toxic to normal O2 function, so how can we continue to use both NO and O2 and survive? The answer is actually rather simple-NO works at very low concentrations, as Paracelsus would have expected. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.