It is one of the best-selling drugs in history. Since its introduction in 1998, it has swiftly become the flagship product for pharmaceutical giant Pfizer, ringing in sales of up to $2 billion every year. The United States, Mexico, and Canada spend more than $1.4 billion on it every year, while the U.S. military alone shells out an astonishing $41.6 million annually to help its troops make GI Joe stand at attention. This blockbuster drug is, of course, Viagra. Yet despite its enormous success, the little blue pill that helps 62 million men worldwide get their boy scouts to pitch a tent almost never was, and owes its existence to an unlikely chain of historical events involving chest pains, an observant nurse, and a substance more closely associated with demolitions than erections.

In 1846, German-Swiss Chemist Christian Friedrich Schönbein was experimenting in his kitchen in Basel when he accidentally spilt a mixture of sulfuric and nitric acid on the counter. He reached for the nearest cloth – a cotton apron – to wipe up the mess, then hung it up over the stove to dry. But as soon as the apron dried, it promptly exploded. Schönbein had accidentally discovered nitrocellulose, the world’s first nitrate explosive. Over the next 100 years, nitrocellulose would revolutionize the world. In the form of guncotton, it became the first practical replacement for gunpowder in firearms, while in 1869 American inventor John Wesley Hyatt would combine it with camphor to produce celluloid, the world’s first commercially successful plastic. One of celluloid’s most widespread uses was in movie film, though its extreme flammability led to countless theatres and film storehouses going up in flames until, starting in the 1950s, it was finally replaced by cellulose acetate “safety” film.

The year after Schönbein’s discovery, Italian chemist Ascanio Sobero, working under French chemist Théophile-Jules Pelouze at the University of Turin, combined the same nitric-sulfuric acid mixture with glycerine to produce an oily liquid he called pyroglycerine, but which soon became known by its more infamous name: nitroglycerine. Nitroglycerine was the world’s first true high explosive. Unlike “low explosives” like gunpowder and nitrocellulose which merely deflagrate or burn rapidly, high explosives like nitroglycerine detonate, chemically decomposing via an explosive shock wave that passes through the material at supersonic speeds. Nitroglycerine is thus able to deliver three times the energy of gunpowder 25 times faster, making it far better suited to industrial blasting. But there is an enormous catch: nitroglycerin is extremely unstable, readily detonating at the slightest shock. Even manufacturing nitroglycerine is highly dangerous; the reaction between glycerine, nitric, and sulphuric acid is exothermic, producing a large amount of heat that can detonate the explosive. Indeed, Sobrero was so frightened of his own invention that he warned vigorously against its being used industrially, arguing that it could never be safely controlled.

But another of Pelouze’s students, Alfred Nobel, saw the enormous potential of nitroglycerine, and in 1864 he and his brother Emil refitted his family’s defunct armaments factory in Heleneborg, Sweden to manufacture the powerful new explosive. The Nobels introduced a number of innovations in an attempt to make nitroglycerine manufacture safer. For example, factories were built on hillsides so the nitroglycerine could flow gently via gravity, avoiding the use of mechanical pumps which could set off the explosive. The ingredients themselves were mixed in large steel or lead vats cooled with water and stirred with air to prevent the exothermic reaction from running away. If the temperature got too high, the bottom of the vat could be opened, safely dropping the batch into a large tank of cold water – a process known as “drowning.” Factory workers were even made to sit on one-legged stools to prevent them from falling asleep on the job.

While the Nobels’ product, which they trademarked as “blasting oil,” was an instant commercial success, despite their best efforts nitroglycerine remained a highly-volatile and dangerous substance, resulting countless accidents and deaths. This included an 1864 explosion that destroyed the Heleneborg factory and killed Emil Nobel. In 1869, the explosion of two one-ton wagons of nitroglycerine near the village of Cwm-y-glo in Wales led the British Government to pass the Nitro-Glycerine Act, banning the manufacture and transport of the explosive in the British Isles. Other countries soon followed suit. Faced with the loss of his brother and his livelihood, Alfred Nobel set out to find a means of taming nitroglycerine once and for all. After experimenting with wood pulp, charcoal, cement and other substances, in 1867 Nobel finally hit upon using Kieselguhr, a type of chalky diatomaceous earth found near his factory in the Krümmel hills of Germany. Kieselguhr absorbed the nitroglycerine to form a flexible, putty-like substance that was insensitive to regular shocks and could only be set off with a explosive blasting cap – another of Nobel’s inventions. Nobel named the new safety explosive “Dynamite.” It was a runaway success, forever changing the face of construction, mining, and warfare, and making Nobel a very wealthy man. In 1875 Nobel invented blasting gelatin or “gelignite,” an even safer and more powerful mining explosive composed of nitroglycerin, wood pulp, and potassium nitrate; while in 1887 he patented Ballistite, a smokeless propellant for rifles and artillery. In 1888, allegedly an erroneously-published obituary described Nobel as a “merchant of death,” accusing him of “[becoming] rich by finding ways to kill more people faster than ever before.” This obituary supposedly so disturbed Nobel that in 1895 he bequeathed his vast fortune to fund the creation of five Nobel prizes honouring important contributions to Chemistry, Physics, Physiology and Medicine, Literature, and Peace.

But while dynamite was considerably safer to use than liquid nitroglycerine, it still had its drawbacks. For example, improperly stored dynamite could “sweat” nitroglycerine, rendering it extremely unstable. There were also stranger effects. Exposure to dynamite and nitroglycerine, typically via absorption through the skin, induced severe headaches known to explosives workers as “bang head.” Indeed, this phenomenon was first described by the inventor of nitroglycerine, Ascanio Sobero, who in 1847 reported:

 “…a very minute quantity put on the tongue produced a violent headache for several hours.”

Regular exposure built up a tolerance, causing the headaches to taper off by the end of the work week. This tolerance, however, faded over the weekend, and workers returning to the factory the next week experienced a combination of dizziness, rapid heartbeat, and headaches known as “Monday disease.” Stranger still, workers suffering from angina pectoris – chest pain caused by constricted arteries in the heart – found that their symptoms disappeared during the work week, only to return on the weekend as “Sunday heart attacks.”

These strange phenomena caught the attention of British physician William Murrell, who in 1878 began administering diluted preparations of nitroglycerine to patients suffering from angina and hypertension. The results of these experiments were promising, leading Murrell to publish his findings in the medical journal The Lancet in 1879. Over the following decades, nitroglycerine was increasingly prescribed for all varieties of heart disease. It was even prescribed to Alfred Nobel a few months before his death in 1896, leading him to write:

“Isn’t it the irony of fate that I have been prescribed nitro-glycerin, to be taken internally! They call it Trinitrin, so as not to scare the chemist and the public.”

 Even today, nitroglycerine continues to be prescribed to patients suffering from angina, administered via injection, pill, sublingual spray, or transdermal patch. In all cases the active ingredient is diluted to a concentration of 1%, eliminating its explosive potential. But while 140 years of clinical experience has proven beyond a doubt that nitroglycerine does work, it is only fairly recently that scientists determined exactly how it works. At the time of Murrell’s experiments in 1878, many doctors believed that angina was caused by high blood pressure. However, Murrell’s work revealed that nitroglycerine could relieve chest pain even when the patient’s blood pressure was normal. Murrell thus hypothesized that angina was instead caused by constricted blood vessels, and that nitroglycerine worked by relaxing and expanding these vessels, a process known as vasodilation. A similar effect had previously been observed by English Chemist Frederick Guthrie while working with a compound called Amyl Nitrite. In 1859, Guthrie reported that Amyl Nitrite, when inhaled, produced:

“…after a lapse of about 50 seconds, a sudden throbbing of the arteries of the neck, immediately followed by a flushing of neck, temples, and forehead and an acceleration action of the heart.”

 This observation led Scottish physician T. Lauder Brunton to develop amyl nitrite into the first effective drug for the treatment of hypertension and angina in 1867, a full decade ahead of William Murrell’s use of nitroglycerine. Like nitroglycerine, amyl nitrite is still used today to treat heart disease, though its use has declined due to the widespread use of nitrite compounds as recreational club drugs known as “poppers.”

The similar physiological effects of nitroglycerine and amyl nitrite led some scientists to speculate that the element nitrogen was key to their mechanism of action. However, it would not be until the 1970s that this connection was fully understood. In 1977, pharmacologist Ferid Murad and his colleagues at the University of Virginia discovered that nitroglycerine and similar compounds worked by stimulating the release of a substance they termed endothelium-derived relaxing factor or EDRF. While the team initially expected EDRF to be a large, complex organic molecule, to their surprise the mystery substance turned out to be something far simpler: nitric oxide, or NO. This humble and irritating gas, normally encountered as an air pollutant, is a powerful vasodilator and used by the body as a signalling molecule in a wide variety of biological process, including the regulation of blood pressure and heart rate. Nitro compounds like nitroglycerine and amyl nitrite are converted by the body into nitric oxide, accounting for their vasodilating effect. In 1998 Murad, Robert Furchgott and Louis Ignarro, who made the same discovery independently, were awarded the Nobel Prize in Physiology and Medicine.

The discovery of nitric oxide and its pivotal role in human physiology kicked off a revolution in pharmacology, with drug companies raceing to develop compounds that could exploit this metabolic pathway to treat hypertension, angina, and other cardiovascular diseases. Among these was seldinafil, developed by pharmaceutical giant Pfizer in the early 1990s. Seldinafil, which works by inhibiting an enzyme called  phosphodiesterase or PDE 5, had proven moderately effective at regulating blood pressure in animals, and was approved for preliminary clinical trials in 1993. Unfortunately, the drug proved less than effective in humans, requiring multiple doses every day to have any sort of effect and giving certain test subjects severe muscle aches. According to lead researcher Ian Osterloh, Pfizer was about to pull the plug on the study when a particularly observant nurse noticed something strange: when the male participants came in to be examined, they tended to lie down on their stomachs. The nurse soon discovered why: they were all hiding massive, uncontrollable erections.

In most mammals, the Amish Barn Raising is accomplished not by the tensing but rather by the relaxation of muscles, allowing blood to flow into and engorge the erectile tissue of the corpus cavernosa and and corpus spongiosum. This relaxation is in turn triggered by the release of nitric oxide. By complete accident, the observant nurse had discovered that the nitric oxide released by seldinafil was acting not, as expected, upon the blood vessels of the heart, but rather those of the subjects’ one-eyed trouser snakes. Recognizing an unfilled medical need, Pfizer abandoned its hypertension research and began studying seldinafil as a treatment for erectile dysfunction. Initial studies, which involved subjects watching erotic videos while a special device measured the girth and hardness of their zipper sausages, yielded promising results, leading to further trials involving more than 300 subjects from the UK, Sweden, and France. In nearly every case seldinafil proved significantly more effective than the placebo.

After four years of testing the compound was approved by the FDA for the treatment of erectile disfunction, and in 1998 seldinafil hit the market under the brand name Viagra. And the rest, as they say, is history. So if ever your meat clock needs a hand getting from 6 to 12, be sure to thank Alfred Nobel, William Murrell, Ian Osterloh, and all the others for helping you add a little bang to your buck.

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