Guest post by Rowena Fletcher-Wood
It was the 1990s, and drug giant Pfizer was on the trail of an elusive angina medication to relieve constricted blood vessels and lower blood pressure. Pharmaceutical chemists in Sandwich, UK, were focusing their efforts on drugs that release NO (nitric oxide), a highly reactive radical that expands blood vessels and releases physical tension. One promising candidate was sildenafil, which was trialled in Morriston Hospital, Swansea.
It’s always difficult to recruit volunteers for a drug trial: even the best trials in animals, computer simulations and in vitro can’t take into account the full complexity of the human body, it’s strikingly unobvious differences from the rat and the complex interconnectedness of its mechanisms. Unexpected things happen, some of them bad, and some of them beneficial.
Sildenafil, later renamed Viagra for marketing, seemed to be a no-go for angina relief, and the trials were unsuccessful. Pfizer recalled the drug, and an unexpected thing happened: the volunteers resisted. ‘[P]eople didn’t want to give the medication back’, said Pfizer’s Brian Klee, ‘because of the side effect of having erections that were harder, firmer and lasted longer.’
At once, Pfizer started to investigate these reports. Using penile tissue from impotent men, senior scientist Chris Wayman introduced pulses of electricity both before and after introducing Viagra to their surrounding solution. The effect was immediate and pronounced: Viagra-treated tissue relaxed its blood vessels where untreated tissues did not, just as phallic vessels would relax to welcome the heavy flow of blood to the region. This revealed another significant property of Viagra: limiting erections to when the patient was sexually stimulated – and so foregoing the social inconvenience and dangerous blood restriction of constant arousal.
Catalytic domain of human phosphodiesterase 5 with bound Sildenafil. Image by A2-33 (Own work) CC BY-SA 3.0, via Wikimedia Commons
Pfizer was as impressed as the volunteers. One thing led to another, and very soon Viagra was on the market, and selling at an unprecedented rate as the first oral treatment for erectile dysfunction. Although other treatments did precede Viagra, they were not comfortable options: regular injection or an unpleasant prosthetic implant.
Viagra works in a very clever way, by mimicking a compound in the body and so blocking one of the enzymes that it binds to: the enzyme binds Viagra instead, and its function is blocked. This enzyme is PDE-5, a phosphodiesterase, and it works by mopping up cGMP, or cyclic guanosine monophosphate, which is the stuff that provides the erection. How? It all comes back to NO. Naturally produced by the stimulated brain, NO basically sets up a small factory making cGMP, only to have it swallowed up and broken back down by PDE-5, unless Viagra comes along. It’s striking chemical similarity to cGMP is enough to confuse PDE-5, inhibiting its action and leading to increased cGMP levels. Viagra is naturally decomposed and cleaned out by the body, with no further effects than a prolonged reaction to stimulation and a surprising effectiveness in relieving altitude sickness.
Worth volunteering for?
