"Viagra was the first really successful PDE inhibitor, both mechanistically and commercially," Beavo says. Viagra has generated more than $1 billion in sales. It is among the most widely prescribed drugs.
Viagra is a very selective drug. It acts on one specific PDE found in the penis. In the presence of nitric oxide, a signaling molecule released from the nerves in the penis, inhibition of this PDE helps cause an erection.
Here is why inhibition of the PDE has that effect: nitric oxide causes the production of a secondary signaling chemical, cyclic GMP, which leads to erection. During sexual stimulation, men with erectile dysfunction may have trouble producing enough cGMP. Normally, the PDE breaks down the cGMP into molecules that cannot cause erection. By inhibiting the breakdown of cGMP, Viagra leads to more cGMP. In other words, PDEs cause reductions in the needed chemical in the penis, and Viagra blocks the PDE to prevent this from happening. Viagra generally does not have side effects caused by inhibition of other PDEs.
"We use Viagra's mechanism of action as a beautiful example of drug and physiological selectivity when we talk to students," Beavo says. Researchers are now seeking other PDE inhibitors that will also act selectively, without toxic side effects throughout the body. Since many PDEs have been discovered only within the past year, the search is just beginning.
Beavos lab recently characterized PDE7 and PDE8, which can be induced in certain kinds of immune cells -- particularly T-cells. These two families of PDE do not break down cGMP; instead, they reduce cAMP, a similar signaling molecule, found in those immune cells. Since these PDEs appear to be very important for immune system activity, researchers are studying whether inhibitors of these enzymes might have an effect on anti-immune and hyper-inflammatory diseases such as rheumatoid arthritis and allergies. Other PDEs are thought to mediate other processes. PDE3
Contact: Walter Neary
University of Washington