New pathway for treating erectile dysfunction identified by MCG researchers

A potential new pathway for treating erectile dysfunction that focuses on decreasing contraction of smooth muscles – rather than enhancing their relaxation which is how drugs like Viagra work – has been identified by researchers at the Medical College of Georgia.

In an animal model, researchers have used the experimental drugY-27632 to block Rho- kinase, an enzyme key to smooth muscle contraction; the result was an immediate, sustained erection.

"It's a dramatic response which leaves us hopeful that we have found a potential new approach to treating erectile dysfunction," said Dr. Thomas M. Mills, MCG physiologist and investigator on the study published in the January issue of Nature Medicine.

The research also received the Jean Francois Ginestie Prize for the best basic science manuscript presented at the 9th World Meeting on Impotence Research held in November in Australia by the International Society of Impotence Research.

Erectile dysfunction treatment has focused on the process that turns on smooth muscle relaxation and produces an erection rather than blocking constrictors, said Dr. Ronald W. Lewis, chief of the MCG Section of Urology and consultant on the Y-27632 study. "We are very excited about this research because it takes a unique approach that has not been looked at before," he said.

Contrary to the rest of the body, blood pressure and blood flow inside the penis increase when smooth muscles relax; increased blood flow results in an erection. Nitric oxide, a gas that helps regulate blood pressure by enabling relaxation of blood vessels, is key as well to relaxation of the penis' smooth muscle, Dr. Mills said. Consequently most drugs used to treat erectile dysfunction, such as Viagra, work by prolonging the effect of nitric oxide and so enhancing its activity.

However, MCG researchers have taken nitric oxide out of the equation, focusing instead on the body's extremely effective mechanisms for keeping the penis in its more typical, flaccid state. "Most of the time, the penis is not erect," Dr. Mills said. "That means there are things that keep the smooth muscle contracted and keep the penis flaccid most of the time."

He and fellow researchers believe that the powerful, known vasoconstrictors norepinephrine (noradrenaline) and endothelin 1 are major players in keeping the penis' smooth muscles contracted.

These vasoconstrictors work by activating an enzyme called myosin light chain kinase which adds a phosphate to myosin, a major protein involved in contraction. Another enzyme, myosin phosphatase, removes phosphate, promoting relaxation.

"There is always a balance in this tissue between constriction, which keeps the penis in the flaccid or non-erect state, and relaxation of the smooth muscle, which produces an erection," Dr. Lewis said.

Norepinephrine and endothelin 1 assist smooth muscle contraction in two ways. They activate the kinase resulting in contraction. "They may also increase Rho- kinase activity which inhibits phosphatase which would normally take off the phosphate and cause relaxation," Dr. Mills said.

In the laboratory, the researchers are blocking Rho-kinase activity with Y-27632 so the smooth muscle tissue can relax.

"We really think that in the penis, these vasoconstrictors are being released all the time, because something has to keep blood vessels constricted and erection turned off," Dr. Mills said.

Now the researchers want to understand what causes the constant production of constrictors and how an erection naturally occurs in the presence of such activity.

"We are trying to figure out how in the body these endogenous vasoconstrictor mechanisms are being shut off in order for nitric oxide to be effective and an erection to occur," said Kanchan Chitaley, a graduate student in physiology at the University of Michigan who is first author of the article. Ms. Chitaley came to MCG from the University of Michigan last January with Dr. R. Clinton Webb, chairman of the MCG Department of Physiology.

When Dr. Webb came, he brought with him Y-27632, produced by the Welfide Corp. in Osaka, Japan. He's studying its potential for treating a wide range of hypertension and he and Dr. Mills decided to test its efficacy in erectile dysfunction as well.

Study results published in Nature Medicine are based on injecting Y-27632, but the MCG researchers already are looking at a topical application.

Despite the effectiveness of drugs such as Viagra that enhance relaxation, a lot of men are not helped by any available medication; for some men, penile implants, are the only option and many don't consider that a viable one, said Dr. Lewis, who just completed a two-year term as president of the International Society of Impotence Research.

Dr. Lewis, who was involved in early studies of Viagra, said the drug has proven effective in 60 to 70 percent of the general population and about 40 percent in specific groups such as diabetics or men who've had radical prostate surgery.

Dr. Christopher J. Wingard, an MCG physiologist, also is an investigator on the Y-27632 study.