NEW
METHOD FOR TREATING IMPOTENCE
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.
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