Sildenafil citrate (Viagra), a drug used to treat
erectile dysfunction in millions of men, reduces the
stimulatory effects of hormonal stress on the heart by
half, according to results of a new study by researchers at
Johns Hopkins.
While sildenafil is more widely known for helping
genital blood vessels expand to maintain an erection and,
more recently, as a treatment for pulmonary hypertension,
it has been thought to have little direct effect on the
human heart.
In the heart, sildenafil blunts the strengthened
heartbeat caused by chemically induced stress, thereby
lessening the excess amount of blood and force used to pump
it to the body, according to study senior author and
cardiologist David Kass of the Johns Hopkins School of
Medicine and its
Heart Institute.
"Sildenafil effectively puts a 'brake' on chemical
stimulation of the heart," said Kass, the Abraham and
Virginia Weiss Professor of Cardiology.
The researchers' findings, which appear in the journal
Circulation online Oct. 24, are believed to be the
first confirmation in humans that sildenafil has a direct
effect on the heart. Previous research by Kass and his team
showed that sildenafil had such effects in mice, blocking
the short-term effects of hormonal stress in the heart.
Related studies by the group also showed that sildenafil
prevents and reverses the long-term effects in the heart
from chronic high blood pressure.
Moreover, Kass said, the latest Hopkins results
confirm that sildenafil helps control heart function only
when the heart is under duress, but has little impact under
normal conditions.
Separate research from Kass and his team published
earlier this year in the journal Nature Medicine showed
that, in mice, sildenafil could reverse the negative
effects on heart muscle weakened by heart failure and
enlargement, a condition called hypertrophy. "But we had no
firm evidence as to whether or how this therapy might work
in the human heart. Our latest research provides firm
evidence this drug does indeed have an important impact on
the heart."
Thirty-five healthy men and women, with an average age
of 30 and no previous signs of coronary artery disease,
participated in the six-month study. Within a three-hour
timeframe, each participant received two separate
injections of dobutamine (5 micrograms per kilogram for
five minutes), a synthetic adrenalinelike chemical that
increases heart rate and pumping strength.
Between injections, study participants were randomly
assigned to a group that was treated with sildenafil (100
milligrams taken orally) or to a group given a sugar pill
placebo. All participants were then given the second
dobutamine injection to see what effects sildenafil or
placebo had on the heart.
Measurements of heart function were made before and
after each injection. This included blood pressure
readings, electrocardiograms and echocardiograms, as well
as blood samples to confirm relatively equal levels of
sildenafil and other enzymes.
Results showed that each dobutamine injection
stimulated heart function, increasing heart rate and the
force of each heartbeat used to pump blood throughout the
body.
"This stimulation is similar to the way the nervous
system normally increases heart function when triggered by
emotional or exercise stress, or in diseases such as heart
failure," Kass said.
After the first injection of dobutamine, the force of
heart contraction increased by 150 percent in both groups.
And in the placebo group, this increase repeated itself
after the second injection. However, in the group treated
with sildenafil, the increased heartbeat was slowed by 50
percent, resulting in a smaller increase in blood flow and
blood pressure generated by the heart in response to
chemical stimulation.
Between injections, heart function was not altered in
the sildenafil group, demonstrating the absence of adverse
side effects on the resting human heart.
"Knowing more about the effects of sildenafil on heart
function will allow for safer evaluation of its use as a
treatment for heart problems," Kass said. "Until now, it
was widely thought that drugs like sildenafil had no
effects on the human heart and that its only purpose was
vasodilation in the penis and the lungs.
"Our results set the stage for further studies of
sildenafil's immediate and long-term effects on the heart
and its ability to modify other neurohormonal and stress
stimuli, including adrenaline and hypertension," he
said.
While the precise biological actions of sildenafil in
the heart are not fully understood, the drug is known to
work by stopping the action of an enzyme called
phosphodiesterase 5, or PDE5A, the researcher said. This
enzyme is involved in the breakdown of a key molecule,
cyclic GMP, which helps control stresses and limit
overgrowth in the heart. PDE5A is also the biological
pathway blocked in the penis by sildenafil to promote the
relaxation of blood vessels and maintain erections.
Funding for this study was provided by the National
Institutes of Health, the Peter Belfer Laboratory
Foundation and the Bernard Family Foundation. The makers of
the drug had no involvement in the design or support of the
research.
The study, conducted solely at Hopkins, was led by
cardiologist Barry Borlaug. Other researchers involved in
this study were Vojtech Melenovsky, Tricia Marhin and
Patricia Fitzgerald.
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