Anyone with a nose knows the rotten-egg odor of
hydrogen sulfide, a gas generated by bacteria
living in the human colon. Now an international team of
scientists has discovered that cells inside the
blood vessels of mice — as well as in people, no
doubt — naturally make the gassy stuff, and that it
controls blood pressure.
Having discovered that hydrogen sulfide, or H2S, is
produced in the thin, endothelial lining of
blood vessels, the researchers, including scientists from
Johns Hopkins, report Oct. 23 in Science
that H2S regulates blood pressure by relaxing blood
vessels. As the newest member of a family of so-
called gasotransmitters, this messenger molecule is akin in
function, if not form, to chemical signals
like nitric oxide, dopamine and acetylcholine that relay
signals between nerve cells and excite or put
the brakes on mind-brain activities.
"Now that we know hydrogen sulfide's role in
regulating blood pressure, it may be possible to
design drug therapies that enhance its formation as an
alternative to the current methods of
treatment for hypertension," said Solomon H. Snyder,
Distinguished Service Professor of
Neuroscience,
Pharmacology and
Psychiatry at Johns Hopkins and a co-author of the
paper.
Conducting their investigations using mice missing a
gene for an enzyme known as CSE — long
been suspected as responsible for making H2S — the
researchers first measured hydrogen sulfide
levels in a variety of tissues in CSE-deficient mice and
compared them to normal mice. They found
that the gas was largely depleted in the cardiovascular
systems of the altered mice. By contrast,
normal mice had higher levels — clear evidence that
hydrogen sulfide is normally made by mammalian
tissues using CSE.
Next, the scientists applied tiny cuffs to the tails
of the mice and measured their blood
pressure, noting spikes of about 20 percent, comparable to
serious hypertension in humans.
Finally, the team tested how blood vessels of
CSE-deficient mice responded to the chemical
neurotransmitter methacholine, known to relax normal blood
vessels. The blood vessels of the altered
mice relaxed hardly at all, indicating that hydrogen
sulfide was largely responsible for relaxation.
Because gasotransmitters are highly conserved in
mammals, the findings of the research are
believed to have broad applications to human physiology and
disease.
"In terms of relaxing blood vessels, it looks like
hydrogen sulfide might be as important as
nitric oxide," Snyder said, referring to the first
gasotransmitter that two decades ago was discovered
to regulate blood pressure.
Just because these two gas molecules perform similar
functions doesn't mean they're
redundant, said Wang, the paper's principal author. "Nature
has added on layer upon layer of
complexity to provide a better and tighter control of body
function — in this case, of blood pressure,"
he said.
Studying gaseous messengers can be tricky, said
Snyder, an authority on nitric oxide whose lab
in 1990 discovered that the enzyme triggering nitric oxide
production is activated by a protein
mechanism known as calcium-calmodulin.
"When a nerve fires, it releases a bit of
neurotransmitter. Then it fires again, very quickly, and
releases more of the neurotransmitter, which is always in
reserve and at the ready in large storage
pools called vesicles," he said. "However, gases can't be
stored; they diffuse. So every time there's a
nerve impulse, an enzyme must be activated to make it."
Although CSE, the enzyme that activates hydrogen
sulfide, was characterized more than half a
century ago, the new work is the first to reveal that it is
activated in the same way as the nitric
oxide-forming enzyme, thus establishing how hydrogen
sulfide regulates blood pressure by relaxing
blood vessels.
"It's difficult to overestimate the biological
importance of hydrogen sulfide or its implications
in hypertension as well as diabetes and neurodegenerative
diseases," Wang said. "In fact, most human
diseases probably have something to do with
gasotransmitters."
The research was supported by grants from the U.S.
Public Health Service, the Canadian
Institutes of Health Research and a Research Scientist
Award.
Johns Hopkins authors on the paper are Asif K.
Mustafa, Weitong Mu and Snyder.
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