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DURHAM, N.C. - After studying more than 500 human blood
vessels, Duke University Medical Center researchers have
defined which types of an important class of
contraction-controlling receptors line different types of blood
vessels. The scientists also have demonstrated that the aging
process changes this distribution.

With this specific knowledge of the distribution of three
known subtypes of receptors known as alpha-1 adrenergic
receptors (AR), the researchers say it should be easier to
create highly specific drugs for treating such disorders as
high blood pressure, shock, heart and prostate disease. These
drugs would work by preventing specific kinds of blood vessels
from constricting.

The results of the Duke research were published in the Dec.
7 issue of the journal Circulation.

The AR receptors are proteins that line blood vessels and
are crucial in controlling contraction of the vessels in
response to different hormones and drugs in the bloodstream.
Each subtype - called alpha 1a, alpha-1b and alpha-1d - reacts
differently when stimulated by a hormone or drug, so knowing
which subtype predominates in a given vessel can be very
important in tailoring specific drugs.

"This is the first study to extensively characterize the
distribution of these receptors in arteries and veins
throughout the human body and their modification by age," said
the lead researcher, Duke anesthesiologist Dr. Debra Schwinn.
"Our findings give us a scientific basis for developing
potential agents that can target specific sites in the
treatment for a wide range of human diseases."

It took five years for researchers to collect the vessels,
which were gathered either as discarded tissues from surgery or
from rapid autopsy programs. The exhaustive review led to five
new insights into AR receptors:

• Arteries tend to have more alpha-1a receptors than veins,
  which have all three subtypes. Additionally, the alpha-1a
  subtype predominates in the arteries supplying blood to the
  gut.
• The alpha-1a is the only subtype in human coronary
  arteries which supply blood flow to the heart.
• The alpha-1a and alpha-1b subtypes are responsible for
  the contraction of the interior mammary artery, one of the
  main arteries that supplies blood to the heart after coronary
  artery bypass surgery.
• While the alpha-1a subtype is the major subtype in the
  mammary arteries of those under the age of 55, by the time a
  person reaches the age of 65, the expression of the alpha-1b
  subtype has tripled.
• Contrary to earlier beliefs, the AR subtype expression is
  different in humans than it is in animal models.

There are nine known subtypes of adrenergic receptors, with
three each in the alpha-1, alpha-2 and beta groups.

A telling example of the adrenergic receptor system in
action is the classic fight-or-flight stress phenomenon. When a
human or animal is threatened by what it perceives as a
dangerous or stressful situation, its brain releases hormones -
epinephrine and norepinephrine - that when detected by AR
receptors, redistribute the body's blood flow from
non-essential areas of the body toward the brain and heart. The
receptors accomplish this by causing certain vessels to
constrict.

"Our findings suggest that when under stress, the alpha-1a
subtype may mediate the constriction of the vessels in these
non-essential areas, like the gut," Schwinn said. "One of the
major diseases of the elderly is ischemia, or reduced blood
flow, to the gut. If we could block the contraction the vessels
caused by the alpha-1a subtype with a drug, then maybe we could
increase the blood flow to the gut."

The researchers also found that as humans age, the
distribution of AR subtypes changes. In the mammary artery, for
example, the density of AR receptors doubles, with the largest
gains in the alpha-1b subtype. Further studies are needed to
determine whether or not these findings will apply to all
vessels, but Schwinn said she is confident they will.

A recent clinical trial in elderly people of a drug that
selectively blocks only the alpha-1a and alpha-1d subtypes
caused less blood pressure perturbation than a non-selective
agent, suggesting the importance of the alpha-1b subtype in
aging vessels, she said.

"Cardiac biology is much different in the elderly than in
the young," Schwinn continued. "It is important for doctors to
take this into account. This increase in the number of AR
receptors may be one of the reasons that hypertension is so
common in the elderly."

Specific knowledge of these subtypes may also play a role in
improving the care of men suffering from prostate enlargement.
Physicians are currently treating men with this condition with
AR antagonists, or blockers.

"Avoidance of the alpha-1b subtype in treating prostate
disease should avert the side effects - mainly hypotension -
associated with many current drugs, which don't distinguish
between AR subtypes," Schwinn said.

The study was funded in part by the National Institure of
Aging and the National Heart, Lung and Blood Institute.