Dec. 8, 1999 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.
Joining Schwinn in the study were, from Duke, Dr. Xiaowen L. Rudner, Dr. John Booth, Bonita Funk, Kelli Cozart, Elizabeth D'Amico, Dr. Habib El-Moalem, Stella Page and Dr. Charlene Richardson. Dr. Dan Berkowitz, Dr. Bradford Winters and Leo Marucci from Johns Hopkins Medical School also participated in the study.
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