Findings Could Lead to Development of New Drugs That Treat High Blood Pressure, Heart Disease
Irvine, Calif. -- A team of UC Irvine College of Medicine researchers has discovered a key receptor in major blood vessels that binds with a protein to help regulate blood pressure and circulation. The finding eventually could result in new treatments for hypertension and other diseases of the cardiovascular system.
Olivier Civelli, professor of pharmacology, and senior pharmacology researchers Hans-Peter Nothacker and Zhiwei Wang found a receptor in rats that binds to a protein called urotensin II. The receptor is located in the brain, heart and major arteries. Urotensin II was discovered recently as an important regulator of the cardiovascular system, working to constrict arteries and possibly to increase blood pressure in response to stress and exercise. The researchers report their findings in the October issue of Nature: Cell Biology.
"Urotensin II has been shown to regulate blood flow through arteries in the body, but this is the first time we've matched it with a receptor," said Civelli, the Eric L. and Lila D. Nelson Chair in Neuropharmacology. "While there are many chemicals that act on blood pressure, urotensin II acts just a little differently, so we may be able to develop drugs that can treat high blood pressure in patients for whom existing drugs aren't effective."
Hypertension is a very complex disorder that is the single most common reason for doctor visits in the United States. Approximately 50 million people nationwide have high blood pressure, but less than one third of them have it under control, according to the American Heart Association. Hypertension is considered a major risk factor for cardiovascular problems such as heart attack and stroke.
Civelli and his colleagues found that urotensin II constricts arteries more mildly and for a longer period of time than other chemicals known for similar effects on blood pressure. The researchers also found that urotensin II works by binding to its receptor in a part of the brain called the brainstem and in the heart and major blood vessels--including the pulmonary artery, which supplies blood to the lungs, and the aorta, the major vessel leading from the heart.
In addition, the researchers found that urotensin II is manufactured in the kidney, indicating that this organ plays an important role in how the protein regulates blood pressure.
The scientists found the receptor through a laborious technique known as an "orphan receptor strategy," in which receptors are tested to see if they bind against neurotransmitters, hormones and other chemicals, much like bait is used to catch a fish. Once a receptor finally binds to a chemical, researchers then determine what the chemical looks like and how it functions. In this case, the scientists tested a variety of chemicals in the brain and came upon one chemical that binds to the receptor--urotensin II.
Receptors act as the gateway between nerve cells. When bound to a specific chemical, they stimulate nerves to fire off their own neurotransmitters, which can initiate certain behaviors or inhibit others. Receptors also can act as a gateway between blood vessels and nerve cells, binding with chemicals in the body that in turn stimulate nerve cells to constrict or loosen blood vessels.
The researchers are now focusing on learning how the receptor helps blood vessels and the brain control blood pressure. Pinpointing how urotensin II interacts with the wide range of neurotransmitters, proteins and other chemicals that work to maintain normal blood pressure could result in more effective treatments for high blood pressure, Civelli said.
Civelli has been conducting research on receptors in the nervous system for more than a decade. Recently, Civelli and his colleagues found a receptor that plays a role in regulating eating behavior and could be used to design drugs that fight obesity, and a receptor that appears to help the body regulate its reactions to stress.
Anne Marie McNeill, Yumiko Saito, Sven Merten and Sue Duckles of the UCI College of Medicine and Brian O'Dowd of the University of Toronto in Canada assisted Civelli, Wang and Nothacker in their research.
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