A study published in this week's Proceedings of the National Academy of Sciences identified the molecule that binds to a receptor (a molecule on the cell surface that triggers a reaction within the cell) in the brain that is known to regulate blood pressure and release of insulin. Furthermore, the researchers discovered that this molecule acts as a neurotransmitter, in that it conveys messages throughout different regions of the brain.
"We have known for decades that when a particular receptor in the brain is over-stimulated, blood vessels constrict and blood pressure rises," said George Prell, PhD, Associate Professor of Pharmacology and Biological Chemistry at Mount Sinai School of Medicine and first author on the study. "What we didn't know was which molecule in the body was binding to this receptor to trigger this reaction. Now that we have identified this substance, we can begin to look at ways of blocking its action. We also found that excessive accumulation of this molecule in the pancreas will impair insulin release, thus it is possible that this molecule is the long searched for link between these two disorders."
The researchers found that imidazole-4-acetic acid-ribotide binds to imidazol(in)e receptors which are widespread throughout the brain, and are abundant in the brainstem in areas critical to blood pressure regulation. In addition, they found that when this molecule binds to the receptor it leads to elevated blood pressure. When an antagonist (another molecule that blocks the action of the first) is given, imidazole-4-acetic acid-ribotide's high blood pressure effect is inhibited.
While some causes of high blood pressure are clearly established, the majority of cases are considered "essential hypertension," that is high blood pressure for which the cause is unknown. The researchers hypothesize that elevated levels of this ribotide may account for a major fraction of cases of essential hypertension.
In addition, imidazole-4-acetic acid-ribotide stimulates another group of imidazol(in)e receptors which regulate insulin release. Among natural substances in the body, this molecule is one of the most potent releasers of insulin ever discovered. However, while low concentrations of the ribotide stimulate insulin release and are therefore therapeutic, much larger concentrations block release, a condition that produces diabetes. Thus it is important that the ribotide levels in the pancreas be well controlled.
"Many drugs used to treat hypertension, such as clonidine, appear to act by displacing imidazole-4-acetic acid-ribotide from these imidazol(in)e receptors which will then block the ribotide's hypertensive effect," said Dr. Prell. "To date these drugs have been problematic because they act at multiple receptors and thus have many side effects. Now that we know the endogenous molecule that binds to imidazol(in)e receptors, we have the potential to custom design drugs that can specifically target the ribotide-receptor interactions to reduce blood pressure and diminish the onset of diabetes while avoiding other side effects."
George D. Prell, Giorgio P. Martinelli, Gay R. Holstein, Jasenka Matulic-Adamic, Kyoichi A. Watanabe, Susan L. F. Chan, Noel G. Morgan, Musa A. Haxhiu, and Paul Ernsberger
Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors
PNAS published September 13, 2004, 10.1073
Copyright © 2004, Mount Sinai School of Medicine.
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