Endothelin Antagonists Present Great Promise PDF Print E-mail
Thursday, 10 September 2009 11:04
One of the most intriguing developments in recent medical science is the discovery of the human chemical endothelin (ET). Since its detection in 1988, over 22,000 scholarly articles (about 3 per day) have been published on the subject, a new class of drugs has been developed, and 25 Phase I, II and III clinical trails are now underway. As the scientific and medical communities involved in ET move towards 25 years of understanding the protein, which future developments hold potential? At what risk? Do medicinal compounds look promising?

Donald Kohan, Professor of Medicine in the Division of Nephrology at the University of Utah Sciences Center and a leading global expert on endothelins is addressing these and other issues at the 11th International Conference on Endothelin being held September 9-12, 2009 in Montreal, CN. Dr. Kohan's invited presentation, "Clinical Relevance of ET Antagonist: An Update," is part of the program being sponsored by the American Physiological Society (APS; www.the-aps.org). A copy of the complete program is at http://the-aps.org/meetings/aps/ET11Montreal/index.htm.

Identified in 1988, ET is produced by most tissues in the body. The protein is highly concentrated in the brain, lungs, kidney, heart, blood vessels and even in some cancer cells. ET is also the most potent vasoconstrictor (causing the blood vessels to constrict) known. It plays a major role in embryonic development and disease. ET binds to two different types of receptors: endothelin A (ETR-A) and endothelin B (ETR-B). When ET connects with its receptors they react in different ways and have different impacts on disease.

The activated ETR-A receptor sends a signal to the blood vessels to contract, which then increases blood pressure. Conversely, when the ETR-B receptor is activated it signals the blood vessels to expand, thereby leading to a decrease in blood pressure. ET can play a role in health and disease. In health, ET can regulate blood pressure and assist in normal cell growth. However, excessive ET production can lead to kidney, blood vessel, lung and heart disease. In addition, because ET can act as a growth factor through activation of ETR-A, ETR-A blockade may inhibit tumor growth or prevent cancer from metastasizing.

In an attempt to reduce the deleterious effects of ET, scientists have recently developed a new class of drugs. The drugs, known as ET receptor antagonists, bind to the ET receptors and block ET actions. Since the U.S. Food and Drug Administration (FDA) approved the first ET receptor antagonist drug in 2001 (for pulmonary hypertension), two additional related compounds have been approved.. These drugs block either ETR-A alone or both ETR-A and ETR-B receptors. Most recently, the FDA approved a combined ET receptor blocker for the treatment of scleroderma, a disease complicated by ulcers on fingers and toes.

"Endothelin antagonists present great promise," according to Dr. Kohan. To support his view, Kohan points out that studies being conducted in animals and humans suggest that there is a role for targeting ET receptors in kidney disease, difficult to treat high blood pressure, pulmonary hypertension and other disorders. In addition, studies in animals suggest that ET blockers may be of benefit in traumatic brain injury, eye disease and other conditions.

At the same time there are challenges. One challenge is how best to determine which diseases should be treated by targeting A receptors or the A and B receptors combined. Researchers do not currently have a full understanding of how ET receptors always interact with one another. Another consideration is drug side effects. "Studies need to be conducted on ET receptor antagonist-associated toxicity, especially as it relates to possible testicular toxicity, hepatic dysfunction and fluid retention," Kohan says. He also noted that ET receptor blockers should never be taken by pregnant women since ET aids fetal development.

Despite the challenges Kohan believes therapy with ET receptor antagonists hold great promise. After 21 years of examining the protein, Kohan says many scientists and physicians believe that ET is a rich target for the development of new receptor antagonist drugs. Says Kohan, "The antagonists are now clinically approved to treat a few diseases and we look forward to their being of substantial benefit in many more diseases."

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