Endothelin: Still Beyond Reach
Soon, however, researchers discovered that endothelin does much more than regulate blood pressure. Its fingerprints are everywhere, and its role has been documented in more than 22,000 published papers. It also turns out that there are three versions, ET-1, ET-2 and ET-3, that bind to two kinds of endothelin receptors, ETA and ETB.
This growing understanding of endothelin and its receptors led to a search for substances that might regulate the effects of excessive amounts of the protein. Drug companies began scanning their libraries of chemical compounds for likely candidates, and an initial success came in 1993, with the production of the first endothelin receptor antagonist. It and subsequently developed ET blockers close off receptors, preventing endothelin from beginning the chemical processes that would normally ensue.
The first human clinical trial of endothelin receptor antagonists began in the early 1990s, and the target was a big one: congestive heart failure, which affects as many as 5 million people in the United States. Studies had shown that patients who had suffered heart attacks had above-normal levels of ET-1 and that their chance of survival after an attack dropped when ET-1 levels remained high. Moreover, in 1999 researchers found that in animals that had had heart attacks, blocking ET-1 improved survival rates and aided in the repair of damaged heart muscle.
All these findings led researchers to expect great things from trials of receptor antagonists in people with congestive heart failure. Yet the results fell far short of the hopes. Large, long-term, randomized clinical trials tested four types of endothelin receptor antagonists, and none proved effective. People who took endothelin blockers along with standard heart failure drugs fared no better than those who didn’t get them, and in at least one trial, taking the blockers was actually linked to worse results. Side effects, including liver problems, also caused trouble, and one trial had to be stopped early.
These failures could have been related to the trials’ designs. Because the endothelin blockers were given in addition to standard heart failure therapy, it’s possible that their effect was masked by the other drugs. Also, some patients may have had existing edema or other conditions that complicated trial results, and it’s possible that the drug dosages used weren’t optimal. Or it could be that the drugs were rushed into human trials too soon. Endothelin had been discovered only seven years before the first trial, and its role in the body was just beginning to be understood. Even the animal studies on endothelin blockers for congestive heart failure were suspect, having largely been done on previously healthy animals whose heart attacks had been experimentally induced. Most humans who have attacks, in contrast, have previous heart damage and coronary artery disease.
“Never before had a cardiovascular drug been used so quickly in a clinical trial, before we really understood the system it was targeting,” says Barton of the University of Zurich. But whatever went wrong, the trials’ failures probably closed the door on using ET blockers to treat congestive heart failure—and put a hole in the idea that regulating endothelin, part of so many human systems, might provide a quick path to therapies for a range of diseases.