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Endothelin: Still Beyond Reach

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Nonetheless, many endothelin researchers seem to think the holy grail remains just out of reach, and some are continuing their quest but taking a different tack. Even if ET receptor antagonists can’t cure all the major diseases known to man, perhaps they can help in smaller, subtler ways. Three still-experimental uses of ET blockers might succeed in treating subpopulations of patients with relatively common conditions for which there are no other effective therapies. The first involves diabetics with chronic kidney disease. The surge in the prevalence of type 2 diabetes has brought with it rising numbers of kidney cases, with some 30% to 40% of diabetics developing a condition called nephropathy. According to the National Diabetes Information Clearinghouse, almost a quarter of the U.S. population age 60 and older has diabetes, so that amounts to millions of people with kidney disease. And normally effective treatments, ACE inhibitors and angiotensin II antagonists, don’t work well in people with diabetes.

In diabetic rats, however, an ET receptor antagonist has had several positive effects. It reduced high blood pressure, cut levels of protein in the urine and improved renal blood flow—all signs of better-functioning kidneys. When the rats also received an ACE inhibitor called lisinopril, their kidneys fared even better, reverting almost to normal. And in a recent trial involving 286 people with diabetic kidney disease, an ETA receptor antagonist called avosentan and an ACE inhibitor reduced the amount of protein in the urine, a promising development.

Resistant hypertension is another area in which ET receptor antagonists might play a role. There are many normally effective drugs for reducing blood pressure, and in most cases just one or two of them will get the job done. But for as many as 25 million Americans, taking even three or more drugs doesn’t work. In 1998, Barton found that an ET receptor antagonist reduced blood pressure in rats with resistant hypertension and even appeared to repair some of the damage to arteries that high blood pressure had caused. In a recent trial involving 379 people whose hypertension had not been brought under control by taking three or more of the usual drugs, taking an ET blocker resulted in significant improvement.

Finally, even prostate cancer patients may benefit from attempts to control excessive production of endothelin. In the lab, the combination of the chemotherapy drug paclitaxel (Taxol) and atrasentan decreased prostate tumor growth significantly more than either agent achieved on its own. Endothelin can stop cells from dying, thus helping tumors grow, and blocking it with an ET receptor antagonist may permit chemotherapy drugs to do their job. Clinical trials are currently testing this idea in people.

After years of meticulous work in the lab and on animals, the failure of so many human endothelin trials has been disappointing. And the work in these three latest areas, though promising, may also fail if and when larger human trials are completed. Yet as researchers come to better understand the subtle role this protein plays in various body systems and diseases, scientists seem likely to continue to search for effective therapies, even if the populations that benefit are measured in mere thousands, rather than tens of millions.

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Endothelin’s Trials

Several early trials of endothelin blockers showed no benefit for the treatment of many common conditions, but researchers are holding out hope for these current and soon-to-begin human studies.

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1. “A Novel Potent Vasoconstrictor Peptide Produced by Vascular Endothelial Cells,” by Masashi Yanagisawa et al., Nature, March 1988. In the paper that launched the field of endothelin research, Yanagisawa describes his discovery of the most powerful vasoconstrictor ever found.

2. “Pathophysiological Role of Endothelin Revealed by the First Orally Active Endothelin Receptor Antagonist,” by Martine Clozel et al., Nature, October 1993. Researchers describe the precursor to bosentan, the first endothelin-targeting compound to be used in humans, to treat pulmonary arterial hypertension.

3.“Endothelin: 20 Years From Discovery to Therapy,” by Matthias Barton and Masashi Yanagisawa, Canadian Journal of Physiology and Pharmacology, July 2008. The comprehensive review describes this burgeoning field of research, beginning with endothelin’s discovery as a simple vasoconstrictor.

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