June 18, 2002 DALLAS, June 18 – A drug used to treat gout improves blood vessel function in heart failure patients, possibly by blocking the creation of harmful free radicals, researchers report in today's rapid access issue of Circulation: Journal of the American Heart Association.
"These results are the first to show that treatment with allopurinol can improve vessel dilation in heart failure patients," says Allan D. Struthers, M.D., F.R.C.P., co-author of the study and professor of cardiovascular medicine and therapeutics at Ninewells Hospital and Medical School, Dundee, United Kingdom. "The data are particularly noteworthy because allopurinol is often prescribed anyway in heart failure patients, although for other reasons. It is safe and relatively cheap."
Chronic heart failure (HF), in which the heart cannot pump enough blood to meet the body's needs, is a common condition that causes death and disability. People with HF often experience chest pain and breathlessness when they are physically active because oxygen-rich blood from the lungs backs up in the veins between the lungs and the heart instead of reaching the organs that need it. Fluid also builds up in other parts of the body, such as the ankles, he says.
In people with HF, the vessels fail to relax, forcing the failing heart to work even harder. The diuretic drugs used to treat the fluid retention of heart failure can result in gout, a buildup of uric acid in the blood. Gout occurs when excess uric acid is converted to sodium urate crystal and deposits in joints and other tissues, often in the big toe. Hence, the need for allopurinol, Struthers explains.
HF is also linked to oxidative stress, an increase in harmful free radicals that can damage blood vessels. The free radical superoxide is a form of oxygen that neutralizes nitric oxide, a substance created by the endothelium (the inner lining of the arteries) that dilates healthy vessels to accommodate increased demands during exercise.
In this randomized, placebo-controlled, double-blind crossover study, researchers gave 11 patients with mild to moderate HF allopurinol or placebo daily for one month. While measuring the response, the researchers then gave the subjects a short-acting drug called acetylcholine that acts on the endothelium to cause dilation in healthy vessels. Next, they crossed-over the patients to either allopurinol or placebo and repeated the experiment. They discovered that the allopurinol increased average forearm blood flow nearly 50 percent more than the placebo, says Struthers.
The researchers also administered two vessel-dilating drugs that act independent of the endothelium. In both cases, the drugs worked about the same in subjects getting allopurinol and placebo—further evidence that allopurinol works on the endothelium.
"Allopurinol is thought to work by blocking the action of xanthine oxidase, which produces the superoxide that promotes oxidative stress," he says. "Much of the previous work on reducing free radicals has focused on using antioxidant vitamins to negate their effect. This represents an alternate strategy of preventing the formation of oxygen-free radicals."
It is also possible the drug reduces concentrations of uric acid, the culprit in gout. Earlier studies have shown an association between mortality and uric acid concentration, he says. Uric acid concentrations fell nearly 60 percent in patients taking allopurinol, even though their levels were in the normal range to begin with, he says.
"We cannot tell from this study, whether allopurinol produced its benefit by way of decreasing superoxide anions or decreasing uric acid or both," he says.
Struthers' says similar results have been found in patients with diabetes and high cholesterol levels, two other conditions associated with high levels of free radicals.
In an accompanying editorial, Ulf Landmesser, M.D., and Helmut Drexler, M.D., professors at Medical School Hannover (Germany), praised the work saying, "If this concept holds true and can be confirmed in a larger patient population – it could pave the way to an inexpensive and possibly effective addition to the treatment of patients with chronic heart failure."
Perhaps allopurinol could improve the quality of life for patients with CHF by improving their exercise capacity, the ability to exert themselves without experiencing painful symptoms, a possibility outlined by Drexler in a 1998 Circulation article, Struthers says.
Co-authors are Colin A. J. Farquharson, M.B.CH.B., M.R.C.P.(UK); Robert Butler, M.D., M.R.C.P. (UK); Alexander Hill, Ph.D.; and Jill J. F. Belch, M.D., F.R.C.P.
This research was funded by the British Heart Foundation.
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