Prostate drug doxazosin blocks receptor in heart muscle, increasing risk of heart failure

Doxazosin, a drug commonly prescribed to help improve urinary flow in men with enlarged prostates, increases the likelihood of heart failure by blocking specific receptors in heart muscle cells, according to a study conducted at the San Francisco VA Medical Center.

The cell receptors, named alpha 1-adrenergic receptors, increase the contraction of smooth muscles. Drugs such as doxazosin promote better urinary flow by blocking the action of these receptors, thus relaxing the muscles that control the flow of urine.

In the study, mice that lacked alpha 1 receptors were subjected to conditions mimicking high blood pressure. Half died of heart failure and the rest developed dilated cardiomyopathy, a severe form of heart disease. Both outcomes were apparently due to loss of alpha 1 signaling ability in heart muscle cells.

One hundred percent of normal mice survived when subjected to the same conditions. The study appears in the April, 2006 issue of Journal of Clinical Investigation.

"While you can't jump to conclusions about humans based on mouse results, it might not be a good idea to block this receptor," says principal investigator Paul C. Simpson, MD, a staff cardiologist at SFVAMC. "I think doctors and researchers need to pay more attention to the possibility that these drugs are making people worse."

The study authors note that in a large national prospective study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, sponsored by the National Heart, Lung, and Blood institute and conducted from 1994 to 2002, a test of doxazosin was stopped early because subjects taking it proved to be at substantially increased risk for heart failure.

Nonetheless, according to Simpson, a very large number of men with prostate problems continue to take drugs known as alpha 1 blockers.

"This current study gives a probable mechanism for heart failure in those patients, and shows that alpha blockers could potentially be a direct cause," concludes Simpson, who is also a professor of medicine at the University of California, San Francisco.

Simpson says that another major conclusion of the study is that alpha 1 receptors could potentially be used as targets for drugs designed to treat heart failure. "We've studied what happens when these receptors aren't present," he says. "But what happens when you take a drug that specifically activates them? Can you stimulate them to cause the heart muscle cell to recover when it's injured, or grow stronger when it's weak?"

Simpson points to a history of research work going back to 1982 that has indicated the potential beneficial effects of alpha 1 receptor stimulators. "One reason that some researchers have been reluctant to follow this idea is that alpha receptor stimulators have been shown to increase blood pressure," he notes. However, he says that past experiments have shown that the levels of alpha 1 receptor activation necessary to help the heart are lower than levels that raise blood pressure.

Currently, Simpson and his team are pursuing two lines of research. In the first, they are investigating alpha 1 receptors in greater depth. "There are three main subtypes of alpha receptors," he explains, "and we want to know whether it's one, two, or all of them that you want to activate." To that end, the researchers are conducting studies using mice "with one, two, all, and no alpha receptors."

Simpson's second line of research involves analyzing human heart samples in order to discover which of the three subtypes of receptors are present in the human heart.

"First we want to know which receptors to activate," concludes Simpson. "And then we have to figure out how to do that in humans."

Co-authors of the paper are Timothy D. O'Connell, PhD, of SFVAMC and UCSF (at the time of research, and now at the University of South Dakota); Philip M. Swigart, PhD, and M.C. Rodrigo, PhD, of SFVAMC and UCSF; Shinji Ishikaza, MD, PhD, Shuji Joho, MD, PhD, and Lynne Turnbull, PhD, all of UCSF (at the time of the research); Laurence H. Tecott, MD, PhD, of UCSF; Anthony J. Baker, PhD, of SFVAMC and UCSF; and Elyse Foster, MD, and William Grossman, MD, of UCSF.

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