A blood pressure drug in use for more than half a century might not work entirely in the way scientists had long thought. Reporting today in Nature Medicine, researchers have found in mice that spironolactone, a diuretic known to regulate hypertension through the kidneys, exerts part of its beneficial effect through the vasculature system, too.
“The blood vessel might directly contribute to blood pressure control and might be a new target for treating high blood pressure,” says Iris Jaffe, codirector of the Molecular Cardiology Research Center at the Tufts Medical Center in Boston who led the current study.
Both the 55-year-old drug sprinolactone and the newer, more selective agent eplerenone (marketed by Pfizer under the brand name Inspra) are thought to work by blocking the mineralocorticoid receptors in the kidneys to prevent sodium retention and, thus, increase water excretion. However, a handful of recent studies have hinted that the kidney does not tell the whole story. To explore the role of the vascular system, Jaffe and her colleagues created mice specifically lacking these receptors in the smooth muscle cells that line the blood vessel walls. They found that the mice had lower blood pressure as they aged, but not because of changes in salt or water handling in the kidney. Instead, the lack of vascular mineralocorticoid receptors led to a decrease in the activity of a certain class of calcium channels of the L-type variety. The change in calcium levels in turn eased the degree of smooth muscle contraction and reduced baseline tension in the blood vessels, with blood pressure lowering consequences.
“It is a comprehensive body of work using sophisticated methodology,” says cardiologist Jane Leopold, who studies how blood vessels respond to stress at the Brigham and Women’s Hospital in Boston. Since a number of calcium channel inhibitors are known to exert antihypertensive effects, “the obvious extrapolation in terms of clinical relevance is that we should be using a combination of mineralocorticoid receptor antagonists and L-type calcium channel blockers to treat hypertension associated with aging,” says Leopold, who was not involved in the latest research.
The findings also hint at the possibility of developing new therapies that target the mineralocorticoid receptors in the blood vessels while leaving the ones in the kidneys alone. A major limitation of the currently available drugs is that they often raise levels of potassium in the blood serum, leading to a condition known as hyperkalemia that causes many people to stop taking sprinolactone and epleronone. According to Jaffe, “If we can get the vascular benefits of blocking the mineralocorticoid receptor without hitting the kidney we would avoid the hyperkalemia and that might make these drugs more generally useful in bigger patient populations.”
For an interview with Jaffe, stay tuned for the September episode of the Nature Medicine podcast. Subscribe now in iTunes and your computer will automatically download the show as soon as it becomes available.