Study Suggests Possibility of New Heart and High Blood Pressure Medications
Researchers at the University of Maryland School of Medicine have discovered that calcium channel blockers -- widely used to treat heart problems and high blood pressure -- work differently than previously thought. Their findings, published in the December issue of the American Journal of Physiology, may open the door to a different approach to treatment, with new, more effective medications that have a more precise therapeutic focus than current treatments.
The researchers found that calcium channel blockers primarily affect a group of cellular calcium channels in small arteries called "store-operated" channels. Prior to this discovery, scientists thought the blockers selectively affected what are known as "voltage-gated" channels.
"Our research has significant implications for the future treatment of heart disease and hypertension," says the study's senior author, Mordecai P. Blaustein, M.D., professor and chair of the Department of Physiology at the University of Maryland School of Medicine. "Armed with this knowledge, it should be possible to look for a new class of drugs that would cause fewer side effects."
"There are some observations that are a leap forward, not merely an incremental step," says C. William Balke, M.D., professor of medicine and physiology and head of the Division of Cardiology at the University of Maryland School of Medicine and the University of Maryland Medical Center. "This could easily be a leap. It certainly could change our paradigm for the treatment of hypertension," adds Dr. Balke.
Calcium, a mineral, is essential for the functioning of a number of systems in the body, including the pumping action of the heart and the contraction and relaxation of the smooth muscles that line blood vessel walls to regulate blood pressure. Too much tone or constriction can cause small arteries to narrow and increase their resistance to blood flow, leading to high blood pressure and forcing the heart to work harder.
Calcium channel blockers (CCBs) are often prescribed for angina (chest pain due to spasm of coronary arteries) and high blood pressure. They block or reduce the entry of calcium into cells of the heart muscle and arteries. These medications decrease the heart's contractions and dilate-or widen-the arteries, allowing blood to flow through them more effectively. While the effects of CCBs are well known, scientists have not understood exactly how the medications work. Also, it has not been clear why CCBs produce side effects in some patients.
To understand what happens with calcium and calcium channel blockers at the cellular level, the researchers used a high powered imaging system to observe individual cells that line small arteries, and to measure changes in the concentration of calcium, and how those changes affect the arteries.
Within these individual cells are pathways, called ion channels, which regulate the entry of calcium in vascular smooth muscle. The amount of calcium entry determines how much the small arteries contract to produce myogenic tone, a type of muscle contraction in blood vessels critical for the control of blood flow and blood pressure. Altered myogenic tone may play a role in the development of high blood pressure.
The researchers focused on two types of ion channels: store-operated, which permit calcium entry when calcium stores within the cell are emptied, and voltage-gated, which permit calcium entry after being activated by a change in voltage across the cell membrane.
The researchers used elevated concentrations of magnesium, a known blocker of store-operated channels, and nifedipine, a calcium channel blocker, to test the properties of a variety of calcium ion channels. The researchers also used high concentrations of potassium to isolate the function of voltage-gated channels that were not blocked by high magnesium.
"We were surprised when our research showed that the calcium channel blockers work on the store-operated channels," says Dr. Blaustein. "We repeated this again and again because the results were so unexpected. Before this work, nobody recognized that store-operated channels were the main target of calcium channel blockers in increasing blood flow and lowering blood pressure. Our findings suggest that it may be possible to identify new anti-hypertensive and anti-angina medications that target only store-operated channels."
Co-Investigators in the study are Jin Zhang, M.D., Ph.D., a post-doctoral fellow, and W. Gil Wier, Ph.D., professor of physiology at the University of Maryland School of Medicine. The NIH's National Heart, Lung, and Blood Institute and the Maryland Chapter of the American Heart Association funded the research.
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