A new way across the channel.

Sometimes the heart does things we don't want it to do. One source of malfeasance on the physiological level is the tiny pores that let calcium in and out of the heart muscle cells, thereby controlling contractions. Drugs introduced in the past decade that blockade these channels are immensely useful in treating angina and arrhythmias. Their success has prompted a search for agents that keep the channels open, which would be useful for diseased hearts that need stimulation. At the recent American Heart Association Science Writers Forum, Richard Tsien of Yale University in New Haven, Conn., discussed the discovery in his laboratory of a new mode of action for the pore, one that explains just how calcium channel stimulators work.

Open calcium channels allow the ions to flow into heart muscle cells, generally resulting in muscle contraction. Previously, two modes of action, which Tsien compares to gears, were known. In mode 0, which is like neutral, the pores are closed and the cell isn't contracting. In mode 1, which is like first gear, the channels open for brief periods. Tsien and his colleagues looked at how drugs known to control the flow work. They found that the inhibitors move the channels into neutral and stimulators move the channels into a previously unknown mode in which they are almost always open. The researchers also found that drug-free cells occasionally wind up in this third gear.

But while the discovery explains how the stimulators work, no such drug is likely to be on the market soon, Tsien says, since, unlike the calcium channel blockers, no drug specific for heart cells has yet been found. They made their observations using a tiny clamp developed in West Germany that sits astride a single calcium channel. Measuring the activity of a single channel among some 20,000 heart muscle cells is like picking out one fan's voice in a Super Bowl crowd, Tsien says.

There may be a second type of calcium channel in heart muscle cells, one that doesn't respond to the current crop of calcium antagonists. If so, Tsien notes, it would open up another way to control the channel and the heart.