Excitation-Contraction Coupling and Digitalis

T HE PRIMARY task of heart muscle is to develop force and shorten at regular intervals. The action potential is the initial step in triggering contraction of the heart, and it may also be an important regulator of contraction strength. The process that links this membrane electrical event to the contraction is given the broad name of excitation-contraction coupling. The more we have increased our understanding about the events leading to muscle contraction, the more we can see that excitation-contraction coupling is not a simple event, but is a complex sequence of steps. This complexity is important because it endows the process with the flexibility to adjust strength of contraction over a wide range. At the same time, the complexity leads to two other characteristics that are less desirable. It makes the process more susceptible to dysfunction, so that abnormalities of excitation-contraction coupling could play an important role in failure of the heart in disease states. And the complexity has also made excitationcontraction coupling difficult to study experimentally. Nevertheless, a number of recent observations in skeletal and in heart muscle provide the basis for improved understanding of this important regulator of contraction. If one arbitrarily divides the entire active muscle process into three parts, one can identify excitation as the action potential, contraction as the process of force development and shortening, and the steps in between as coupling. The action potential results from a sequential alteration of permeability of the cell membrane to ions in the extracellular solution. The dominant events are movement of sodium ions into and potassium ions out of the cell, but other ions participate in ways not yet entirely settled. Of special importance to our discussion is the possible transmembrane movement of calcium ions. Physiologists have succeeded in showing that some properties of the action potential, including the change in membrane resistance and the inward flow of sodium ions, are not directly related to triggering contraction. The most clearly defined event that correlates with contraction is simply depolarization of the surface membrane.1 Actual force development and shortening are the results of interaction of the proteins actin and myosin. This interaction requires ATP, and is regulated by at least two other proteins-tropomyosin and troponin. In the presence of tropomyosin and less than 107M calcium ions in the myoplasm, troponin inhibits the actin-myosin interaction, permitting the muscle to be relaxed. The inhibition is removed when calcium ions bind to troponin. An increase of free calcium ions in the myoplasm, which can be bound to troponin, may be considered the final link in excitation-contraction coupling. The major question about coupling is how membrane depolarization makes calcium ions available for binding to troponin. Membrane depolarization could lead to an increase in the concentration of intracellular calcium ions either by a release of calcium from an intracellular store or by a change in the membrane permeability to calcium, so that it enters from outside the cell. In skeletal muscle it seems clear that calcium ions must be maintained in an intracellular store, from whence they can be mobilized again and again for repetitive contractions. This conclusion is partly based on the fact that the skeletal muscle cell can continue to contract and relax when the extracellular calcium ion concentration is very low. For many reasons, we