Electropharmacological Control of Cardiac Arrhythmias [antikvár]

Chapter 1 The Ionic Basis of the Heartbeat and of Cardiac Arrhythmias Denis Noble The rhythm of the heart is generated by membrane proteins that control the flow of charged ions (principally sodium, potassium, calcium, and chloride) across the cell membrane. Some of these proteins act as voltage-sensitive gates that open channels that carry ions passively down their electrochemical gradients. Some are voltage-insensitive channels that generate a background (resting) level of membrane current. Others are highly specific CO- or countertransporters that either use the energy of one gradient to move another ion against its gradient or that use the breakdown of adenosine triphosphate (ATP) to drive such a pumping action. The first goal of this chapter is to show how the great wealth of information on these ionic channels and carrier mechanisms obtained since the introduction of the methods of isolated cells, patch clamping, and internal ion indicators has been incorporated into very detailed models of cardiac excitation and rhythm generation. The second goal is to use these models to reconstruct some of the cellu- lar mechanisms of cardiac arrhythmias. Attention will also be called to several new approaches to drug therapy suggested by this work. (There is not space enough here to give the full experimental basis for the models described and used. For that, the reader is referred to the original papers listed at the end of the chapter.) Ionic Mechanisms in the Normal Heartbeat Figure 1 shows the general features of cardiac cells. In addition to the voltage-gated ionic channels used in older models of cardiac excitation, the new models also incorporate the activity of ionic pumps, and take into account internal and external ion concentration changes, including the mechanisms of buffering, sequestration, and release of calcium ions. Some of the models also include activa-don of contraction. The representation of ion concentration changes, particularly of internal The original work reported in this chapter was supported by the British Heart Foundation and the Medical Research Council. Note: All the cellular cardiac models described here are available in the OXSOFT HEART program. Information on the availability of this program in various parts of the world can be obtained from Oxsoft Ltd, 49 Old Road, Oxford 0X3 7|Z, UK. From BN Singh, HU Wellens, M Hiraoka, (eds): Electropharmacological Control of Cardiac Arrhythmias. Mount Kisco, NY, Futura Publishing Company Inc., © 1994.