GENERATION AND CONDUCTION OF IMPULSES IN THE HEART AS AFFECTED BY DRUGS
Authors: WOLFGANG TRAUTWEIN
Journal: Pharmacological Reviews (1963)

On the basis of the present knowledge of cardiac electrophysiology a rather complete picture of the different aspects of the rhythmic activity of the heart can be given. Especially studies on single cells have made possible a detailed analysis of the excitatory process. A complete theory of excitation and impulse generation was first achieved in nerve fibers. This information could then be applied to cardiac electrophysiology and excitation in cardiac fibers could be described mathematically in terms of changes in ionic conductances, the electromotive forces for the ions being constant. Present electrophysiological concepts use a model of the cell membrane which consists of several channels for the flow of ions represented by the parallel membrane conductances for these ions. The electrophysiologist attempts to explain the membrane potential during excitation, as well as all influences altering the excitation process, by a change of one or more of these ionic conductances. The most serious limitation of this concept is the lack of any detailed knowledge of the molecular structures and processes inside the membrane which are the basis for ionic conductances.

Effects of drugs on membrane potential and excitation are explained by the electrophysiologist in terms of changes of ionic conductance or of shifts of the electromotive force for the flow of the ions across the membrane. The most readily explained effects of drugs are those which can be represemited by the change of one specific ionic conductance from the normal to a new constant level. The effect of ACh is the best known and most important example: all its membrane effects are based on the increase of the potassium conductance. Such drug effects are characterized by a fast onset and usually a fast reversibility to the normal state.

A more complicated theoretical situation exists if the effect of a drug cannot be explained solely by a static change of conductance. The ionic conductances depend on the membrane potential and the time after a change of the membrane potential; a drug can work by shifting these relationships. Typical representatives of this group of drugs, quinidine and procainamide, reduce the increase of sodium conductance brought about by depolarization and alter the time constant of this effect. In this manner these drugs raise the threshold for excitation and have antiarrhythmic properties. These drugs also change the static membrane conductance for other ions, and have effects on the intracellular ionic concentration as well as those on cell metabolism. The antiarrhythmic effect, however, can be attributed to the interference with the depolarizing mechanism in the membrane.

The last (and, from the theoretical point of view, the most frustrating) group of drug effects is that in which, in addition to changes of membrane conductances, a change in the electromotive force for the flow of specific ions has to be assumed. The latter possibility is equivalent to a change in intracellular ionic concentration; such a change may also affect membrane conductances. The action of epinephrine probably belongs to this group of effects. In addition to an increase in sodium permeability, shifts of intracellular ion concentrations are involved. Typically, these drug effects change in character with time after application and may depend on the metabolic state of the cell. It is quite possible that the difficulties in theoretical interpretation of the effects of drugs such as epinephrine are due to the limitations of the electrophysiological membrane model.

As a concluding remark the author may state his views concerning a useful direction of future work in this field. He has regretted the considerable lack in electrophysiological information about the effects of many drugs, information which could be gained by the application of relatively simple methods. Especially to be deplored is the fact that experiments at the cellular level are very often missing. From the theoretical point of view it does not seem very useful to go on doing elaborate experiments on the heart in situ as long as the actions of drugs on single fibers have not been observed. For example, no study is available of the direct effects of either digitalis or veratrum alkaloids on the pacemaker in the sinoatrial node. Thus, it is not known whether veratramine causes bradycardia because of an inhibitory effect depressing the pacemaker potential, or whether bradycardia results from a very prolonged action potential in the sinus fibers. Electrophysiological studies of effects at the cellular level should be done with several more local anesthetic agents, the volatile anesthetics, sympathomimetic agents, dichloroisoproterenol, reserpine, and many more fibrillatory drugs, in order to clarify their mechanism of action.

Although the biophysical approach to the problem of drug effects on the cardiac membrane will still lead to much new and valuable information, the trend to a biochemical approach is strong. Many new aspects of drug action would be opened if more information concerning structural and biochemical counterparts of membrane conductances would be provided.