ROLE OF INTRACELLULAR SODIUM OVERLOAD IN THE GENESIS OF CARDIAC-ARRHYTHMIAS

A number of clinical cardiac disorders may be associated with a rise o f the intracellular Na concentration (Na-i) in heart muscle, A clear e xample is digitalis toxicity, in which excessive inhibition of the Na/ K pump causes the Na-i concentration to become raised above the normal level. Especially in digitalis toxicity, bat also in many other situa tions, the rise of Na-i may be an important (or contributory) cause of increased cardiac arrhythmias. In this review, we consider the mechan isms by which a raised Na-i may cause cardiac arrhythmias. First, we d escribe the factors that regulate Na-i and we demonstrate that the equ ilibrium level of Na-i is determined by a balance between Na entry int o the cell, and Na extrusion from the cell. A number of mechanisms are responsible for Na entry into the cell, whereas the Na/K pump appears to he the main mechanism for Na extrusion. We then consider the proce sses by which an increased level of Na-i, might contribute to cardiac arrhythmias. A rise of Na-i is well known to result in an increase of intracellular Ca, via the important and influential Na/Ca exchange mec hanism in the cell membrane of cardiac muscle cells, A rise of intrace llular Ca modulates the activity of a number of sarcolemmal ion channe ls and affects release of intracellular Ca from the sarcoplasmic retic ulum, all of which might be involved in causing arrhythmia. It is poss ible that the increase in contractile force that results from the rise of intracellular Ca may initiate or exacerbate arrhythmia, since this will increase wall stress and energy demands in the ventricle, and an increase in wall stress may be arrhythmogenic. In addition, the rise of Na-i is anticipated to modulate directly a number of ion channels a nd to affect the regulation of intracellular pH, which also may be inv olved in causing arrhythmia, We also present experiments in this revie w, carried out on the working rat heart preparation, which suggest tha t a rise of Na-i causes an increase of wall stress-induced arrhythmia in this model, In addition, we have investigated the effect on wall st ress-induced arrhythmia of maneuvers that might he anticipated to chan ge intracellular Ca, and this has allowed identification of some of th e factors involved in causing arrhythmia in the working rat heart.