The role of intracellular Ca ions in the therapeutic and toxic effects of cardiac glycosides and catecholamines.

Many inotropic maneuvers act by increasing the intracellular calcium concentration [( Ca2+]i). The present report illustrates this with respect to the positive inotropic effects of cardiac glycosides and catecholamines. It is shown that the increased contractility produced by cardiac glycosides is accompanied by an increase in intracellular Na concentration and, furthermore, that the relationship between contraction and Na is very steep. This steep dependence, which may result from a Na-Ca exchange which exchanges several Na ions per Ca, means that maneuvers that have only small effects on Na will have significant effects on contraction. Cardiac glycosides also produce abnormal pacemaker activity and cardiac arrhythmias. These originate from a transient inward current activated by oscillations of [Ca2+]i, which result from spontaneous oscillatory release of Ca ions from the sarcoplasmic reticulum. The local anesthetic group of antiarrhythmic agents abolishes the transient inward current. Catecholamines also increase systolic [Ca2+]i and, in high enough concentrations, can produce oscillations of [Ca2+]i. This tendency of glycosides and catecholamines to produce arrhythmogenic oscillations of [Ca2+]i is a major limitation to their use. Therefore, inotropic agents that act by means other than increasing [Ca2+]i may be of great efficacy.