Ca2+ or K+ concentrations during Na+-free perfusion and Ca2+ or Na+ concentrations during K+-free perfusion were varied and the effects on the contractile force were recorded during failure as well as recovery of the hearts. The initial positive inotropic effect of zero Na+ was directly related to the Ca2+ or K+ concentration of the medium. Time time of failure was not affected by changes in Ca2+ concentrations of the Na+-free medium whereas lowering of K+ concentration prolonged the time of failure. The initial negative inotropic effect of perfusion with zero K+ was increased by low Ca2+ and was changed to a positive effect by high Ca2+; the time of failure was inversely related to the Ca2+ concentration. Lowering of Na+ in zero K+ medium caused fibrillation of the heart. The recovery upon reperfusion with control medium of Na+-deprived hearts was improved by a reduction in Ca2+ concentration during Na+-free perfusion and was adversely affected by increased Ca2+. Increases or decreases in K+ during Na+-free perfusion reduced recovery. The length of the fibrillation period was affected in a characteristic manner by changes in Ca2+ or K+ concentrations. The recovery of the K+-deprived hearts was also influenced by changes in Ca2+ or Na+ concentrations during K+-free perfusion. In addition to altering the electrical properties of the myocardium, the early effect of Na+ or K+ lack appears to be on the Ca2+ movements across the sarcolemma and this is followed by the intracellular Ca2+ overload. The study emphasizes the importance of a proper balance between the Na+, K+, and Ca2+ concentrations for normal functioning of the heart.