Effects of lithium and thallous ions on sodium pump activity in the guinea-pig heart and their relationship to the positive inotropic action.

It has recently been demonstrated that both Tl+ and Li+ produce concentration- and time-dependent positive inotropic effects in guinea-pig atrial preparations although Tl+ inhibits and Li+ stimulates isolated Na+,K+-ATPase in vitro. In order to elucidate the mechanism of the positive inotropic actions of these cations, the effects of Tl+ and Li+ on sodium pump activity were studied. Active 86Rb uptake in guinea-pig ventricular slices, an estimate of sodium pump activity, was highly sensitive to the inhibitory effect of the cardiac glycosides. Preincubation of slices with Tl+ caused a dose- and time-dependent inhibition of active 86Rb uptake. Similar concentration- and time-dependent inhibition of active 86Rb uptake was observed when Na+ in a Krebs-Henseleit solution was partially replaced with Li+. Lithium, however, stimulated a partially purified Na+,K+-ATPase in vitro. During heart slice incubation, Tl+ and Li+ accumulated in a time-dependent manner. This accumulation was not readily reversible when slices were transferred into Tl+- or Li+-free solutions. It appears that the inhibition of sodium pump activity is related to the positive inotropic action of these cations.

Cardiac Na+, K+-adenosine triphosphatase inhibition by ouabain and myocardial sodium: a computer simulation.

The major evidence against the hypothesis that Na+, K+-adenosine triphosphatase (Na+, K+-ATPase) inhibition is the mechanism of the positive inotropic action of digitalis is that the myocardial sodium content does not increase at the time of the inotropic response. In order to understand the relationship between sodium pump inhibition and myocardial sodium content, a computer simulation of the intracellular sodium concentration ([Na+]i) during a cycle of myocardial function was performed. The model for the computer simulation is a small compartment adjacent to the inner surface of the sarcolemma. The change in [Na+]i in this compartment is determined by the rate of sodium influx (published data utilized) and the rate of active sodium transport was estimated from the activities of partially purified dog heart Na+, K+-ATPase preparations assayed with various concentrations of sodium and ouabain. The initial rapid sodium influx results in maximal sodium pump activation, but the pump activity decreases with time as the [Na+]i decreases. Thus, the sodium pump functions at a rate close to its maximal velocity during the initial phase of each cycle but at reduced rates during the later phase. Inhibition of Na+, K+-ATPase by ouabain decreases the maximal velocity during the intiial phase of each cycle but at reduced rates during the later phase. Inhibition of Na+, K+-ATPase by ouabain decreases the maximal velocity of the sodium pump but increases the time in each cycle at which the sodium pump operates at its highest possible rate under these conditions, i.e., a rate close to the inhibited maximal velocity. A 40% inhibition of Na+, K+-ATPase activity, caused by inotropic concentrations of ouabain, increases the peak [Na+]i but fails to cause intracellular sodium accumulation since [Na+]i approaches control levels before the beginning of the next cardiac cycle. With greater enzyme inhibition, caused by arrhythmic concentrations of ouabain, [Na+]i fails to return to the precycle level and thus each subsequent cycle causes a progressive accumulation of myocardial sodium. Computer simulation predicts that a positive inotropic concentration of ouabain causes a myocardial sodium accumulation at a high heart rate but not at a lower heart rate. This was confirmed by experiments with Langendorff preparations of guinea-pig hearts. It is concluded that a moderate sodium pump inhibition by inotropic concentrations of ouabain enhances the intracellular sodium transient (a transient increase in intracellular sodium concentration associated with each membrane excitation) but does not cause a significant myocardial sodium accumulation at normal heart rates. A progressive myocardial sodium accumulation occurs only when the degree of Na+, K+-ATPase inhibition exceeds a critical magnitude.

Effect of ouabain on sodium movement in cardiac cells.

A computer simulation indicates that intracellular sodium concentration within a space near the inner surface of sarcolemma fluctuates during a cycle of myocardial function. The sodium transient (a transient increase in sodium ion concentration associated with membrane excitation) is enhanced by the inhibition of (Na+, K+)-ATPase by ouabain, but an accumulation of myocardial sodium does not occur until the inhibition exceeds a critical point. The critical magnitude of sodium pump inhibition that causes a progressive sodium accumulation is dependent on the heart rate.