CARDIAC NA+,K+-ADENOSINE TRIPHOSPHATASE INHIBITION BY OUABAIN AND MYOCARDIAL SODIUM - COMPUTER-SIMULATION

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  • 1 January 1976
    • journal article
    • research article
    • Vol. 199  (2) , 287-297
Abstract
The major evidence against the hypothesis that Na+,K+-ATPase inhibition is the mechanism of the positive inotropic action of digitalis is that the myocardial Na content does not increase at the time of the inotropic response. In order to understand the relationship between Na pump inhibition and myocardial Na content, a computer simulation of the intracellular Na 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 Na influx (published data utilized) and the rate of Na efflux due to active Na transport. The relationship between [Na+]i and the rate of active Na transport was estimated from the activities of partially purified dog heart Na+,K+-ATPase preparations assayed with various concentrations of Na and ouabain. The initial rapid Na influx results in maximal Na pump activation, but the pump activity decreases with time as the [Na+]i decreases. Thus, the Na 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 of the Na pump but increases the time in each cycle at which the Na 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 Na 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 Na 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. A moderate Na pump inhibition by inotropic concentrations of ouabain enhances the intracellular Na transient (a transient increase in intracellular Na concentration associated with each membrane excitation) but does not cause a significant myocardial Na accumulation at normal heart rates. A progressive myocardial Na accumulation occurs only when the degree of Na+,K+-ATPase inhibition exceeds a critical magnitude.

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