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Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure

2003; Elsevier BV; Volume: 35; Issue: 1 Linguagem: Inglês

10.1016/s0022-2828(02)00280-8

1095-8584

Fons Verdonck, Paul G.A. Volders, Marc A. Vos, Karin R. Sipido,

Ion Transport and Channel Regulation

Abstract Altered intracellular Na + ([Na + ] i ) is a potentially important factor in the functional adaptation of the hypertrophied and failing heart. We review the currently reported changes in [Na + ] i and Na + transport in different models of cardiac hypertrophy and heart failure. Direct measurements are limited, but most of these indicate that there is a rise in [Na + ] i , in particular in hypertrophy. In addition to these direct measurements, several studies report a rise in Na + influx or an upregulation of Na + influx transporters. The most extensive literature on Na + regulating pathways concerns the Na/K-ATPase. Total Na/K-ATPase activity decreases in most models of cardiac hypertrophy and failure, though few measurements were actually performed in intact cells. This decrease can been related to a selective reduction of high-affinity (for cardiac glycosides) Na/K pump α-isoforms, across many species and models, including human heart failure. We have used these data to predict changes of [Na + ] i in a simulation model, varying the contribution of total Na/K pump capacity and expression of isoforms with different Na + i affinities, and varying Na + influx. A rise in Na + in cardiac hypertrophy and failure may improve systolic contractile function, though at the cost of worsening of diastolic function and increased risk of ventricular arrhythmias. The benefit of further increasing [Na + ] i, e.g. with cardiac glycosides, is thus compromised. Future therapies may include selective isoform blockers, which could raise [Na + ] i in restricted subcellular compartments, drug associations that reduce the arrhythmic risk, or even drugs that lower [Na + ] i and thus interfere with the remodelling pathways.