Sodium ion transporters in sarcolemma are involved in numerous vital cell functions, such as excitability, excitation-contraction coupling, energy metabolism, pH and volume regulation, development and growth. In a number of cardiac pathologies, the intracellular
sodium concentration ([Na+]i) is elevated. Since [Na+]i and intracellular Ca2+ concentration ([Ca2+]i are coupled through the
Na+/Ca(2+)-exchanger, these cardiac pathologies display disturbed
calcium handling. For instance, [Na+]i is increased in
heart failure (HF) leading to
Na+/Ca(2+)-exchanger mediated increase in [Ca2+]i, reduced contractility and increased propensity to arrhythmias. Several studies support the contention that an increase in [Na+]i and [Ca2+]i transduces a signal the nucleus, that triggers development of cardiac remodelling and
hypertrophy. Pharmacological intervention, which favourably interferes with [Na+]i and [Ca2+]i homeostasis, might prevent
hypertrophy, cardiac remodelling, arrhythmias and HF. The most important
sodium transport mechanisms that may underlie increased [Na+]i are:
Na+/H(+)-exchanger (NHE-1), Na+-HCO(3)(-)
co-transporter (NBC), Na(+)-
K(+)-Cl(-) co-transporter (NKCC), Na(+)-channel, Na+/K(+)-
ATPase and
Na+/Ca(2+)-exchanger (NCX). Preclinical studies showed that pharmacological interventions, targeted against sarcolemmal
sodium ion transporters, proved effective in ameliorating
heart failure. In this respect: 1) NHE-1 inhibition reduces cardiac remodelling,
hypertrophy and HF, although, in the patients following
coronary artery bypass graft surgery, it was associated with an increase of
stroke. 2) The activity of NBC is up-regulated, during the development of
hypertrophy and may be a therapeutic strategy to prevent the development of
hypertrophy and HF. 3) NKCC is increased in post-
infarction HF, and the inhibition of NKCC attenuated post-
infarction remodelling. 4) Inactivation of
sodium channels is impaired in HF, which may result, in increased Na+ influx and prolongation of the action potential. 5) Blockade of NCX may be useful as a part of a combined therapeutic approach. Inhibition of reversed mode, or activation of forward mode NCX reduce Ca2+ overload. 6) Inhibition of Na+/K(+)-
ATPase (
digoxin), is used to increase contractility, however, it enhances progression of HF. Oppositely, new drugs which increase activity of Na+/K(+)-
ATPase may prevent the development of cardiac remodelling
hypertrophy and HF.