Sodium ion transporters as new therapeutic targets in heart failure.
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.
Baartscheer
Antonius
A
Department of Experimental Cardiology, Center for Heart Failure Research Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. A.Baartscheer@AMC.UVA.NL
van Borren
Marcel M G J
MM
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D012964:Sodium / Q000378:metabolism*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000627:therapeutic use; D027982:Sodium-Bicarbonate Symporters / Q000037:antagonists & inhibitors / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000502:physiology
D002352:Carrier Proteins; D049994:Sodium Potassium Chloride Symporter Inhibitors; D027982:Sodium-Bicarbonate Symporters; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase