Sodium-hydrogen exchangers (NHE) in human cardiovascular diseases: interfering strategies and their therapeutic applications

Sodium-hydrogen exchangers (NHE) are among the main regulators of cell volume and intracellular concentration of hydrogen and sodium ions. By indirectly affecting sodium/calcium exchange across the plasma membrane, NHE can also influence the intracellular concentration of calcium. Excess activation of NHE or inappropriate sodium extrusion due to failure of ATP-dependent Na+/K+ transport system can be deleterious during cardiac or peripheral organ ischemia. Besides being responsible for the regulation of intracellular pH and sodium-calcium inward currents, NHE isoform 1 (NHE-1), which is predominantly expressed in the cardiovascular system, influences the tone of the vessel wall in response to a variety of stimuli, including hypertonic stress. Because of the extensive involvement of NHE-1 in cardiac myocyte contracture and necrosis, stunning, reperfusion arrhythmias, as well as hypertension and myocardial diseases such as diabetic cardiomyopathy, efforts have been made in developing inhibitors of this transporter. We here review the biology and regulation of NHE, focusing on current knowledge of the role of NHE-1 as a potential target in the development of novel compounds that could play a role in cardiovascular homeostasis, both in physiological and pathological conditions. © 2013 Elsevier Inc.