Na⁺/Ca²⁺ exchange and cardiovascular diseases

Abstract

The Na⁺/Ca²⁺ exchanger (NCX) is a plasma membrane transporter that is expressed in many mammalian cell types, such as muscle, nerve, and epithelium. This exchanger is bidirectional, being controlled by membrane potential and transmembrane ion gradients, and is important in maintaining Ca²⁺ homeostasis. However, the role of NCX in cardiovascular diseases is not clear. We identified the role of NCX1 in salt-sensitive hypertension using SEA0400, a specific inhibitor for Ca²⁺ entry via NCX1, and genetically engineered mice. We found that SEA0400 lowered arterial blood pressure in salt-dependent hypertensive rat models, but not in normotensive rats or other types of hypertensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increased arterial blood flow, indicating peripheral vasodilation. SEA0400 reversed ouabain-induced cytosolic Ca²⁺ elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deficient mice had low salt-sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle were hypersensitive to salt. SEA0400 lowered the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca²⁺ entry via NCX1 in arterial smooth muscle. In addition, we found that transgenic mice overexpressing cardiac NCX1.1 developed cardiac hypertrophy, and transgenic mice overexpressing cardiac NCX1.1 mutant, devoid of Na⁺-dependent inactivation, produced dilated cardiomyopathy. Thus, up-regulated Na⁺/Ca²⁺ exchange may be involved in various cardiovascular diseases. [Jpn J Physiol 55 Suppl:S55 (2005)]