From Anrep's phenomenon to myocardial hypertrophy: Role of the Na⁺/H⁺ exchanger

In this review, the enhanced activity of the cardiac Na⁺/H⁺ exchanger is considered to be a key step in the intracellular signaling pathway leading to cardiac hypertrophy, and the inhibition of the exchanger is a pharmacological tool to prevent or regress it. This enhanced activity has been demonstrated after stretching neonatal rat cardiomyocytes and cat papillary muscles. In the latter preparation, the activation of the exchanger results in a mechanical counterpart, the slow force response to stretch. The chain of events triggered by a stretch begins with the release of angiotensin II (Ang II), which in turn releases endothelin (ET) and ends with the increase in [Ca²⁺]_i through the Na⁺/Ca²⁺ exchanger (NCX) in its reverse mode and the activation of the calcineurin/NFAT pathway. It should be emphasized that the link proposed herein between myocardial stretch and Ang II/ET relies upon the release of small amounts of these peptides. Higher concentrations of either of them may trigger Ca²⁺ influx through mechanisms other than NCX, and induce cardiac hypertrophy by the activation of widely recognized intracellular signaling pathways.