Na(+)/H(+) exchanger 1 (NHE-1) inhibition attenuates the hypertrophic response and
heart failure in various experimental models. As the hypertrophic program is rapidly initiated following insult, we investigated whether early and transient administration of a NHE-1 inhibitor will exert salutary effects on cardiomyocyte
hypertrophy or
heart failure using both in vitro and in vivo approaches. Neonatal cardiomyocytes were treated with the novel, potent, and highly specific NHE-1 inhibitor BIX (N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-
guanidine; 100 nM) for 1 hour in the presence of 10 µM
phenylephrine, after which the cells were maintained for a further 23 hours in the absence of NHE-1 inhibition. One-hour treatment with the NHE-1 inhibitor prevented
phenylephrine-induced
hypertrophy, which was associated with prevention of activation of
calcineurin, a key component of the hypertrophic process. Experiments were then performed in rats subjected to coronary artery
ligation, in which the NHE-1 inhibitor was administered immediately after
infarction for a 1-week period followed by a further 5 weeks of sustained coronary artery occlusion in the absence of
drug treatment. This approach significantly attenuated
left ventricular hypertrophy and improved both left ventricular systolic and diastolic dysfunction, which was also associated with inhibition of
calcineurin activation. Our findings indicate that early and transient administration of an NHE-1 inhibitor bestows subsequent inhibition of cardiomyocyte
hypertrophy in culture as well as
cardiac hypertrophy and
heart failure in vivo, suggesting a critical early NHE-1-dependent initiation of the hypertrophic program. The study also suggests a preconditioning-like phenomenon in preventing
hypertrophy and
heart failure by early and transient NHE-1 inhibition.