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 an 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 N-[4-(1-Acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (100 nM) for one 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 one-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.
- The American Society for Pharmacology and Experimental Therapeutics