Background— Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na ⁺ /H ⁺ exchanger NHE-1 to cardiac remodeling in GC-A–deficient (GC-A ^−/− ) mice. Methods and Results— Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A ^−/− mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca ²⁺ levels. Chronic treatment of GC-A ^−/− mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca ²⁺ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A ^−/− mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca ²⁺ /calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A ^−/− mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy. Conclusions— On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca ²⁺ , and CaMKII as well as Akt activity.