Na⁺/H⁺ exchanger (NHE-1) inhibition was demonstrated to induce the regression of cardiac hypertrophy (CH) in several experimental models and to inhibit mitochondrial death pathway in "in-vitro" experiments. Since recent reports show that NHE-1 inhibition delays the transition from CH to failure, and apoptosis plays a key role in this process, we investigated the effect of chronic treatment with the NHE-1 blocker cariporide on CH and apoptosis in the SHR. One month of cariporide treatment (30 mg/kg/day) induced the regression of CH (cardiomyocyte cross sectional area: 468±20 vs. 285±9 µm² in untreated and cariporide-treated SHR; p < 0.05). Apoptosis was assessed by TUNEL staining, the expression of Bcl-2, Bax, and activation of caspase-3 and PARP-1 by immunoblot. Cariporide treatment decreased the TUNEL- positive cells, the Bax/Bcl-2 ratio (3.16±0.32 vs. 1.70±0.17, untreated and cariporide-treated respectively; p < 0.05); caspase-3 and PARP-1 activation (465±62 vs. 260±22 and 2239±62 vs. 1683±85 AU, untreated and cariporide-treated respectively; p < 0.05). Angiotensin II, a growth factor and apoptotic stimulus, was used to induce O₂^- production that activated the ERK1/2- p90RSK pathway increasing NHE-1 phosphorylation. These effects were prevented by losartan, N-(2-mercaptopropionyl)-glycine and by cariporide. In conclusion, we present data demonstrating that chronic NHE-1 inhibition with cariporide decreases both hypertrophy and apoptosis susceptibility in the SHR heart. The antiapoptotic effect would be the consequence of two different actions of cariporide: the prevention of cytosolic Na⁺ and Ca²⁺ overload due to the inhibition of the sarcolemmal NHE-1; and a direct mitochondrial effect preventing mitochondrial permeability transition pore opening.