Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signaling antagonizes the physiological effects mediated by the renin-angiotensin system (RAS). The objective of this study was to determine whether the targeted-disruption of Npr1 gene (coding for GC-A/NPRA) leads to the activation of cardiac RAS genes involved on the hypertrophic remodeling process. The Npr1 gene-knockout (Npr1^-/-) mice showed 30-35 mmHg higher systolic blood pressure (SBP) and a 63% greater heart weight to body weight (HW/BW) ratio as compared with wild-type (Npr1^+/+) mice. The mRNA levels of both angiotensin-converting enzyme (ACE) and angiotensin II (Ang II) type 1a receptor (AT1a) were increased by 3-fold and 4-fold, respectively, in Npr1^-/- null mutant mice hearts as compared with the wild-type Npr1^+/+ mice hearts. In parallel, the expression levels of interleukin-6 (IL-6) and tumor necrosis factor- (TNF-) were increased by 4- to 5-fold , in Npr1^-/- mice hearts as compared with control animals. The NF-B binding activity in nuclear extracts of Npr1^-/- mice hearts was increased by 4-fold as compared with wild-type Npr1^+/+ mice hearts. Treatments with captopril or hydralazine equally attenuated SBP; however, only captopril significantly decreased the HW/BW ratio and suppressed cytokine gene expression in Npr1^-/- mice hearts. The ventricular cGMP level was reduced by almost 6-fold in Npr1^-/- mice as compared with wild-type control mice. The results of the present study indicate that disruption of NPRA/cGMP signaling leads to the augmented expression of cardiac RAS pathways that promote the development of cardiac hypertrophy and remodeling.