Atrial natriuretic peptide (ANP) via its guanylyl cyclase-A (GC-A) receptor counteracts the systemic actions of angiotensin II (Ang II). Cardiomyocyte-restricted disruption of GC-A in mice (CM GC-A KO) induces cardiac hypertrophy and fibrosis, suggesting that local, cardiac actions of ANP inhibit cell growth. In the present study we investigated whether ANP/GC-A can counteract the cardiac hypertrophic actions of Ang II. Cardiac remodelling in response to exogenous Ang II (100, 300 or 2500 ng/kg/min, 14 days) was significantly exacerbated in CM GC-A KO mice. Cardiac CaMKII and calcineurin activity in response to Ang II were more pronounced in CM GC-A KO as compared to control mice. Systolic Ca2+i levels were increased in GC-A--deficient cardiomyocytes as compared to controls while diastolic Ca2+i levels were not different between genotypes. Even more, Ang II-induced Ca2+i increases were significantly enhanced in CM GC-A KO cells. Local ANP/GC-A signalling inhibits Ang II - stimulated, CaMKII and Ca2+/calcineurin - mediated excessive cardiac remodelling.