The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) counteract the systemic, hypertensive and hypervolemic actions of angiotensin II (Ang II) via their guanylyl cyclase-A (GC-A) receptor. In the present study we took advantage of genetically modified mice with conditional, cardiomyocyte-restricted disruption of GC-A (CM GC-A KO mice) to study whether NPs can moderate not only the endocrine but also the cardiac actions of Ang II in vivo. Fluorometric measurements of Ca²⁺_i transients in isolated, electrically paced adult cardiomyocytes showed that ANP inhibits the stimulatory effects of Ang II on free cytosolic Ca²⁺-transients via GC-A. Remarkably, GC-A - deficient cardiomyocytes exhibited greatly enhanced Ca²⁺_i-responses to Ang II which was partly related to increased activation of the Na⁺/H⁺-exchanger NHE-1. Chronic administration of Ang II to control and CM GC-A KO mice (300 ng/kg BW/min via osmotic minipumps during two weeks) provoked significant cardiac hypertrophy, which was markedly exacerbated in the later genotype. This was concomitant to increased cardiac expression of NHE-1 and enhanced activation of the Ca²⁺/calmodulin - dependent prohypertrophic signal transducers CaMKII and calcineurin. On the basis of these results, we conclude that NPs exert direct local, GC-A - mediated myocardial effects to antagonize the Ca²⁺_i-dependent hypertrophic growth response to Ang II.