In adult mouse cardiac myocytes, cytosolic cGMP levels are low (~10 nM), but can be markedly increased by stimulation of particulate guanylyl cyclases (GC-A, GC-B) with natriuretic peptides (CNP>>ANP/BNP). In contrast, stimulation of the soluble guanylyl cyclase (sGC) with NO-donors such as SNAP had no effect. However, constitutive activity of this cyclase is involved in basal cGMP production, since stimulating cardiomyocytes with the sGC inhibitor ODQ showed a decrease of basal cGMP levels. This basal cGMP production is balanced by phosphodiesterase (PDE) activity. Inhibiting PDE1,2 and 5 had only little effect, whereas PDE3 represents the major cGMP-PDE family controlling cGMP levels at basal state, in the presence of cGMP agonists (such as SNAP, ANP, and CNP) and in a model of cardiac hypertrophy (transverse aortic constriction model). In addition we could show that cGMP pools produced by GC-B after CNP stimulation are mainly regulated by PDE3, so that the receptor and this PDE form one functional unit important for the regulation of cGMP/cAMP cross-talk and modulation of cAMP levels.