Recent studies have demonstrated that inhibition of the hMR has favourable effects on patients with congestive heart failure (CHF). Since blocking of beta-adrenergic receptors has proven beneficial in CHF as well, the cAMP pathway might be involved in the development and progression of CHF. To determine if hMR and hGR interact with genotropic cAMP signalling, we transfected HEK293 cells with a CRE-reporter-plasmid and determined the CRE-transactivation activities of hMR and hGR. In HEK-hMR but not in HEK-mock cells aldosterone (ALD) led to a slight activation of CRE. Forskolin-induced CRE-activity was potentiated by 1 nmol/l ALD via the hMR. If db-cAMP was used to induce CRE-activation 1 nmol/l ALD had no effect. In the absence of hMR only high concentrations of ALD (100 nmol/l) amplified the effect of forskolin. Activation of hGR by 100 nmol/l dexamethasone evoked an identical effect. Furthermore, db-cAMP induced CRE-activation was potentiated by 100 nmol/l ALD or dexamethasone. Conclusions: (i) ALD activates CRE via the hMR. (ii) ALD, via hMR, potentiates the cAMP pathway at the level of the adenylyl cyclase. (iii) ALD and dexamethasone, via hGR, potentiate the cAMP-pathway downstream of the adenylyl cyclase. (iv) Interaction of hMR and cAMP-signalling may contribute to the cardiovascular actions of ALD.