The CBP and p300 co-activators play a key role in many aspects of gene regulation being recruited to the DNA via transcription factors which are targets for specific signalling pathways. It has previously been demonstrated that in neuronal cells the ability of CBP and p300 to activate transcription can be directly stimulated by NGF or calcium-activated signalling pathways. Here we demonstrate that, in cardiac cells, the activity of CBP and p300 is stimulated by phenylephrine (PE) treatment and that they are required for the activation of ANF gene expression by PE. Activation of CBP/p300 by PE involves the p42/p44 MAPK pathway and targets primarily the N-terminus of p300 and the C-terminus of CBP which are not homologous to one another. To our knowledge, this is the first report of a specific stimulus modulating the activity of CBP and p300 in cardiac cells and suggests that these factors play an important role in the hypertrophic effect of PE.