Background:The guanine exchange factor Epac is a cAMP sensor. Results: We have identified a tetrahydroquinoline analog named CE3F4 that blocks Epac activation in response to cAMP in vitro and in living cultured cells. Conclusion: CE3F4 behaves as an uncompetitive antagonist of Epac with respect to cAMP. Significance: CE3F4 may serve as a basis for the development of new therapeutic drugs.

Rationale: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood.Objective: To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury. Methods and Results: