Regulation of atrial release of atrial natriuretic peptide (ANP) is coupled to changes in atrial dynamics. However, the mechanism by which mechanical stretch controls myocytic ANP release must be defined. The purpose of this study was to define the mechanism by which cAMP controls myocytic ANP release in perfused, beating rabbit atria. The cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine (IBMX) inhibited myocytic ANP release. The activation of adenylyl cyclase with forskolin inhibited ANP release, which was a function of an increase in cAMP production. Inhibitors for L-type Ca 2ϩ channels and protein kinase A (PKA) attenuated a minor portion of the forskolin-induced inhibition of ANP release. Gö-6976 and KN-62, which are specific inhibitors for protein kinase C-␣ and Ca 2ϩ /calmodulin kinase, respectively, failed to modulate forskolin-induced inhibition of ANP release. The nonspecific protein kinase inhibitor staurosporine blocked forskolin-induced inhibition of ANP release in a dose-dependent manner. Staurosporine but not nifedipine shifted the relationship between cAMP and ANP release. Inhibitors for Ltype Ca 2ϩ channels and PKA and staurosporine blocked forskolin-induced accentuation of atrial dynamics. These results suggest that cAMP inhibits atrial myocytic release of ANP via protein kinase-dependent and L-type Ca 2ϩ -channeldependent and -independent signaling pathways. atrial natriuretic peptide; forskolin; phosphodiesterase; channels ENDOCRINE ATRIUM SYNTHESIZES and releases a family of natriuretic peptides including atrial natriuretic peptide (ANP) and brain natriuretic peptide (7,19). C-type natriuretic peptide, a third member of the natriuretic peptide family (32) that is synthesized in the atrium, may have paracrine/autocrine function for the regulation of ANP release (17).There have been reports on the variable modulators for the control of ANP release (23). However, the specific control mechanism for ANP release must be defined. The most prominent activator for atrial secretion of ANP has been shown to be the stretch and/or release of atrial wall (2, 10, 16). However, the intracellular mechanism responsible for the activation of ANP release by mechanical stimulation is unknown.The potential roles of cyclic nucleotides and Ca 2ϩ in the regulation of ANP release have been subjects of interest. Recently we found that both cGMP and Ca 2ϩ are negative regulators for atrial myocytic release of ANP (4, 14, 17). There are diverse reports on the effects of cAMP in the regulation of ANP secretion. Forskolin, an activator of adenylyl cyclase (AC), has been shown to decrease ANP release from cultured atrial myocytes (12,20,30) and perfused rat heart (25); 3-isobutyl-1-methylxanthine (IBMX), a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE) (12), and 8-bromoadenosine 3Ј,5Ј-cyclic monophosphate (8-BrcAMP) (12, 30), have also been shown to inhibit ANP secretion. In contrast, it has also been shown that cAMP-elevating agents (1,5,24) and cell membranepermeant cAMP analogs (1,5,27...

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