Protein kinase-dependent and Ca -independent cAMP inhibition of ANP release in beating rabbit atria

Cui, Xun, Jin Fu Wen, Jing Yu Jin, Wen Xie Xu, Sung Zoo Kim, Suhn Hee Kim, Ho Sub Lee, and Kyung Woo Cho. Protein kinase-dependent and Ca2 -independent cAMP inhibition of ANP release in beating rabbit atria. Am J Physiol Regulatory Integrative Comp Physiol 282: R1477–R1489, 2002; 10.1152/ajpregu.00316.2001.—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 Ca2 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 Cand Ca2 /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 Ca2 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 Ca2 -channeldependent and -independent signaling pathways.