Forskolin Stimulates Prostaglandin Synthesis in Rabbit Heart by a Mechanism That Requires Calcium and Is Independent of Cyclic AMP

Infusion of forskolin, an adenylate cyclase activator, in concentrations (2,uM) that do not alter basal prostaglandin (PG) synthesis inhibit synthesis of PG elicited by isoproterenol in rabbit heart. This inhibitory action of forskolin appears to be dependent on cyclicAMP (cAMP). Bolus injection of forskolin (75 nmol), however, was found to stimulate PG synthesis in rabbit heart. The purpose of this study was to elucidate the mechanism of the stimulatory action of forskolin on PG synthesis (prostaglandin 12 measured as 6-ketoprostaglandin F,. [6-keto-PGF1J) in isolated perfused rabbit heart. Forskolin enhanced PG production in a dose-dependent manner. 1,9-Dideoxyforskolin, a forskolin analogue devoid of adenylate cyclase-stimulating activity, also enhanced PG synthesis. The cAMP analogue chlorophenylthio-cAMP failed to stimulate output of 6-keto-PGFi,a, although this agent produced dose-related changes in mechanical function in rabbit heart. Furthermore, the adenylate cyclase inhibitor (-)-N6-(R-phenylisopropyl)adenosine potentiated, whereas the phosphodiesterase inhibitor cilostamide attenuated, forskolin-stimulated PG production. (-)-N6-(R-Phenylisopropyl)adenosine and cilostamide had no effect on the mechanical actions of chlorophenylthio-cAMP, suggesting selectivity of these agents for adenylate cyclase and phosphodiesterase, respectively. 6-Keto