Forskolin: effects on cyclic AMP and contractile function in the isolated rat and guinea pig heart

The new inotropic agent, forskolin, is thought to act by stimulation of adenyl cyclase at a site remote from the beta-receptor. In this study we have characterized the action of forskolin in isolated, perfused rat and guinea-pig hearts. In both species, forskolin increased heart rate, left ventricular pressure and tissue cyclic AMP in a concentration-dependent manner. Significant responses were obtained with a minimum concentration of 2 X 10(-9)M forskolin in the rat and 2 X 10(-8)M in the guinea-pig. In both species maximal effects were observed with 2 X 10(-6)M forskolin. For any given forskolin concentration, the increases in cyclic AMP were greater in the rat heart than in the guinea-pig heart. In the rat heart, two beta-adrenoceptor blocking agents (1.6 X 10(-6)M propranolol or 2.6 X 10(-6)M timolol) were both able to reduce the increases in function and tissue cyclic AMP content caused by forskolin (2 X 10(-7) and 2 X 10(-8)M). However, no inhibition by beta-blockade was observed in hearts from catecholamine-depleted (reserpinized) animals or in hearts treated with high concentrations (2 X 10(-6)M) of forskolin. These results indicate that catecholamines may in some way be able to potentiate the actions of forskolin.