Relationship between inhibition of cardiac muscle phosphodiesterases, changes in cyclic nucleotide levels, and contractile response for CI-914 and other novel cardiotonics

Abstract

In the present study, the inhibitory effects of CI-914, a novel cardiotonic agent, as well as other recently identified positive inotropic agents and reference phosphodiesterase (PDE) inhibitors on the different molecular forms of cardiac PDE were examined, and correlated with changes in tissue levels of cyclic AMP and cyclic GMP, and the contractility of isolated guinea pig left atria produced by these agents. CI-914 was found to be a potent, selective inhibitor of peak III PDE, which is a low Km, cyclic AMP-specific form of the enzyme, with little effect on peak I or peak II PDE, both of which hydrolyze cyclic AMP as well as cyclic GMP. CI-914 also exerts a selective effect on cyclic nucleotides; increasing cyclic AMP levels in a concentration-dependent manner, while having no significant effect on cyclic GMP levels. Increases in contractility produced by CI-914 correlated with changes in the tissue level of cyclic AMP. Non-selective phosphodiesterase inhibitors such as theophylline, and less selective inhibitors such as papaverine, carbazeran, and milrinone increased tissue levels of both cyclic AMP and cyclic GMP. Increases in cyclic GMP, or the cyclic AMP/cyclic GMP ratio, did not appear to have an effect on contractility. These results provide support for the hypothesis that CI-914 increases contractility by selectively inhibiting the activity of the peak III phosphodiesterase. These results also indicate that cyclic AMP and cyclic GMP do not act in an opposing "yin-and-yang" fashion to regulate atrial contractility.