PDE3 inhibition in dilated cardiomyopathy: Reasons to reconsider

Background: PDE3 cyclic nucleotide phosphodiesterases have important roles in regulating cAMP- and cGMP-mediated signaling. Drugs that inhibit these enzymes raise cAMP and cGMP content in cardiac and vascular smooth muscle and increase the phosphorylation of proteins by cAMP- and cGMP-dependent protein kinases (PK-A and PK-G), thereby eliciting inotropic and vasodilatory responses. Methods: Although these actions are beneficial acutely in patients with dilated cardiomyopathy, long-term use of these agents was shown in several clinical trials to increase mortality. Several new clinical studies, however, suggest PDE3 inhibitors may be safe and effective when used in conjunction with beta-adrenergic receptor antagonists, whereas new studies at the cellular and molecular levels indicate that there are several isoforms of these enzymes in cardiac and vascular myocytes that are likely to regulate cAMP content in different intracellular compartments. Conclusions: Both sets of observations suggest that PDE3 inhibition may be refined to allow more selective effects on phosphorylation of PK-A substrates, possibly allowing the beneficial effects of PDE3 inhibition to be separated from the adverse long-term consequences of their use.