cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium.

In mouse models of cardiac disease, the type 5 (PDE5)-selective cyclic nucleotide phosphodiesterase inhibitor sildenafil has antihypertrophic and cardioprotective effects attributable to the inhibition of cGMP hydrolysis. To investigate the relevance of these findings to humans, we quantified cGMP-hydrolytic activity and its inhibition by sildenafil in cytosolic and microsomal preparations from the left ventricular myocardium of normal and failing human hearts. The vast majority of cGMP-hydrolytic activity was attributable to PDE1 and PDE3.

Cyclic nucleotide phosphodiesterase PDE1C1 in human cardiac myocytes.

Isoforms in the PDE1 family of cyclic nucleotide phosphodiesterases were recently found to comprise a significant portion of the cGMP-inhibited cAMP hydrolytic activity in human hearts. We examined the expression of PDE1 isoforms in human myocardium, characterized their catalytic activity, and quantified their contribution to cAMP hydrolytic and cGMP hydrolytic activity in subcellular fractions of this tissue. Western blotting with isoform-selective anti-PDE1 monoclonal antibodies showed PDE1C1 to be the principal isoform expressed in human myocardium.

Tolerance to the therapeutic effect of tadalafil does not occur during 6 months of treatment: A randomized, double-blind, placebo-controlled study in men with erectile dysfunction.

Introduction: Tolerance can cause a decrease in drug efficacy during chronic therapy, possibly leading to treatment failures.

Aim: The aim of this article is to determine whether tolerance developed to the effects of tadalafil on erectile function (EF) over a 6-month treatment period.

Methods And Main Outcome Measures: Post hoc analysis of data from a multicenter, double-blind, randomized, placebo-controlled, parallel group study was performed.

Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival.

In response to biological and mechanical injury, or in vitro culturing, vascular smooth muscle cells (VSMCs) undergo phenotypic modulation from a differentiated "contractile" phenotype to a dedifferentiated "synthetic" one. This results in the capacity to proliferate, migrate, and produce extracellular matrix proteins, thus contributing to neointimal formation. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP or cGMP, are critical in the homeostasis of cyclic nucleotides that regulate VSMC growth.

The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis.

This study assessed the effects of selective inhibitors of 3',5'-cyclic nucleotide phosphodiesterases (PDEs) on adipocyte lipolysis. IC224, a selective inhibitor of type 1 phosphodiesterase (PDE1), suppressed lipolysis in murine 3T3-L1 adipocytes (69.6 +/- 5.