The possible role of type II (cGMP-stimulated cAMP hydrolysis) phosphodiesterase (PDE) in the accentuated antagonism of muscarinic effects on heart rate during beta-stimulation via endogenous nitric oxide (NO) was evaluated. The canine isolated sinoatrial node preparation was cross circulated with arterial blood of a support dog. The sinoatrial rate of the preparation was 96 +/- 5 beats/min (n ...

An important component of the antianginal efficacy of glyceryl trinitrate (GTN) is attributable to its selective venodilator effect, resulting in decreased cardiac preload and myocardial oxygen demand. Tolerance to nitrates occurs during chronic exposure, and the current study assessed whether this was due to increased phosphodiesterase (PDE) activity in the venous circulation. Tolerance was in...

OBJECTIVES The aim of this study was to evaluate the impact of the phosphodiesterase (PDE) inhibitor pentoxifylline on platelet function profiles in patients receiving dual antiplatelet therapy (DAPT). BACKGROUND Previous studies have shown that, in patients receiving DAPT, the adjunctive use of a PDE inhibitor enhances platelet inhibition, particularly in those presenting with diabetes melli...

Phosphodiesterase (PDE)4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. In this study, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T an...

Despite the routine use of phosphodiesterase type-5 inhibitors (PDE-5i) for treatment of erectile dysfunction, their role in prostate cancer (PC) chemoprevention remains unclear with only a few studies exploring the link between PDE-5i use and PC. We tested the association between PDE-5i use and PC risk in the REDUCE study. REDUCE was a four-year multi-center study testing the effect of daily d...

Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP) properties and I(Ca,L) in the sinoatri...

OBJECTIVE The internal thoracic artery (ITA) is a useful conduit for coronary artery bypass grafting (CABG) and the patency rate is indispensable. Recently we have developed a method for increasing ITA blood flow during surgery by directly injecting phosphodiesterase III inhibitor (PDE III-I) into the left ITA (LITA) to prevent its contracture. In this study, we compared the reactivity of LITA ...

To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 Å resolution, and the structure of apo PDE2 at 2.0 Å resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by usin...

Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substanti...

Pulmonary hypertension (PHT) is associated with increased vascular resistance due to sustained contraction and enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC); the abnormal tone and remodeling in the pulmonary vasculature may relate, at least in part, to decreased cyclic nucleotide levels. Cyclic nucleotide phosphodiesterases (PDEs), of which 11 families have been ident...