Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021

Cell Signal. 1996 Dec;8(8):575-81. doi: 10.1016/s0898-6568(96)00112-x.


In extracts of human platelets, three isoenzymes of cyclic nucleotide phosphodiesterase (PDE), namely, PDE2, PDE3, and PDE5, were identified; activities of PDE1 and PDE4 were not detected. In human platelets, the cGMP-hydrolytic activity was about six times higher than the cAMP-hydrolytic activity, and PDE5 and PDE3 are the major phosphodiesterase isoenzymes that hydrolyze cGMP and cAMP, respectively. PDE5 exhibited organ-specific expression in humans, and platelets were among the tissues richest in PDE5. A novel inhibitor of PDE5, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl ] piperidine-4-carboxylate sesquihydrate (E4021), was a potent and highly selective inhibitor of human platelet PDE5. However, E4021 (up to 10 microM) did not inhibit 9,11-epithio-11,12-methano-thromboxane A2-induced platelet aggregation, in vitro. E4021 plus SIN-1 (3-morpholino-sydnonimine), at concentrations that had little effect individually, inhibited aggregation. These results suggest the unique distribution of phosphodiesterase isoenzymes in human platelets and the PDE5 inhibitors might be useful as a new class of antiplatelet drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Blood Platelets / drug effects
  • Blood Platelets / enzymology*
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Humans
  • In Vitro Techniques
  • Isoenzymes / blood*
  • Isoenzymes / isolation & purification
  • Molsidomine / analogs & derivatives
  • Molsidomine / pharmacology
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / blood*
  • Phosphoric Diester Hydrolases / isolation & purification
  • Phthalazines / pharmacology
  • Piperidines / pharmacology
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / pharmacology
  • Quinazolines / pharmacology
  • Signal Transduction
  • Thromboxane A2 / analogs & derivatives
  • Thromboxane A2 / pharmacology
  • Tissue Distribution


  • E 4021
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Phthalazines
  • Piperidines
  • Platelet Aggregation Inhibitors
  • Quinazolines
  • Thromboxane A2
  • linsidomine
  • STA 2
  • Molsidomine
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human
  • MY 5445