title: Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Mie University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: M
authors.initials: M
authors.lastname: Fujioka
authors.forename: M
authors.initials: M
authors.lastname: Miyahara
authors.forename: N
authors.initials: N
authors.lastname: Isaka
authors.forename: H
authors.initials: H
authors.lastname: Shiku
authors.forename: T
authors.initials: T
authors.lastname: Nakano
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000097:blood* / Q000302:isolation & purification; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000097:blood* / Q000302:isolation & purification; D010793:Phthalazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C091517:E 4021; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; D013928:Thromboxane A2; C002385:linsidomine; C037866:STA 2; D008981:Molsidomine; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C052490:MY 5445