title: Mechanism of inhibition of platelet aggregation by HCL-31D.
abstract: The antiplatelet effect of the pyridazinone analogue, 4, 5-dihydro-6-[4-[2-hydroxy-3-(3,4 dimethoxybenzylamino)propoxy]naphth-1-yl]-3(2H)-pyridazinone (HCL-31D), was investigated in vitro with rabbit platelets. HCL-31D dose-dependently inhibited the platelet aggregation and ATP release induced by collagen (10 microg/ml), arachidonic acid (100 microM) or thrombin (0.1 U/ml) with an IC(50) of about 0.95-5.41 microM. HCL-31D (0.5-5 microM) increased the platelet cyclic AMP level in a dose-dependent manner. Furthermore, HCL-31D potentiated cyclic AMP formation caused by prostaglandin E(1) but not that caused by 3-isobutyl-1-methylxanthine (IBMX). HCL-31D also attenuated phosphoinositide breakdown and intracellular Ca(2+) elevation induced by collagen, arachidonic acid or thrombin. HCL-31D inhibited the formation of thromboxane B(2) induced by collagen or thrombin but not by arachidonic acid. In addition, HCL-31D did not affect platelet cylooxygenase and thromboxane synthase activity. These data indicate that HCL-31D is an inhibitor of phosphodiesterase and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
authors.affiliation: Graduate Institute of Medical Sciences, Tri-Service General Hospital, National Defense Medical Center, National Taiwan Normal University, Taipei, Taiwan. tcchou@ms5.hinet.net
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: C Y
authors.initials: CY
authors.lastname: Li
authors.forename: A R
authors.initials: AR
authors.lastname: Lee
authors.forename: T M
authors.initials: TM
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D010716:Phosphatidylinositols / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000378:metabolism
chemical_list: C405630:HCL 31D; D010716:Phosphatidylinositols; D010975:Platelet Aggregation Inhibitors; D011412:Propanolamines; D011724:Pyridazines; D013929:Thromboxane B2; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; D006152:Cyclic GMP; D002118:Calcium