Effects of DK-002, a synthesized (6aS,cis)-9,10-Dimethoxy-7,11b-dihydro-indeno[2,1-c]chromene-3,6a-diol, on platelet activity.
In the present study, the mechanism of antiplatelet activity of DK-002, a synthesized (6aS,cis)-9,10-Dimethoxy-7,11b-dihydro-indeno[2,1-c]chromene-3,6a-diol, was investigated. DK-002 inhibited the thrombin, collagen, and ADP-induced rat platelet aggregation in a concentration-dependent manner, with IC50 values of 120, 27, and 47 microM, respectively. DK-002 also inhibited thrombin-induced dense granule secretion, thromboxane A2 synthesis, and [Ca2+]i elevation in platelets. DK-002 did not show any significant effect on ADP-induced inhibition of cyclic AMP elevation by prostaglandin E1, but DK-002 was confirmed to inhibit ADP-induced [Ca2+]i elevation and shape change. DK-002 inhibited 4-bromo-A23187-induced [Ca2+]i elevation in the presence of creatine phosphate/creatine phosphokinase (CP/CPK, a ADP scavenging system) and indomethacin (a specific inhibitor of cyclooxygenase). DK-002 also inhibited Ca2+ mobilization in thrombin- or 4-bromo-A23187-stimulated platelets through its inhibitory effects on both Ca2+ release from intracellular stores and Ca2+ influx, in the presence of CP/CPK and indomethacin. Taken together, the present study shows that DK-002 has inhibitory effects on stimulation of platelets, and suggests that its antiplatelet activity might be related to the inhibitory mechanism on Ca2+ mobilization in stimulated platelets.
Lee
Ki-Seon
KS
Department of Preventive Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Khil
Lee-Yong
LY
Chae
Sang-Ho
SH
Kim
Deukjoon
D
Lee
Byung-Hoon
BH
Hwang
Gwi-Seo
GS
Moon
Chang-Hyun
CH
Chang
Tong-Shin
TS
Moon
Chang-Kiu
CK
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000648:ultrastructure; D002118:Calcium / Q000097:blood; D003402:Creatine Kinase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects; D066298:In Vitro Techniques; D007192:Indenes / Q000737:chemistry / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood; D013917:Thrombin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood
D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; C508299:DK-002; D007192:Indenes; D007476:Ionophores; D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D003402:Creatine Kinase; D013917:Thrombin; D002118:Calcium; D007213:Indomethacin