HA-29: an inhibitor of thromboxane A2 formation with antagonism of thromboxane A2/prostaglandin endoperoxide receptor in rabbit platelets.
HA-29, 2-[(3-methoxyphenyl)methyl]-pyrano[2,3-c]pyrazol-6(1H)-one, was investigated for its inhibitory mechanism of action in washed rabbit platelets. This compound inhibited the aggregation and ATP release of rabbit platelets induced by arachidonic acid and collagen in a concentration-dependent manner, without affecting those induced by ADP, PAF and thrombin. Prolongation of the incubation time of HA-29 with platelets did not cause further inhibition and the aggregability of the agent-treated platelets could be restored after washing of platelets. The concentration-response curve of U-46619-induced platelet aggregation was shifted to the right by HA-29 in a concentration-dependent manner, but the maximal aggregation was suppressed by HA-29. The pA2 and pA10 values of HA-29 on U-46619-induced platelet aggregation were 4.26 and 3.58, respectively, with a slope value of -1.4. The U-46619-induced aggregation was markedly disaggregated by HA-29 even it was added 5 min after U-46619. HA-29 inhibited the secondary aggregation and ATP release, but not the primary aggregation of human platelet-rich plasma induced by ADP and epinephrine. Thromboxane B2 formation caused by arachidonic acid, collagen and thrombin was markedly suppressed by HA-29. HA-29 also inhibited the formation of prostaglandin D2 caused by arachidonic acid. HA-29 inhibited almost completely the formation of inositol monophosphate caused by U-46619, but not that by collagen or thrombin. HA-29 did not affect U-46619-induced contraction of rat aorta. It is concluded that the antiplatelet effect of HA-29 is due to the inhibition of thromboxane A2 formation and blockade of thromboxane A2/prostaglandin endoperoxide receptor.
Lin
C H
CH
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Kuo
S C
SC
Huang
L J
LJ
Huang
T F
TF
Teng
C M
CM
D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008563:Membrane Lipids / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000097:blood; D011714:Pyrans / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000097:blood; D013931:Thromboxanes / Q000097:blood*
D008563:Membrane Lipids; D010975:Platelet Aggregation Inhibitors; D011714:Pyrans; D011720:Pyrazoles; D017482:Receptors, Thromboxane; D013931:Thromboxanes; C077193:HA 29; D013929:Thromboxane B2; D013928:Thromboxane A2; D000255:Adenosine Triphosphate; D015230:Prostaglandin D2