The hepoxilin analog PBT-3 inhibits heparin-activated platelet aggregation evoked by ADP.
We have previously shown that PBT-3, a stable synthetic analog of hepoxilins, inhibits the aggregation of human platelets in vitro evoked by collagen through inhibition of thromboxane A(2) formation and action on the TP receptor. We now show that PBT-3 is capable of potently inhibiting the second phase of aggregation evoked by ADP in both washed human platelets and platelet-rich plasma (PRP), a phase associated with thromboxane formation. Aspirin blocks this second phase as well; so does the thromboxane receptor antagonist SQ 29,548. When ADP-evoked aggregation in PRP is activated by heparin through an enhancement of thromboxane formation, PBT-3, aspirin as well as SQ 29,548 block this activation through different mechanisms. These data confirm the inhibitory action of PBT-3 on aggregation of human platelets through inhibition of both thromboxane formation and blockade of thromboxane receptor action and suggest that this family of compounds may be useful in the treatment of thrombotic disorders in combination with heparin.
Reynaud
D
D
Programme in Integrative Biology, Research Institute, Hospital for Sick Children, M5G 1X8, Toronto, ON, Canada.
Hinek
Alexander
A
Pace-Asciak
C R
CR
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005231:Fatty Acids, Unsaturated; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology
D000925:Anticoagulants; D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; C453725:PBT-3 compound; D010975:Platelet Aggregation Inhibitors; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; C045749:SQ 29548; D006493:Heparin; D015126:8,11,14-Eicosatrienoic Acid; D001241:Aspirin