Mechanism of the inhibition of platelet aggregation produced by prostaglandin F2 alpha.
The inhibition of human platelet aggregation produced by PGF2 alpha is not specific for thromboxane A2 mimetics. Aggregation waves induced by PAF and thrombin are also inhibited by PGF2 alpha (8 microM); ADP is unaffected. These effects are still seen in platelets from aspirin-treated donors and platelets desensitized to thromboxane-like agonists (e.g. 11,9-epoxymethano PGH2). In contrast the thromboxane receptor antagonist EP 045 (up to 20 microM) had no effect on primary aggregation induced by PAF, thrombin and ADP. We have previously shown that EP 045 (IC50 = 0.5 microM), but not PGF2 alpha (28 microM), displaces the specific binding of [3H] 9,11-epoxymethano PGH2 to washed human platelets. PGF2 alpha produces small increases in cAMP levels, and both this effect and the anti-aggregation are diminished by the adenyl cyclase inhibitor SQ 22536. The rise in cAMP induced by PGF2 alpha is inhibited to a greater extent by the presence of ADP than by thrombin, PAF or a thromboxane mimetic. The ability of aggregating agents to inhibit this increase correlates inversely with their sensitivity to inhibition by PGF2 alpha. We suggest that the very weak effect of PGF2 alpha on cyclic AMP production is sufficient to account for its inhibitory activity, and it is unlikely to be a competitive antagonist at the platelet thromboxane receptor as suggested by others.
Armstrong
R A
RA
Jones
R L
RL
Wilson
N H
NH
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D015237:Dinoprost; D006801:Humans; D010972:Platelet Activating Factor / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D044262:Prostaglandin H2; D011460:Prostaglandins F / Q000494:pharmacology*; D011463:Prostaglandins H / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D011460:Prostaglandins F; D011463:Prostaglandins H; D011465:Prostaglandins, Synthetic; D044262:Prostaglandin H2; D000244:Adenosine Diphosphate; C034549:EP 045; D015237:Dinoprost; D000242:Cyclic AMP; D013917:Thrombin; D006152:Cyclic GMP; D001241:Aspirin