Antiaggregatory activity of 8-epi-prostaglandin F2 alpha and other F-series prostanoids and their binding to thromboxane A2/prostaglandin H2 receptors in human platelets.
8-Epi-prostaglandin F2 alpha (8-epi-PGF 2 alpha) is a nonenzymatic, free radical-catalyzed peroxidation product of arachidonic acid that has potent biological activity, including contraction of vasculature and inhibition of aggregation induced by thromboxane (TX) A2 mimetics. In the present study, we demonstrate that 8-epi-PGF2 alpha could inhibit platelet aggregation induced by the TX mimetics U46619 and I-BOP as well as low-dose collagen but not thrombin or the primary wave of aggregation caused by high-dose ADP. The secondary (TX-dependent) wave of aggregation induced by high-dose ADP, however, was not affected. This suppression was dose dependent where 3.6 and 3.3 microM of 8-epi-PGF2 alpha caused 50% inhibition of platelet aggregation induced by U46619 and I-BOP, respectively, whereas 10 microM caused approximately 72% inhibition of collagen-induced aggregation. In contrast, 8-epi-PGF2 alpha significantly potentiated reversible platelet aggregation in response to low-dose ADP. These results indicate that 8-epi-PGF2 alpha has partial agonist activity. 9 alpha,11 beta-PGF2, a structural isomer of 8-epi-PGF2 alpha, inhibited platelet aggregation induced by collagen, high- and low-dose ADP and thrombin, demonstrating marked differences between structural isomers where 9 alpha,11 beta-PGF2 inhibited platelet aggregation induced by TX-dependent as well as TX-independent stimuli. In addition to platelet aggregation, we performed competition-binding assays on washed human platelets using [125I]BOP to further investigate the interaction of 8-epi-PGF2 alpha and 9 alpha,11 beta-PGF2 with TXA2/PGH2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Yin
K
K
Department of Physiology, New York Medical College, Valhalla.
Halushka
P V
PV
Yan
Y T
YT
Wong
P Y
PY
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000328:Adult; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology*; D011463:Prostaglandins H / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost