Reduction by arachidonic acid of prostaglandin I2-induced cyclic AMP formation. Involvement of prostaglandins E2 and F2 alpha.
Arachidonic acid reverses the increase in cyclic AMP levels of washed human platelets exposed to prostaglandin (PG)I2, under conditions where the PGH2 analogue U46619 is ineffective. This effect of arachidonic acid was inhibited by aspirin, a cyclooxygenase inhibitor, but not by the thromboxane (Tx) synthase inhibitor Ridogrel, which induces, by inhibiting the conversion of PGH2 into TxA2, an overproduction of PGE2, PGD2 and PGF2 alpha. Addition of PGE2 or PGF2 alpha, which share a receptor with PGI2, to washed human platelets also induced a decrease in cyclic AMP levels, but PGD2, which interacts with a different receptor, had no effect. Thus neither PGD2, PGG2, PGH2, TxA2 nor TxB2 formed from arachidonic acid via the cyclooxygenase pathway is involved in the decrease in cyclic AMP levels. These findings were confirmed using forskolin, a diterpene from the labdane family, which enhanced the formation of cyclic AMP synergistically with the PGs. Also, arachidonic acid, unlike U46619, is able to reverse the inhibition of platelet aggregation by PGI2 after a lag phase of about 4 min. Our data indicate that arachidonic acid decreased cyclic AMP levels through its cyclooxygenase metabolites PGE2 and PGF2 alpha probably interacting competitively with the receptor of PGI2. In addition, intracellular cyclic AMP levels and the degree of aggregation of platelets by arachidonic acid seem to be inversely correlated.
Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur/INSERM U285, Paris, France.
A
A
Faili
J
J
Randon
B B
BB
Vargaftig
M
M
Hatmi
D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D004347:Drug Interactions; D011464:Epoprostenol / Q000037:antagonists & inhibitors*; D006801:Humans; D010421:Pentanoic Acids / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
D010421:Pentanoic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D005576:Colforsin; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015237:Dinoprost; D011464:Epoprostenol; D000242:Cyclic AMP; D015232:Dinoprostone; C060219:ridogrel; D001241:Aspirin; D015230:Prostaglandin D2