Cyclic GMP analogs inhibit gamma thrombin-induced arachidonic acid release in human platelets.
Elevation in intracellular cyclic GMP levels is the proposed proximal mechanism for the vasodilatory and platelet inhibitory action of nitrovasodilators and of nitric oxide, the putative endothelium-derived relaxing factor. In this study, the stable cyclic GMP analogs, 8-bromo-cGMP and N2, 2'-O-dibutyryl-cGMP were found to inhibit the release of [3H]-arachidonic acid from gamma thrombin-stimulated human platelets in a time- and dose-dependent manner. Inhibition of the formation of arachidonic acid metabolites, 12-HETE and thromboxane B2, paralleled that of arachidonic acid release and was accompanied by a dose-dependent inhibition of platelet aggregation. The formation of phosphatidic acid, a metabolite of phospholipase C, however, was relatively preserved. At a concentration of 8-bromo-cGMP (2 mM) that produced near-total inhibition of arachidonic acid release, phosphatidic acid formation remained at 60% of control levels. Thus, cGMP analogs have a preferential inhibitory effect on the release and subsequent metabolism of arachidonic acid. The phospholipase A2/arachidonic acid pathway appears to be an important target for the physiologic action of cGMP, and EDRF, and for the pharmacologic action of nitrovasodilators.
Sane
D C
DC
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Bielawska
A
A
Greenberg
C S
CS
Hannun
Y A
YA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009569:Nitric Oxide / Q000494:pharmacology; D010974:Platelet Aggregation; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013917:Thrombin / Q000502:physiology*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D001095:Arachidonic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D016718:Arachidonic Acid; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D003995:Dibutyryl Cyclic GMP; D013929:Thromboxane B2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D006152:Cyclic GMP