title: Cyclic GMP analogs inhibit gamma thrombin-induced arachidonic acid release in human platelets.
abstract: 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: D C
authors.initials: DC
authors.lastname: Sane
authors.forename: A
authors.initials: A
authors.lastname: Bielawska
authors.forename: C S
authors.initials: CS
authors.lastname: Greenberg
authors.forename: Y A
authors.initials: YA
authors.lastname: Hannun
mesh_terms: 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
chemical_list: 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