title: YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets.
abstract: Nitric oxide (NO), the physiological activator of soluble guanylyl cyclase (sGC), induces inhibitory effects on platelet activation via elevation of cGMP levels and stimulation of the cGMP-dependent protein kinase. YC-1, a benzylindazole derivative, was shown to activate sGC in intact platelets, resulting in inhibition of platelet aggregation. In a previous study, we demonstrated that YC-1 not only stimulates purified sGC but also potentiates the stimulatory action of submaximally effective NO and carbon monoxide (CO) concentrations. Here, we investigated the potentiating effect of YC-1 in intact platelets. YC-1 together with NO or CO led to complete inhibition of platelet aggregation at concentrations that were ineffective by themselves. Maximally effective 2, 2-diethyl-1-nitroso-oxyhydrazine (3 microM) and YC-1 (100 microM) concentrations each elevated the cGMP levels in intact platelets approximately 13-fold, and administration of the two drugs together resulted in enormous potentiation of cGMP formation, which greatly exceeded the effect on the purified enzyme and yielded a >1300-fold increase in cGMP levels. Similar results were obtained using CO instead of NO. Furthermore, YC-1 not only stimulated sGC but also inhibited cGMP-hydrolyzing phosphodiesterases in platelets. The enormous elevation of cGMP levels led to enhanced phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein. Thus, by the combination of two effects (i.e., potentiation of NO-induced sGC stimulation and phosphodiesterase inhibition), YC-1-like substances are potent activators of the sGC/cGMP pathways and are therefore interesting candidates to act as modulators of cGMP-mediated effects, especially within the cardiovascular system.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, D-14195 Berlin, Germany. friebe@zedat.fu-berlin.de
authors.forename: A
authors.initials: A
authors.lastname: Friebe
authors.forename: F
authors.initials: F
authors.lastname: Müllershausen
authors.forename: A
authors.initials: A
authors.lastname: Smolenski
authors.forename: U
authors.initials: U
authors.lastname: Walter
authors.forename: G
authors.initials: G
authors.lastname: Schultz
authors.forename: D
authors.initials: D
authors.lastname: Koesling
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002248:Carbon Monoxide / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis*; D004357:Drug Synergism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D007191:Indazoles; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D002248:Carbon Monoxide; D000242:Cyclic AMP; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine