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Vol. 54, Issue 6, 962-967, December 1998
Institut für Pharmakologie, Freie Universität Berlin,
D-14195 Berlin, Germany (A.F., F.M., G.S., D.K.), and
Medizinische Universitätsklinik, Institut für Klinische
Biochemie und Pathobiochemie, Universität Würzburg,
D-97080 Würzburg, Germany (A.S., U.W.)
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 µM) and YC-1 (100 µM) 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.
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