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.

A domain responsible for HIF-1α degradation by YC-1, a novel anticancer agent

“…24). It increases the catalytic rate of soluble guanylyl cyclase and enhances the enzyme response to nitric oxide or carbon monoxide (25). In terms of its pharmacological action, YC-1 prevents thrombus formation by inhibiting platelet aggregation (26), reduces the blood pressure by relaxing vascular smooth muscle (27), and helps penile erection by relaxing corpus cavernosal smooth muscle (28).…”

“…Its N-terminal half contains the basic domain (aa. [17][18][19][20][21][22][23][24][25][26][27][28][29][30], a helix-loop-helix domain (aa. , and a PAS domain (aa.…”

Effect of Carbon Monoxide on Dopamine and Glutamate Uptake and cGMP Levels in Rat Brain

“…Furthermore, while the effect of CO on cGMP induction is reported in the cerebellum, no significant elevation in cGMP formation was observed in cortical regions (Laitinen et al, 1997). Although the activation of isolated sGC with CO is much weaker than with NO, CO can be a powerful activator in stimulating cGMP in the presence of an indazole; Friebe et al (1998) have shown a 100-fold increase in the affinity of Figure 5 Effects of CO treatment on total nitrate and nitrite levels after in vivo NOS inhibition (different from control, *po0.05 for c.striatum and **po0.001 for hippocampus).…”

Endothelium-Dependent Vasoconstriction in Isolated Vessel Grafts: A Novel Mechanism of Vasospasm?

“…YC-1 has a variety of molecular targets other than sGC [12][13][14][15][16]. Nevertheless, it was prudent to determine whether sGC is involved in YC-1's vasoconstrictor action.…”