Anti-Platelet Action of Nitric Oxide and Selective Phosphodiesterase Inhibitors

Sly, M. K.; Eberhart, Robert C.; Prager, Morton D.

doi:10.1097/00024382-199708000-00009

Cited by 20 publications

(11 citation statements)

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“…ONO-1505 was also shown to augment established anti-aggregatory effects of sodium nitroprusside in rat platelets, converting a submaximum effect of the NO donor to effective abolition of ADP-induced aggregation. It is noteworthy that ONO-1505 was unable to confer anti-aggregatory activity on a subthreshold concentration of NO donor, suggesting that a functionally relevant elevation of platelet cyclic GMP was obligatory (Sly et al 1997). Because ONO-1505 did not affect ADP-induced aggregation per se, but only modulated the anti-aggregatory activity of exogenous NO, it is unlikely that inhibition of de-novo thromboxane synthesis in platelets played any functional role in these effects.…”

Section: Discussionmentioning

confidence: 98%

Modulation of Nitric Oxide-dependent Vascular and Platelet Function In-vitro by the Novel Phosphodiesterase Type-V Inhibitor, ONO-1505

Laight

Änggård

Carrier

1999

Journal of Pharmacy and Pharmacology

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We have characterized the in-vitro modulation of both nitric oxide (NO)-dependent vasodilator activity and anti-platelet function by the novel type-V phosphodiesterase inhibitor, ONO-1505 (4-[2-(2-hydroxyethoxy)ethylamino]-2-(1H-imidazol-1-yl)-6-methoxyquin azoline methanesulphonate). ONO-1505 elicited vasorelaxation in the rat isolated aorta. If the concentration of ONO-1505 was < or = 10 microM the vasorelaxation was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME), by methylene blue, and by endothelial denudation. Furthermore, pretreatment of the rat isolated aorta for 10 min with ONO-1505 in the presence of L-NAME potentiated vasorelaxation to the NO-donor, sodium nitroprusside. Similarly, ONO-1505, although having no effect on adenosine diphosphate (ADP)-induced rat platelet aggregation in-vitro, augmented established anti-aggregatory effects of sodium nitroprusside. The data therefore show that the novel phosphodiesterase V inhibitor ONO-1505 augments endogenous and exogenous nitrovasodilator activity in-vitro; they also imply modulation of the NO pathway in the haemodynamic actions of this compound, previously reported in-vivo.

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Section: Discussionmentioning

confidence: 98%

Modulation of Nitric Oxide-dependent Vascular and Platelet Function In-vitro by the Novel Phosphodiesterase Type-V Inhibitor, ONO-1505

Laight

Änggård

Carrier

1999

Journal of Pharmacy and Pharmacology

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“…PDE-5 is the major PDE that degrades cGMP, and PKG-I␣ can phosphorylate PDE-5 both in vivo and in vitro, activating it (23,27). Although the physiological function for the phosphorylation and activation of PDE-5 has not been analyzed in endothelial cells, a similar mechanism has been described for platelets on NO sensitization (30). Activation of PDE-5 may then provide a negative feedback regulation of cGMP and PKG-I␣, because PDE-5 activation by PKG can also control the ability of PKG to phosphorylate other substrates when the intracellular concentration of cGMP reaches a high level, such as after CNP stimulation.…”

Section: Discussionmentioning

confidence: 99%

Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: a mechanism dependent on PKG-Iα activation by NO/cGMP

Rivero-Vilches

Frutos²,

Saura³

et al. 2003

American Journal of Physiology-Cell Physiology

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cGMP is generated in endothelial cells after stimulation of soluble guanylyl cyclase (sGC) by nitric oxide (NO) or of particulate guanylyl cyclase (pGC) by natriuretic peptides (NP). We examined whether localized increases in cytosolic cGMP have distinct regulatory roles on the contraction induced by H2O2 treatment in human umbilical vein endothelial cells. cGMP concentrations and temporal dynamics were different upon NO stimulation of sGC or C-type NP (CNP) activation of pGC and did not correlate with their relaxing effects measured as planar cell surface area after H2O2 challenge. cGMP production due to sGC stimulation was always smaller and more brief than that induced by pGC stimulation with CNP, which was greater and remained elevated longer. The NO effects on cell relaxation were cGMP dependent because they were blocked by sGC inhibition with 1H-(1,2,4)Oxadiazolo(4,3-a)quinoxaline-1-one and mimicked by 8-Br-cGMP. An antagonist of the cGMP-dependent protein kinase type-I (PKG-I) also inhibited the NO-induced effects. The cell contraction induced by H2O2 produces myosin light chain (MLC) phosphorylation and NO prevented it completely, whereas CNP only produced a partial inhibition. Transfection with a dominant negative form of PKG type-I alpha completely reversed the NO-induced effects on MLC phosphorylation, whereas it only partially inhibited the effects due to CNP. Taken together, these results demonstrate that the NO/sGC/cGMP pathway induces endothelial cell relaxation in a more efficient manner than does CNP/pGC/cGMP pathway, an effect that might be related to a selective stimulation of PKG-1 alpha by NO-derived cGMP. Consequently, stimulated PKG-I alpha may phosphorylate important protein targets that are necessary to inhibit the endothelial contractile machinery activated by oxidative stress.

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“…Because the vasodilatatory effect of amrinone has been documented both experimentally and clinically we propose that it probably prevents the I/R injury both by inhibiting the SOR production and by eliminating the residual vasospasm encountered after ischaemia 22,23,33 . The antithrombotic and erythrocyte deformability inhibitory role of amrinone has also been documented, which should also modulate the microcirculation and inhibit the neutrophil aggregation, one of the great sources of SOR 34 . The agent has inhibited human platelet calcium mobilization and adhesion molecule (P‐selectin) expression and has protected against experimental coronary thrombosis in vivo in dogs 35 .…”

Section: Discussionmentioning

confidence: 97%

Effect of amrinone on mucosal permeability in experimental intestinal ischaemia/reperfusion injury

Ekíngen

Sönmez

Onur

et al. 2005

ANZ Journal of Surgery

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Anti-Platelet Action of Nitric Oxide and Selective Phosphodiesterase Inhibitors

Cited by 20 publications

References 0 publications

Modulation of Nitric Oxide-dependent Vascular and Platelet Function In-vitro by the Novel Phosphodiesterase Type-V Inhibitor, ONO-1505

Modulation of Nitric Oxide-dependent Vascular and Platelet Function In-vitro by the Novel Phosphodiesterase Type-V Inhibitor, ONO-1505

Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: a mechanism dependent on PKG-Iα activation by NO/cGMP

Effect of amrinone on mucosal permeability in experimental intestinal ischaemia/reperfusion injury

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