Dipyridamole Potentiates Platelet Inhibition by Nitric Oxide

Bult, Hidde; Fret, Hermine R.L.; Jordaens, F H; Herman, Arnold G.

doi:10.1055/s-0038-1646418

Cited by 39 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings are in accord with previous studies reporting that dipyridamole enhances NO-induced inhibition of platelet aggregation. 29,[42][43][44] Finally, our in vitro data could be confirmed by in vivo/ex vivo studies with healthy volunteers treated with extendedrelease dipyridamole (Persantin Retard). This treatment caused a clear, statistically significant 2-fold enhancement of SNP-induced VASP phosphorylation measured in platelets ex vivo compared with platelets obtained before drug intake ( Figure 5).…”

Section: Aktas Et Al Dipyridamole and Platelet Inhibitionsupporting

confidence: 54%

Dipyridamole Enhances NO/cGMP-Mediated Vasodilator-Stimulated Phosphoprotein Phosphorylation and Signaling in Human Platelets

Aktas

Utz

Hoenig-Liedl

et al. 2003

Stroke

109

View full text Add to dashboard Cite

Background and Purpose-Dipyridamole and in particular dipyridamole in combination with low-dose aspirin are very effective in preventing recurrent stroke. However, the mechanism(s) underlying this dipyridamole effect have not been elucidated. Since dipyridamole inhibits the cGMP-specific phosphodiesterase type V in vitro, we hypothesized and tested whether therapeutically relevant dipyridamole concentrations enhance NO/cGMP-mediated effects in intact human platelets studied ex vivo. Methods-Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), an established marker of NO/cGMP effects in human platelets, was quantified by phosphorylation-specific antibodies and Western blots. Serotonin secretion and thromboxane synthase activity were determined by fluorometric quantification of derivatized serotonin and synthase products, respectively. Results-Endothelium-derived factors such as NO and prostaglandin I 2 are known to elevate both cGMP and cAMP levels with concomitant platelet inhibition and VASP phosphorylation. In our in vitro experiments, therapeutically relevant concentrations (3.5 mol/L) of dipyridamole amplified only cGMP-mediated VASP phosphorylation due to the NO donor sodium nitroprusside, but not cAMP-mediated effects. Furthermore, thromboxane synthase activity and serotonin secretion, events important for initial platelet activation, were inhibited by sodium nitroprusside, an effect also enhanced by dipyridamole, demonstrating the functional relevance of these observations. Finally, the ex vivo enhancement of NO/cGMP effects was also observed with platelets obtained from healthy volunteers treated with extended-release dipyridamole. Key Words: dipyridamole Ⅲ phosphodiesterase inhibitors Ⅲ platelet aggregation inhibitors Ⅲ stroke T he role of activated platelets in acute and chronic vascular diseases is well established. Accordingly, antiplatelet drugs significantly reduce the risk of severe events, such as ischemic stroke, myocardial infarction, and vascular death in atherosclerotic vascular disease. In numerous clinical studies, the efficacy of antiplatelet drugs in the treatment and secondary prevention of vascular diseases, particularly stroke, has been proven. [1][2][3] Platelet activation is inhibited by factors released from endothelial cells that constitute the inner cell layer of the vessel wall. The most important inhibitory endotheliumderived factors are NO and prostaglandin I 2 (PGI 2 ), which inhibit platelets by increasing the level of intracellular cyclic nucleotides. 4,5 Subsequent stimulation of cGMP-and cAMPdependent protein kinases leads to the phosphorylation of a variety of proteins. 6 In platelets, this inhibits agoniststimulated calcium signaling, 7,8 fibrinogen binding, 9 adhesion, 10 and aggregation 5 and stimulates phosphorylation of the cytoskeletal and focal adhesion protein vasodilatorstimulated phosphoprotein (VASP). 4,5,11 This phosphorylation correlates strongly with the inhibition of platelets. 9,11 Interestingly, antiplatelet treatment with clopidogrel or ticlo...

show abstract

Section: Aktas Et Al Dipyridamole and Platelet Inhibitionsupporting

confidence: 54%

Dipyridamole Enhances NO/cGMP-Mediated Vasodilator-Stimulated Phosphoprotein Phosphorylation and Signaling in Human Platelets

Aktas

Utz

Hoenig-Liedl

et al. 2003

Stroke

109

View full text Add to dashboard Cite

show abstract

“…Nonetheless, other selective cGMP PDE inhibitors such as MY-5445 have been shown to inhibit platelet aggregation induced by ADP and arachidonic acid in addition to collagen in human platelet-rich plasma (Hidaka and Endo 1984). Similarly, dipyridamole in combination with a subthreshold concentration of NO suppressed ADP-and U-46,619-induced platelet aggregation using human whole blood (Bult et al 1991). Echistatin was previously shown to attenuate platelet aggregation induced by ADP, U-46,619 or collagen using dog (ex vivo) or human (in vitro) platelets (Dennis et al 1989;Shebuski et al 1990).…”

Section: Discussionmentioning

confidence: 99%

“…The disparity between in vitro and in vivo antiplatelet activity of E4021 is likely attributed to partial dependency on endothelium-derived relaxing factor (EDRF), which is unlikely present in platelet suspension or whole blood removed from the circulatory system. In vivo EDRF inhibits platelet activation through an increase in platelet cGMP by stimulating soluble guanylate cyclase (Busse et al 1987;Moncada et al 1991;Guthmann et al 1992), an action that can be further augmented by selective inhibition of cGMP degradation with E4021 (Bult et al 1991). In fact, E4021 was shown to be more active in relaxing intact than denuded porcine coronary artery preparations (Saeki et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of platelet adhesion and aggregation by E4021, a type V phosphodiesterase inhibitor, in guinea pigs

Chiu¹,

Vemulapalli²,

Chintala³

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

E4021 (sodium 1-[6-chloro-4-(3, 4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-4-ca rboxylate sesquihydrate) is a highly selective and potent inhibitor of type V phosphodiesterase(PDE5). The in vitro and in vivo effect of E4021 on platelet function was evaluated, using echistatin, a potent disintegrin, as a positive reference agent. E4021 inhibits aggregatory response to collagen in washed human platelets (IC50 = 5 microM, vs. 0.14 microM with echistatin). In the ex vivo-platelet aggregation assay using whole blood from treated guinea pigs, E4021 (9 mg/kg i.v.) showed a moderate inhibition (43%) against collagen (0.125 microg/ml), whereas echistatin (250 microg/kg i.v.) exerted a 88% inhibition. The absence of endothelium-derived factors (NO) may account for the moderate in vitro and ex vivo antiplatelet activity of E4021. In an in vivo model of reversible platelet aggregation elicited by collagen (100 microg/kg i.v.), both E4021 and echistatin attenuated the intrapulmonary platelet accumulation in guinea pigs (-36% and -44%, respectively). In addition, E4021 (9 mg/kg i.v.) and echistatin (250 microg/kg i.v.) caused a similar inhibition of platelet adhesion at sites of microfilament-induced vascular injury in guinea pigs (52% and 65%, respectively). The two agents in combination did not show additive effect, suggesting that E4021 inhibits platelet activation and impairs interactions of adhesion receptors with matrix proteins. E4021 caused a selective increase in cGMP concentrations in the platelets isolated from treated guinea pigs: cAMP was not affected. It is concluded that the antiplatelet activity of E4021 is mediated through cGMP mechanism by virtue of selective inhibition of PDE5 in the platelets.

show abstract

“…Another elegant study shows that intracoronary dipyridamole reduces the incidence of adverse cardiovascular events in the first 48 hours after balloon angioplasty of small coronary arteries [19•]. • Dipyridamole clearly enhances the vasodilatation caused by nitric oxide, reducing the threshold for platelet suppression [20]. Clinical benefits of dipyridamole may be attributed not only to platelet inhibition, but also to leukocyte blockade.…”

Section: Treatmentmentioning

confidence: 98%

The action of dipyridamole to prevent thrombosis: Practical implications for the treatment and prevention of stroke

Booze¹,

Serebruany²

2006

Curr Treat Options Cardio Med

View full text Add to dashboard Cite

Aggrenox (Boehringer Ingelheim, Ingelheim, Germany), a novel combination of low-dose aspirin with dipyridamole, represents a safe and promising combination alternative for mild but sustained platelet inhibition, and reduction of both arterial and venous thrombi occurrences. In a large, well-controlled randomized trial (ESPS-2 ) evaluating antiplatelet agents for stroke prevention, Aggrenox was twice as effective as monotherapy with either aspirin or dipyridamole. There is an increasing body of evidence that a delicate strategy with Aggrenox provides modest inhibition of platelet activity, especially in a chronic, long-term setting. Mild platelet inhibition beyond conventional aggregation may represent a substantial advantage over aggressive antiplatelet regimens for the treatment, and especially for secondary prevention, of cerebrovascular ischemic events. Although there is no doubt that the concept of inhibiting platelets is vital for the treatment of vascular ischemic disease in general and ischemic stroke and transient ischemic attack (TIA) in particular, the optimal degree of such inhibition still remains an unsolved mystery. It seems that the concepts of "the more, the better" and "one size fits all" may no longer be valid for ideal antiplatelet protection in such high-risk populations. Without routine individual laboratory assessment of platelet function, mild regimens have the advantage of being more suitable for the majority of patients and will contribute substantially to the success of dipyridamole. Conversely, if we can determine baseline platelet status and intelligently apply therapy based on platelet activity in each particular patient, clinical outcomes may be better. Avoiding excessive bleeding risks after aggressive strategies in patients with normal or already decreased platelet function, but targeting those who exhibit activated platelets, may improve risk stratification and save lives. Therefore, Aggrenox should be considered a drug of choice to prevent the second stroke. Eliminating, or at least minimizing, the most frequent side effect, namely transitory headaches at the beginning of therapy with Aggrenox, will benefit patients and increase the use of this agent. Should the PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) trial show an advantage in event reduction with Aggrenox over clopidogrel, the increase will be especially dramatic. In short, based on current evidence most guidelines include Aggrenox as a first-line option for secondary prevention of ischemic stroke or TIA, and some recent versions suggest it may be preferable in other clinical scenarios.

show abstract

Dipyridamole Potentiates Platelet Inhibition by Nitric Oxide

Cited by 39 publications

References 31 publications

Dipyridamole Enhances NO/cGMP-Mediated Vasodilator-Stimulated Phosphoprotein Phosphorylation and Signaling in Human Platelets

Dipyridamole Enhances NO/cGMP-Mediated Vasodilator-Stimulated Phosphoprotein Phosphorylation and Signaling in Human Platelets

Inhibition of platelet adhesion and aggregation by E4021, a type V phosphodiesterase inhibitor, in guinea pigs

The action of dipyridamole to prevent thrombosis: Practical implications for the treatment and prevention of stroke

Contact Info

Product

Resources

About