Mechanism of the Antiplatelet Action of Dipyridamole in Whole Blood: Modulation of Adenosine Concentration and Activity

Gresele, Paolo; Arnout, Jozef; Deckmyn, Hans; Vermylen, Jozef

doi:10.1055/s-0038-1661437

Cited by 119 publications

(52 citation statements)

References 19 publications

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“…Dipyridamole has been shown to inhibit platelet aggregation by preventing the re-uptake of adenosine (Gresele et al, 1986). Adenosine could also exert vascular effects such as vasodilation and this may also lead to neuroprotection (Gamboa et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Kim

Sawada

Soydan

et al. 2008

J Cereb Blood Flow Metab

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Recent studies suggest that dipyridamole (DP) may exert stroke protective effects beyond platelet inhibition. The purpose of this study is to determine whether statin and DP could enhance stroke protection through nitric oxide (NO)-dependent vascular effects. Mice were pretreated with DP (10 to 60 mg/kg, q 12 h, 3 days) alone or in combination with a statin (simvastatin; 0.1 to 20 mg/kg per day, 14 days) before transient intraluminal middle cerebral artery occlusion. Although simvastatin (1 mg/kg per day, 14 days) increased endothelial NO synthase (eNOS) activity by 25% and DP (30 mg/kg, q12 h, 3 days) increased aortic cGMP levels by 55%, neither statin nor DP alone, at these subtherapeutic doses, increased absolute cerebral blood flow (CBF) or conferred stroke protection. However, the combination of subtherapeutic doses of simvastatin and DP increased CBF by 50%, decreased stroke volume by 54%, and improved neurologic motor deficits, all of which were absent in eNOS-deficient mice. In contrast, treatment with aspirin (10 mg/kg per day, 3 days) did not augment the neuroprotective effects of DP and/or simvastatin. These findings indicate that statin and DP exert additive NO-dependent vascular effects and suggest that the combination of statin and DP has greater benefits in stroke protection than statin alone through vascular protection.

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Section: Discussionmentioning

confidence: 99%

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Kim

Sawada

Soydan

et al. 2008

J Cereb Blood Flow Metab

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“…12,13 Indeed, DP has been shown to inhibit platelet aggregation in whole blood in vitro and potentiate the antiaggregatory effect of adenosine in vitro. 14,15 …”

Section: Adenosine and Platelet Inhibitionmentioning

confidence: 99%

Translational Therapeutics of Dipyridamole

Kim

Liao

2008

ATVB

121

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Abstract-Dipyridamole (DP) is a phosphodiesterase inhibitor that increases the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) by preventing their conversion to AMP and GMP, respectively. By increasing cAMP and cGMP levels in platelets, DP reversibly inhibits platelet aggregation and platelet-mediated thrombotic disease. In addition, DP may potentiate some of the vascular protective effects of endothelium-derived nitric oxide (NO), which increases cGMP by stimulating soluble guanylyl cyclase. Endotheliumderived NO is an important regulator of vascular tone, blood flow, and tissue perfusion. Indeed, endothelial NO synthase-deficient (eNOS Ϫ/Ϫ ) mice exhibit elevated systemic blood pressure and have larger myocardial and cerebral infarct size after ischemic injury. Other NO/cGMP-dependent effects that may be potentiated by DP include inhibition of vascular smooth muscle proliferation and prevention of endothelial-leukocyte interaction. In addition, DP increases local concentrations of adenosine and prostacyclin, which could affect vascular tone and inflammation. Finally, DP has antioxidant properties, which could stabilize platelet and vascular membranes as well as prevent the oxidation of low-density lipoprotein. These platelet and nonplatelet actions of DP may contribute to some of its therapeutic benefits in vascular disease. (Arterioscler Thromb Vasc Biol. 2008;28:s39-s42)

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“…[1][2][3] Several possible mechanisms underlying these recognized clinical benefits have been described in earlier studies. 20 Dipyridamole increases the plasma concentration of the endogenous platelet inhibitor adenosine by inhibition of adenosine uptake into red blood cells 21,22 and attenuation of adenosine catabolism. 23 In addition, it directly stimulates the release of endothelial PGI 2 .…”

mentioning

confidence: 99%

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

Aktas

Utz

Hoenig-Liedl

et al. 2003

Stroke

109

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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...

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Mechanism of the Antiplatelet Action of Dipyridamole in Whole Blood: Modulation of Adenosine Concentration and Activity

Cited by 119 publications

References 19 publications

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Translational Therapeutics of Dipyridamole

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

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