Translational Therapeutics of Dipyridamole

Abstract

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)

Enhanced ex vivo inhibition of platelet function following addition of dipyridamole to aspirin after transient ischaemic attack or ischaemic stroke: First results from the TRinity AntiPlatelet responsiveness (TrAP) study

“…Given the modest effectiveness of available antiplatelet regimens for secondary prevention of vascular events following TIA or ischaemic stroke, it is not surprising that a large proportion of patients might be deemed 'dipyridamole nonresponsive' on an ex vivo test of platelet function in whole blood. However, we accept that the C-ADP assay does not assess all of the potential inhibitory mechanisms of action of dipyridamole on platelet activation and function (McCabe et al, 2004b;Kim & Liao, 2008), and that ex vivo dipyridamole non-responsiveness on the PFA-100 may not reflect dipyridamole non-responsiveness in vivo. The antiplatelet effects of dipyridamole may be mediated via several different cellular …”

Rescue Therapy with Nifurtimox and Dipyridamole for Severe Acute Chagas Myocarditis with Congestive Heart Failure in NMRI Albino Mice

“…23 The molecular structure of dipyridamole allows it to accept electrons, thus functioning as a free radical scavenger, with a greater capacity than α-tocopherol and ascorbic acid, suggesting that dipyridamole beneficial effect observed in the present study is associated with its antioxidant capacity. 7 In this study, the early mortality observed in all experimental groups can be explained by cardiac functional impairment caused by AChM, which was aggravated by subjecting the mice to general anesthesia. In vigil state, mice usually have a heart rate of around 580 bpm, while under anesthesia with pentobarbital-ketamine, as reported in the present study, it ranges between 373 and 382 bpm.…”

“…According with the microvascular theory, dipyridamole could be seen as the adjunctive drug, because it induces coronary vasodilation through nitric oxide (NO), improving blood flow; it has antiplatelet effect preventing thrombi formation; it increases extracellular levels of adenosine, improving cardiac function in patients with HF; it promotes an anti-inflammatory effect suppressing free radical formation and it improves the redox state of cells undergoing inflammatory phenomena 7,8 .…”

Combination Antithrombotic Therapies

“…Dipyridamole also stimulates endothelial cell prostacyclin and nitric oxide synthesis and increases platelet cGMP (an inhibitor of platelet aggregation) and nitric oxide levels. 107 It has been reported that aspirin plus extended-release dipyridamole treatment was associated with more rapid and consistent inhibition of platelet aggregation in whole blood compared with either agent alone. 108 In the European Stroke Prevention Study-2 (ESPS-2), aspirin (25 mg BID), extended-release dipyridamole (200 mg BID), aspirin plus extended-release dipyridamole, and placebo were compared in a randomized, double-blind fashion in 6602 patients who had suffered a stroke or TIA within the preceding 3 months.…”