What is the mechanism by which dipyridamole prevents adenosine reuptake?

From the Guidelines

Dipyridamole prevents adenosine reuptake by inhibiting the nucleoside transport proteins located on cell membranes, particularly erythrocytes and vascular endothelial cells, as suggested by the mechanism of action described in the American College of Chest Physicians evidence-based clinical practice guidelines 1. The mechanism of action of dipyridamole involves the blockade of the uptake of adenosine, which binds to A2 receptors, stimulates platelet adenyl cyclase, and increases cyclic AMP, an inhibitor of platelet aggregation.

• The blockade of adenosine uptake leads to increased extracellular adenosine concentrations.
• This elevated adenosine then binds to adenosine receptors on vascular smooth muscle cells and platelets, causing vasodilation and inhibition of platelet aggregation.
• The increased adenosine inhibits platelet activation and aggregation through stimulation of platelet adenosine A2 receptors and subsequent increase in cyclic AMP, as described in the guidelines for the prevention of stroke in patients with stroke or transient ischemic attack 1. The therapeutic effects of dipyridamole as an antiplatelet agent are particularly important in cardiac stress testing, where dipyridamole-induced adenosine accumulation causes coronary vasodilation, increasing blood flow to healthy coronary arteries while revealing perfusion defects in stenotic vessels.
• The combination of dipyridamole and aspirin has been evaluated in several large randomized clinical trials, including the European Stroke Prevention Study (ESPS-1) and ESPS-2, which demonstrated the efficacy of the combination in reducing the risk of stroke and death 1.
• However, the most recent and highest quality study, the American Heart Association/American Stroke Association guidelines, recommends the use of dipyridamole and aspirin for secondary stroke prevention, with consideration of individual patient characteristics, side effects, and comorbid illnesses 1.

From the FDA Drug Label

Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5-1. 9 mg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP).

Dipyridamole prevents adenosine reuptake by inhibiting the uptake of adenosine into platelets, endothelial cells, and erythrocytes. The mechanism of this inhibition is dose-dependent and occurs at therapeutic concentrations. This leads to an increase in local adenosine concentrations, which in turn stimulates platelet adenylate cyclase and increases cAMP levels, ultimately inhibiting platelet aggregation 2.

From the Research

Mechanism of Dipyridamole in Preventing Adenosine Reuptake

• Dipyridamole acts by inhibiting nucleoside transport, which increases adenosine levels leading to inhibition of platelet aggregation and vasodilatation mainly in the coronary tree 3.
• The mechanism of action of dipyridamole involves the inhibition of adenosine reuptake by red blood cells, resulting in increased extracellular levels of adenosine 4, 5.
• Adenosine deaminase, an enzyme breaking down adenosine, reverses the inhibitory action of dipyridamole, suggesting that adenosine plays a key role in the mechanism of action of dipyridamole 4.
• The inhibitory effect of dipyridamole on platelet aggregation can be obtained by combining a pure adenosine uptake inhibitor with a pure phosphodiesterase inhibitor, further supporting the role of adenosine in the mechanism of action of dipyridamole 4.

Role of Adenosine in the Mechanism of Action of Dipyridamole

• Adenosine-induced vasodilation is potentiated by dipyridamole, and the magnitude of this effect correlates with plasma dipyridamole concentrations 6.
• The effects of dipyridamole on resistance vessels are preferentially explained by potentiation of adenosine mechanisms rather than potentiation of nitric oxide or other cGMP-mediated actions 6.
• Dipyridamole inhibits adenosine uptake by erythrocytes and other cells, resulting in increased extracellular levels of adenosine, which inhibits platelet aggregation via the A2A receptor 7.

Comparison with Other Drugs

• Ticagrelor, a P2Y12 antagonist, also inhibits adenosine uptake by erythrocytes and other cells, resulting in increased extracellular levels of adenosine, which contributes to its antiplatelet effects 7.
• The adenosine contribution to drug-induced inhibition of platelet aggregation is similar for dipyridamole and ticagrelor, but is significantly greater for ticagrelor than for PAM (the active metabolite of prasugrel) 7.